(1999-Gionchetti)Review–Antibiotic treatment in inflammatory bowel disease rifaximin, a new possi

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十年前引起开发竞备的BETi不是纸老虎

十年前引起开发竞备的BETi不是纸老虎进入到临床阶段的候选药物好比骏马，大多都是没遇到它们生命中的伯乐。

然而现实中却是骏马常见而伯乐不常见。

10年BETi坎坷开发史人体里的每个细胞都拥有同一套的基因序列，但基因的转录在不同的细胞类型中是处于开启或关闭状态，这就造成不同细胞发挥出不同的功能。

基因转录的表观遗传调控有部分是受到组蛋白和其他蛋白质上特定赖氨酸残基的乙酰化来介导的。

含有保守折叠结构的溴区结构域（bromodomain）特异性结合乙酰-赖氨酸，从而促进基因转录和下游通路。

已知有46种人类bromodomain蛋白，根据系统发育/结构模型可分为8组，Bromodomain and Extraterminal（BET）则是其中一组，BET由4个家族成员构成（BRD2/BRD3/BRD4/BRDT），每个家族成员包含两个N末端bromodomains（BD1和BD2）和一个C末端额外终端结构域。

2009年田边三菱制药最早报道了BETi（MS417），随后2010年丹娜法伯癌症研究院报道了JQ1，由于BETi在广泛的细胞系和动物模型中具有效果，从现在依旧活跃在临床阶段的BETi统计的临床前数据显示，涉及的癌症包括AML、CML、T-ALL、MM、淋巴瘤、肺癌、食道癌、卵巢癌、GBM、前列腺癌、乳腺癌、头颈癌、成神经细胞瘤和胰腺癌等，检验过的细胞系超过150多种，吸引了大量厂家布局BETi。

2012年首款BETi进入临床，当时采取类似激酶抑制剂的策略，即强效、长半衰期小分子，同时是单药疗法，到2015年有接近20个BETi进入到临床阶段，火极一时。

但早期的临床数据却不尽人意，CYP liabilities、脱靶毒性、接近DLT的剂量（需要暂停给药/间隔给药）和由于表观遗传学导致的有限疗效等。

理想很丰满，现实很骨感。

图1 BETi的10年开发历程（来源：Zenith Epigenetics推介材料）BETi开发热情依旧火热近十年来关于BETi的交易信息几乎没有中断过，但大多数交易额都较低，在1~2亿美元之间徘徊，直到2021年MorphoSys以17亿美元收购Constellation Pharmaceuticals（核心产品为处于3期的BETi和处于2期的EZH2i），似乎宣告着BETi是可以成药且具备一定价值的。

水解酪氨酸能防治糖尿病

Potential mechanisms explaining why hydrolyzed casein-based diets outclass single amino acid-based diets in the prevention of autoimmune diabetes in diabetes-prone BB ratsJ.T.J.Visser 1*N.A.Bos 2L.F.Harthoorn 3F.Stellaard 4S.Beijer-Liefers 1J.Rozing 1E.A.F.van Tol 31Department of Cell Biology,Section Immunology,University of Groningen,University Medical Center Groningen,Groningen,The Netherlands 2Institute of Medical Education,University Medical Center Groningen,University of Groningen,Groningen,The Netherlands 3Mead Johnson Nutrition,Evansville,IN,USA4Department Laboratory Medicine,Laboratory of Liver,Digestive and Metabolic Diseases,University Medical Center Groningen,University of Groningen,Groningen,The Netherlands *Correspondence to:Jeroen Visser,Department of Cell Biology,Section Immunology,University of Groningen,University Medical Center Groningen,A.Deusinglaan 1,9713AV Groningen,The Netherlands.E-mail:j.t.j.visser@med.umcg.nlAbstractBackground It remains controversial whether avoidance of dietary diabetogenic triggers,such as cow ’s milk proteins,can prevent type 1diabetes in genetically susceptible individuals.Here,different extensive casein hydrolysates (HC)and single amino acid (AA)formulations were tested for their effect on mechanisms underlying autoimmune diabetes pathogenesis in diabetes-prone BioBreeding rats.Intestinal integrity,gut microbiota composition and mucosal immune reactivity were studies to assess whether these formulations have differential effects in autoimmune diabetes prevention.Methods Diabetes-prone BioBreeding rats received diets in which the protein fraction was exchanged for the different hydrolysates or AA compositions,starting from weaning until the end of the experiment (d150).Diabetes development was monitored,and faecal and ileal samples were collected.Gut microbiota composition and cytokine/tight junction mRNA expression were measured by quantitative polymerase chain reaction.Cytokine levels of ileum explant cultures were measured by ELISA,and intestinal permeability was measured in vivo by lactulose-mannitol assay.Results Both HC-diet fed groups revealed remarkable reduction of diabetes incidence with the most pronounced effect in Nutramigen W -fed animals.Interestingly,AA-fed rats only showed delayed autoimmune diabetes development.Furthermore,both HC-fed groups had improved intestinal barrier function when compared with control chow or AA-fed animals.Interestingly,higher IL-10levels were measured in ileum tissue explants from Nutramigen W -fed rats.Bene ﬁcial gut microbiota changes (increased Lactobacilli and reduced Bacteroides spp.levels)were found associated especially with HC-diet interventions.Conclusions Casein hydrolysates were found superior to AA-mix in autoimmune diabetes prevention.This suggests the presence of speci ﬁc peptides that bene ﬁcially affect mechanisms that may play a critical role in autoimmune diabetes pathogenesis.Copyright ©2012John Wiley &Sons,Ltd.Keywords autoimmune diabetes;hydrolysed casein;amino acids;intestinal barrier;gut microbiota;mucosal immune systemIntroductionType 1diabetes (T1D)is an autoimmune disease leading to the destruction of the insulin producing b -cells in the islet of Langerhans.Both genetic andR ES E A R C H A RT I C L EReceived:8December 2011Revised:16March 2012Accepted:2April 2012DIABETES/METABOLISM RESEARCH AND REVIEWS Diabetes Metab Res Rev 2012;28:505–513.Published online in Wiley Online Library ()DOI:10.1002/dmrr.2311environmental factors play a causal role in the induc-tion of T1D.It seems well established–in both animal models and clinical studies–that environmental factors such as diet and intestinal microbial antigens play an important role in the onset of T1D[1–3].These diabe-togenic triggers from food sources,including cow’s milk proteins,may induce an immune cascade eventually leading to the autoimmune process typical of T1D[1–3].Two decades ago,it was hypothesized that cow’s milk protein was a potential dietary trigger of T1D[4–6], based on epidemiological data[7],as well as the higher prevalence of antibodies against bovine serum albumin and casein in sera of T1D patients[8].Hence,it has been suggested that cow’s milk protein avoidance may prevent autoimmune diabetes in the diabetes prone(DP) BioBreeding(BB)rat[9].Later epidemiological studies did seem to contradict this hypothesis where a cow’s milk protein containing diet reduced autoimmune diabetes development in the DP-BB rat[10,11].Nevertheless,it remains plausible to hypothesize that avoidance of dietary diabetogenic triggers will modulate diabetes development.Several groups,including our own,have found that casein hydrolysates reduced autoimmune diabetes development in rodent models of T1D[12–16].These observations in animal models led to the instigation of the Trial to Reduce IDDM in the Genetically at Risk[17].The preliminary results of a Trial to Reduce IDDM in the Genetically at Risk pilot study in Finland suggest that casein hydrolysates reduce autoim-mune reactivity against theß-cell in children at risk for T1D development[17].Until now,little is known about the qualitative differ-ences or mechanisms of action of the casein hydrolysates or single amino acids in the prevention of autoimmune diabetes.This is important to know,because it may not be just cow’s milk protein avoidance but also speciﬁc functional peptides in casein hydrolysates that may contribute to the prevention of autoimmune activation in the development of T1D.To study this concept,different casein hydrolysates as well as single amino acid formulations were compared with a whole protein containing lab chow for their efﬁcacy in preventing autoimmune diabetes in the DP-BB rat.For this purpose,different mechanisms that may contribute to the development of autoimmune reactivity,that is,intestinal barrier function,gut microbiota composition and mucosal immune function were studied. MethodsAnimalsDiabetes-prone BioBreeding rats were maintained and bred at the Institutional Central Animal Facility of UMCG as previously described[18].Animal care and handling was in compliance with the principles of laboratory animal care(NIH publication no.85–23;revised1985), and the animal experiments were approved by the local UMCG Ethical Board for Animal Studies.Diets and intervention protocolDietsThe rats received the following diets:(1)A standard control diabetogenic lab chow(Rmh-B2181,AB Diets, Woerden,the Netherlands)with similar macronutrient composition as the experimental basal mix(TD08102, Harlan-Teklad,Madison WI,USA).The basal mix was supplemented with a replacement for the protein fraction by(2)Nutramigen W Hydrolysed Casein(Mead Johnson Nutrition,Zeeland,MI,USA),(3)Pancase™Hydrolysed Casein(Sensient Flavours,Strassbourg,France),and(4) amino acid(AA)mix(Mead Johnson Nutritionals, Emmersville,WI,USA).Intervention protocolThe four groups of DP-BB rats were fed ad libitum the speciﬁc diets from weaning(d21)until the end of the experiment(d150).Faecal samples were collected at 56days of age,65days of age,at diabetes onset or at the end of the experimental period.Intestinal ileal tissue samples were collected at diabetes onset or at the end of the experimental period(d150).Monitoring for diabetes onsetDiabetes-prone BioBreeding rats were monitored for the development of T1D until150days of age.Animals were weighed three times per week.In case of weight loss,blood glucose was measured in tail vein blood using blood glucose test strips(Accu Check Comfort,Roche Diagnostics,The Netherlands).When blood glucose(non-fasting)exceeded 11mmol/L on two consecutive days or once≥15mmol/L, rats were considered diabetic and sacriﬁced.At diabetes onset or at endpoint(if animals did not develop diabetes; 150days of age),rats were sacriﬁced and gut tissue and blood were collected for analysis.The development of T1D in DP-BB rats is characterized by the inﬁltration of lymphocytes and macrophages in the islets of Langerhans(insulitis).These inﬁltrating immune cells destroy the insulin producingß-cells.The degree of insulitis was rated on a scale of1–4as described previously by Visser et al.[19,20].Brieﬂy,1,normal islet appearance and no inﬁltration;2,mild insulitis,where macrophages/mononuclear cells are around and not affecting more than50%of the islet;3,severe insulitis, where macrophages/mononuclear cells completely penetrate and inﬁltrate the islets;4,end-stage islets.Per pancreas section,an average histological insulitis score was calculated by adding up the histological insulitis score of each islet and dividing it by the total number of islets counted.On average,10–20islets were counted per animal.The result is the average score of two analysis performed independently by two persons.506J.T.J.Visser et al.Lactulose-mannitol test for measuring intestinal permeability in vivoThe lactulose-mannitol(LA/MA)test is a non-invasive technique to measure intestinal barrier function in vivo[21]. At65days of age,6–8animals per group were randomly chosen and subjected to a LA/MA test.A LA/MA test as described by Meddings et al.[21]was performed before the onset of diabetes at65days of age.Brieﬂy,a stock solution was made containing4g mannitol and6g lactulose per100mL distilled water.Each rat was given 2mL of the probe.Rats were placed in stainless steel metabolic cages with wire bottoms to separate faeces from urine.Plastic tubes were mounted underneath a spout on the bottom of each cage to collect urine.Rats were denied access to water for 3h,at which point they were allowed free access to water for the remainder of the experiment.Urine was collected for a total of24h,at which point the rats were returned to their normal cages and monitored until150days of age for T1D development.Urine volumes were measured,and the urine composition was analyzed by high performance liquid chromatography(HPLC).HPLC analysisBrieﬂy,cellobiose was added as an internal standard,and the urine wasﬁltered through a0.4-m mﬁlter and diluted as necessary.Samples were deionized and then injected on a Dionex MA-1ion exchange column.Sugars were eluted with NaOH at aﬂow rate of0.4mL/min with a concentration gradient from400to600mM.Peaks were detected using pulsed amperometric detection on a Dionex HPLC and quantiﬁed as peak areas.Calibration was performed on a daily basis with authentic standards at multiple concentrations,and the experimental standards were diluted so that the areas of all peaks fell within the calibration range.Final data were reported as a ratio of fractional excretions(lactulose-mannitol).Fractional excre-tion is deﬁned as the fraction of the gavaged dose recovered in the urine sample.Quantitative PCRFrom the diabetic(between70and150days of age)or nondiabetic rats(150days of age)ileal tissue(Æ1cm) was obtained,frozen in liquid nitrogen and stored at À80 C.RNA was isolated from seven control rats(six diabetic and one nondiabetic),11Pancase S fed rats (eight diabetic and three nondiabetic),12Nutramigen fed rats(six diabetic and six nondiabetic)and12AA-mix fed rats(11diabetic and one nondiabetic).Expression of genes encoding TJ-related proteins,IFN-g and TNF-a could be studied for all animals.Expression of IL-10could be measured for the seven control rats,seven Pancase S fed rats(ﬁve diabetic and two nondiabetic),11Nutramigen fed rats(ﬁve diabetic and six nondiabetic)and ten AA-mix fed rats(nine diabetic and one nondiabetic).Expression of TGF-ßcould be measured for the seven control rats,ten Pancase S fed rats(seven diabetic and three nondiabetic), 11Nutramigen fed rats(ﬁve diabetic and six nondiabetic) and12AA-mix fed rats(11diabetic and one nondiabetic). For RNA isolation,tissue was homogenized in1mL of TRI reagent(Sigma-Aldrich,Zwijndrecht,The Netherlands), and the RNA concentration determined using a nanodrop (ND-1000,Isogen,Maarsen,The Netherlands)at230nm. Isolated RNA of5m g was converted to cDNA using the SuperScript II Reverse Transcriptase kit(Invitrogen Life Technologies,Breda,The Netherlands).In order to measure differences in expression levels of genes encoding for TJ-related proteins(Myo9B,claudin-1,claudin-2, occludin)and cytokines(IL-10,TGF-ß,IFN-g and TNF-a), transcript levels of the subsequent genes and the reference gene hypoxanthine phosphoribosyl-transferase(HPRT) were quantiﬁed using real-time polymerase chain reaction (PCR)as described previously[16].Primer sequences were as follows:Myo9B forward CGCAGTCGTGTGAGCAGTGT and revers ACTCTTCCTC-CGTCCAGTGT;claudin-1forward ATTGGCATGAAGTGCAT-GAG and reverse CCACTAATGTCGCCAGA CCT;claudin-2 forward GCTCCGTGAGTATCTGCTCTG and reverse TCA-CAG TGTCTCTGGCAAGC;occludin forward CCATGTCTGT-GAGGCCTTTT and reverse AAAGAGTATGCCGGCTGAGA; HPRT forward GCGAAAGTGGAAAAGCCAAGT and reverse GCC ACATCAACAGGACTCTTGTAG;IL-10forward AGT-GAAGACCAGCAAAGGC reverse TCATTCATGGCCTTGTA-GACAC;TGF-ßforward GACCGCAACAACGCAATCTA reverse ACCAAGGTA ACGCCAGGAAT.Real-time PCR analysis was performed using iQ SYBR Green Supermix(Bio-Rad Laboratories,Veenendaal,The Netherlands)according to the manufacturer’s instructions on an iCycler iQ Real-Time PCR Detection System(Bio-rad),using the following programme:3min95 C,40 cycles of(30s95 C and30s at60 C,10s at58 C) and then80times an increase in temperature of0.5 C to create a melting curve.Results were expressed as ratio target gene:HPRT according to a mathematical method described by Pfafﬂet al.[22].Snap well assay for measuring IL-10 release by ileum explantsIL-10release by ileum explants was measured in vitro by snap well assay as described by Visser et al.[16].Brieﬂy, a small sample(of a standard length of50mm)was taken from the ileum.In the time(15min)between sacriﬁce and mounting in the snapwells(Corning B.V., Schiphol-rijk,The Netherlands),the samples were kept in incubation medium(IM;DMEM+4.5g glucose, Gibco,Breda,The Netherlands)at4 C.The dissected ileum tissue was cleaned,cut into smaller fragments, rinsed with IM and mounted in snap well inserts,with the mucosal side facing upwards.The insert was then placed in a pre-warmed six wells plate containing2mL of IM in each well.On top of the insert450m L IM was added.After mounting,the inserts in the six wells plate were incubated for8h at37 C.After incubation,theHC-Diets Outclass AA-Diet to Prevent T1D507supernatants of the upper compartments were collected, and IL-10levels were measured by ELISA(Beckton Dickinson).Measuring bacterial DNA in rat faecal samples by qPCRBacterial DNA was isolated of seven control rats(six diabetic and one nondiabetic),12Pancase S fed rats(eight diabetic and four nondiabetic),Nutramigen fed rats(six diabetic and seven nondiabetic)and13AA-mix fed rats (11diabetic and two nondiabetic).Bacterial DNA was isolated and analysed by qPCR as described previously [23].Brieﬂy,DNA from faecal samples was extracted using the PSP Spin Stool Kit(Invitek,Berlin,Germany)according to the manufacturer’s instructions.After isolation,the concentration of DNA was measured with the Nanodrop method as described previously[16].DNA was diluted to 10ng/m L.A qPCR with the SYBR Green detection system (Bio-Rad)was performed on the samples,using group-speciﬁc primers based on bacterial16S ribosomal DNA. To detect all bacteria,the following universal bacte-rial primer set was used:UnivF340-ACTCCTACGGGAGG-CAGCAGT and UniR514-ATTACCGCGGCTGCGGC.The bacteria representative for the Bacteroides spp.group were measured with the primers BactF285-GGTTCTGA-GAGGAAGGTCCC and UnivR338-GCTGCCTCCCGTAG-GAGT;Lactobacillus group LABF-AGCAGTAGGGAATCTTCCA and LABR-CACCGCTACACATGGAG;Eubacterium rectale/ Clostridium coccoides group(Erec)UniF338-ACTCCTACGG-GAGGCAGC and CcocR-GCTTCTTAGTCAGGTACCGT-CAT;Mouse intestinal bacteroides group UniF516-CCAG-CAGCCGCGGTAATA and MIBR-CGCATTCCGCATACTTCTC. Each primer set was evaluated against reference bacterial strains for primer efﬁciency and speciﬁcity.See supple-mentary table1for detailed information about primer sets (design and validation)and reference strains.Each reaction mixture was composed of12.5m L SYBR Green PCR Master Mix(Bio-rad),2m L of primer mix (10pmol/m L each),8.5m L of sterile H2O and2m L of stool DNA(10ng/m L).For the negative control,2m L of sterile H2O was added to the reaction mix.The ampliﬁcation programme consisted of one cycle of95 C for3min (enzyme activation),then40cycles of95 C for10s and 58 C for30s.After the ampliﬁcation programme,the programme was as follows:95 C for1min,58 C for 1min,58 C for10s,then80times an increase in temper-ature of0.5 C to create a melting curve.The qPCR was performed in triplicate,for both standards and samples. Each plate had a standard curve.Internal standard curves were constructed from serial dilutions of reference bacterial strain genomic DNA,in order to translate the qPCR values into number of bacte-ria/g faeces.Brieﬂy,the reference strain was cultured, DNA was extracted,and the amount of DNA was measured using the Nanodrop.The calculations to obtain from the ng/m L outcome of the Nanodrop to the amount of all bacteria per ng DNA were done as follows:Escherichia coli,genome size(i.e.1bacteria)is4.7Â106bp,which is 5.07Â10À15g(1bp=650Dalton and1Dalton=1.66Â10À24g).So1ng DNA isolated from an E.coli culture repre-sents1.97Â105bacteria.The calculations to obtain from the ng/m L outcome of the Nanodrop to the amount of Bacteroides spp.per ng DNA were done as follows:Bacteroides fragilis,genome size (i.e.1bacteria)is5.2Â106bp,which is5.6Â10À15g (1bp=650Dalton and1Dalton=1.66Â10À24g).So 1ng DNA isolated from a B.fragilis culture represents 1.79Â105bacteria.The amount of bacteria per ng sample DNA is then calculated using the standard curve.This calcu-lation was also performed for the other bacteria tested using the speciﬁc genomic size of each bacterium.Because the amount of DNA isolated per gramme faeces is known,the number of bacteria per gramme faeces can be calculated. Statistical analysisStatistical analysis was done by using the software package of Graphpad Prism version4(Graphpad Software,San Diego,CA,USA).Difference in diabetes incidence between the different diets was calculated by the log rank test for Kaplan–Meier survival curves.Differences between the four treatments groups in LA/MA ratio,mRNA expression of ileal tight junction proteins and cytokines,and IL-10production in snapwell cultures was calculated by Kruskal–Wallis test followed by the Mann–Whitney U-test to identify the differ-ences between the groups.Differences in gut microbiota were analysed by paired T-test.Correlations were tested for signiﬁcance using the Spearman correlation method.A p-value<0.05was considered statistically signiﬁcant. ResultsDiabetes incidence and histology of pancreas tissueAll experimental diets delayed the development of autoimmune diabetes,based on clinical manifestations (e.g.weight loss,blood glucose,etc.),in the DP-BB rat as shown in Figure 1.However,only the hydrolysed casein-based diets(Pancase S and Nutramigen W)resulted in both a delay and signiﬁcant reduction of diabetes devel-opment,with the Nutramigen W fed group showed the lowest incidence of diabetes at the age of150days.The development of autoimmune diabetes in the DP-BB rat is characterized by the inﬁltration of lymphocytes and macrophages in the islets of Langerhans(insulitis).As expected,the diabetic rats showed severe insulitis (score above3),and the nondiabetic rats show a low insulitis score(below1.5);no differences were observed between the different treatment groups(data not shown). The insulitis scores in the nondiabetic rats at150days of age are comparable with the insulitis scores of healthy diabetes resistant BB rats[19].508J.T.J.Visser et al.Intestinal barrier functionality established by LA/MA testThe effect of the different diets on the intestinal barrier function in vivo was measured by the LA/MA test.Interestingly,when performing the in vivo intestinal permeability measurement for the combined study groups,the prediabetic urinary LA/MA ratio measured at 65days of age revealed a strong negative correlation with the day of diabetes onset (Figure 2,left image).Hence,early increased intestinal permeability seems to be associated with autoimmune diabetes development later in life.As shown in Figure 2,the hydrolysed casein-based diets signi ﬁcantly reduced the urinary LA/MA ratio re ﬂecting improved intestinal barrier function in vivo ,whereas the AA-mix based diet had no effect on the intestinal barrier function as measured by the LA/MA test.Expression of tight junction mRNA in ileal tissueAt endpoint,as compared with the control diet group,all the experimental diets resulted in an increased ileal mRNA expression of claudin-1(Figure 3).With regard to ileal occludin mRNA expression,Kruskal –Wallis analysis of the four groups together showed no signi ﬁcance (p =0.3).However,separate comparison between the control group and the three different treatment groups by Mann –Whitney U -test showed a difference between the Nutramigen fed group and the control group.It has to be noted that this result might be affected by the two outliers in the Nutramigen fed group.As compared with the control diet group,none of the experimental diets affected ileal Myo9B and claudin-2mRNA expression.Cytokine pro ﬁle of ileum tissueAt endpoint,Kruskal –Wallis analysis showed a trend (p ≤0.1)between dietary intervention and ileal IL-10mRNA expression and production (Figures 4and 5).After performing Mann –Whitney analysis,only the Nutramigen W based diet resulted in a signi ﬁcant increased ileal IL-10mRNA expression as compared with the control diet (Figure 4).Furthermore,a trend (p =0.1)could be observed for increased TGF-ßmRNA expression in ileum tissue of Nutramigen W fed rats.No differences between the various treatment groups could be observed with regard to IFN-g and TNF-a mRNA expression (data not shown).In addition,IL-10protein production of ileal tissue was measured in vitro in the supernatants of snapwell cultures.Again,only DP-BB rats fed the Nutramigen W based diet have a signi ﬁcant increased ileal IL-10protein production (Figure 5),which extended the mRNA data.Gut microbiota analysisFeeding the hydrolysed casein and AA-mix diets resulted in a decline of relative Bacteroides spp.levels in the gut microbiota of DP-BB rats,whereas in the control rats,the Bacteroides spp.levels remained stable over time (Figure 6).The Nutramigen and AA-mix fed groups showed a decline after 65days of age,whereas the Pancase S fed rats showed a decline atendpoint.Figure 1.Kaplan Meijer curve showing diabetes development in DP-BB rats fed the control diet (n =15),Pancase S based diet (n =14),a Nutramigen W based diet (n =15)and an AA-mix based diet (n =15).*,p <0.05for mean day of onset and incidence as compared with controls;#,p <0.05for mean day of onset as com-pared with controls.The experiment was ended at 150days ofageFigure 2.Correlation between urinary lactulose-mannitol (LA/MA)ratio at 65days of age and day of diabetes onset (left image)and urinary LA/MA ratio at 65days of age in DP-BB rats on the indicated diets (right image).Group sizes for (B):Controls (n =6),Pancase S (n =7),Nutramigen W (n =8)and AA-mix (n =8).In (B),the data are expressed as a scatter dot plot with the mean indicated by a horizontal line.*,p <0.05as compared with controls and AA-mix groupHC-Diets Outclass AA-Diet to Prevent T1D 509Interestingly,the control group and the AA-mix fed rats showed a decline of lactobacilli levels over time,whereas the lactobacilli levels in the Pancase S and Nutramigen levels remained stable.The AA-mix fed rats showed already,at 65days of age,very low lactobacilli levels as compared with the controls and hydrolysed casein fed rats.No differences were observed between diabetic and non-diabetic rats and with regard to total bacterial load,mouse intestinal bacteroides and Erec levels (data not shown).DiscussionThe HC-based diets revealed a reduction of autoimmune diabetes incidence in the DP-BB rats at 150days ofageFigure 3.Ileal mRNA expression at endpoint of occludin (A),Myo9b (B),claudin-1(C)and claudin-2(D)in DP-BB rats fed the indi-cated diets.Data are expressed by a scatter dot plot with the mean indicated by a horizontal line.*,p <0.05;**,p <0.01as compared with controls.Group sizes:Controls (n =7),Pancase S (n =11),Nutramigen W (n =11),and AA-mix (n =13)Figure 4.Ileal mRNA expression at endpoint of IL-10(A)and TGF-ß(B)in DP-BB rats fed the indicated diets.Data are expressed as a scatter dot plot with the mean indicated by a horizontal line.*,p <0.05as compared with controls.Group sizes:Controls (n =7),Pancase S (n =11),Nutramigen W (n =11),and AA-mix (n =13)Figure 5.IL-10production in vitro at endpoint by ileal tissue explants mounted in snapwells.Data are expressed as a scatter dot plot with the mean indicated by a horizontal line.*,p <0.01as compared with controls.Group sizes:Controls (n =4),Pancase S (n =6),Nutramigen W (n =9),and AA-mix (n =11)510J.T.J.Visser et al.with the Nutramigen W based diet having the most pronounced effect.Somewhat unexpected in this study,the AA-mix based diet,which completely avoided complete proteins,only showed a delay in the onset of autoimmune diabetes when compared with the control diet.This differential effect on autoimmune diabetes development between the HC diets and the AA-mix based diet suggests involvement of speci ﬁc functionality of small peptides in the casein hydrolysates on mechanisms underlying autoim-mune diabetes pathogenesis in the DP-BB rat.Several observations showed that gut microbiota have a strong impact on diabetes development in animal models of T1D [24–29].Lowering intestinal bacterial load in NOD mice and DP-BB rats by antibiotics reduced and delayed autoimmune diabetes development [24,25,28,29].Gut microbiota manipulation by antibiotics combined with HC even completely prevented autoimmune diabetes in DP-BB rats [24].However,germ-free nonobese diabetic (NOD)mice and DP-BB rats show robust autoimmune diabetes development [27–29].This suggests that a certain level of exposure to gut microbes is essential for protection against T1D development.In addition,in DP-BB rats,the composi-tion of the gut microbiota determined the chance to developautoimmune diabetes [24,26].DP-BB rats with low intes-tinal levels of Bacteroides spp.did not develop autoimmune diabetes,whereas the rats with high levels of these bacteria developed autoimmune diabetes [24].Interestingly,expo-sure of DP-BB rats to Lactobacillus johnsonii N6.2delayed and prevented autoimmune diabetes development [26].In view of these results,it is reasonable to hypothesize that lactobacilli might be associated with the prevention of autoimmune diabetes and Bacteroides spp.bacteria might be associated with the induction of autoimmune diabetes.Intriguingly,recent preliminary data with a small group of four T1D patients indicate that high intestinal Bacteroides spp.levels and low intestinal lactobacilli levels might be associated with an increased chance to develop T1D [30].From the results presented here,it is reasonable to conclude that speci ﬁcally,the HC-based diets induced the development of a more bene ﬁcial or protective gut microbiota associated with a lower chance to develop autoimmune diabetes [24,26,30]and characterized by low Bacteroides spp.and high lactobacilli levels.This change in the gut microbiota might be one of the factors responsible for the delay and/or reduction in autoimmune diabetes development in the DP-BBrat.Figure 6.Longitudinal faecal bacteria levels of the individual rats exposed to the different experimental diets.Relative levels of Bacteroides spp.(top)and lactobacilli (bottom)expressed as proportion (%)of total bacteria.Data are expressed as mean ÆSEM.56d:(56days of age),65d:(65days of age)and End:(endpoint).*,p <0.05as compared with 56days of age.Group sizes:Controls (n =7),Pancase S (n =12),Nutramigen W (n =12),and AA-mix (n =13)HC-Diets Outclass AA-Diet to Prevent T1D 511。

关于海马体的英语阅读理解

关于海马体的英语阅读理解Antidepressant(抗忧郁) drugs such as Prozac were viewed in the early 1900's as wonder pills that would remove depressive blues for good. But in the past five years, growing scientific evidence has shown these drugs work for only a minority of people. And now a research journal says that these antidepressants can make many patients' depression worse. This alarming suggestion centres on the very chemical that is targeted by antidepressants-- serotonin(血清素). Drugs such as Prozac are known as selective serotonin re-uptake inhibitors (or SSRIs) . Their aim is to increase the level of this "feel- good" chemical in the brain. chemical Swiss Army knife, performing a very wide range of jobs in the brain and body. And when we start changing serotonin levels purposely, it may cause a wide range of unwanted effects. These can include digestive problems and even early deaths in older people, according to the study's lead researcher Paul Andrews. "We need to be much more cautious about use of these drugs," says Andrews.Previous research has suggested that the drugs provide ltte benefit for most people with mild depression, and actively help only a few of the most severely depressed. Famous psychologist Irving Kirsch has found that for many patients, SSRIs are no more effective than a placebo pill. A research in 2010 on Danish children found a smal, but significant increase in the risk of heart problems among babies whose mothers had used SSRls in early pregnancy(怀孕). The key to understanding these side-effects is serotonin, says Andrews. Serotonin is also the reason why patients can often end up feeling still more depressed after they have finished a course of SSRI drugs. He argues that SSRI antidepressants disturb the brain, leaving the patient an even greater depression than before.Stafford Light man, professor of medicine at the University of Bristol, and a leading UK expert in brain chemicals and hormones, says Andrews' review highlights some important problems, yet it should also be taken with a pinch of salt. "This report is doing the opposite of what drug companies do," he says. "Drug companies selectively present all thepositives in their research, while this search selectively presents all the negatives that can be found. Nevertheless, Andrews' study is useful in that it is always worth pointing out that there is a downside to any medicine." Professor Lightman adds that there is still a great deal we don't know about SSRIs-- not least what they actually do in our brains.When it comes to understanding why the drugs work only for a limited part of patients, U.S. scientists think they might now have the answer. They think that in many depressed patients, its not only the lack of feel-good serotonin causing their depression, but also a failure in the area of the brain that produces new cells throughout our lives. This area, the hippocampus(海马体) , is also responsible for regulating mood and memory. Research suggests that in patients whose hippocampus has lost the ability to produce new cells, SSRIs do not bring any benefit.1. By saying "serotonin is like a chemical Swiss Army knife" in paragraph 2, the author means that serotonin can_A. make many patients' depression worseB. cause a wide range of unwanted effectsC. affect human body and brain in various waysD. provide little benefit for most depressed people2. In Stafford Light man's opinion,A. Andrews' research has no medical valueB. scientists have found what SSRIs do in the brainC. drug companies don't know the negative effect of antidepressantsD. Andrews and the drug companies focused on different things about the drugs3. Which of the fllowing is TRUE about SSRIs?_A. They are responsible for contrlling mood and memory.B. They create a risk of heart problems in pregnant women.C. They are used to increase the "feel-good" medical in the brain.D. They can work even if the hippocampus can't produce new cells.4. What is the passage mainly about?_A. The aims of drug companiesB. The functions of SSRIsC. The side-effects of antidepressantsD. The causes of depression。

产甲烷菌、产甲烷菌和消化道

产甲烷菌、产甲烷菌和消化道产甲烷菌、产甲烷菌和消化道直到最近，产甲烷菌被分为6级（产甲烷菌、产甲烷菌、产甲烷菌、产甲烷菌、产甲烷菌、产甲烷菌）（6 orders (Methanobacteriales, Methanococcales, Methanomicrobiales, Methanosarcinales, Methanopyrales, Methanocellales），均属于⼴裂⾓菌门。

最近，根据从⼈类肠道中获得的序列，提出了与热等离⼦体催化剂相关的7级产甲烷菌系统学研究。

随后提出了两个名称，甲氧基胞质催化剂（Methanoplasmatales）和甲氧基丙烯酰胺类化合物（Methanomassiliicoccales），后者⽬前已得到原核⽣物系统学国际委员会（International Committee on Systematics of Prokaryotes, ICSP）的验证。

产甲烷是与不同的能量守恒系统耦合的，代表了产甲烷菌唯⼀的能量代谢。

对于这种代谢，产甲烷菌只能使⽤有限数量的底物，这些底物来源于⽔解和发酵细菌对有机物的厌氧降解。

因此，产甲烷菌在微⽣物营养链中有⼀个末端位置。

根据今天使⽤的代谢分类，可以定义产甲烷的氢化、甲基营养和⼄酰营养（或⼄酰碎屑）类别。

⼤多数产甲烷菌是氢氧化菌，利⽤氢⽓（通常是甲酸盐）将⼆氧化碳还原成甲烷。

甲基化产甲烷菌使⽤甲基化化合物，如甲醇、甲胺和甲基硫化物，通过底物特异性甲基转移酶将这些化合物的甲基群转化为CH4。

这种产甲烷的还原当量是通过甲基氧化途径将⼀个甲基额外氧化成⼆氧化碳⽽获得的，与氢氧化途径的第⼀步相反。

该途径的⼀个变体是直接使⽤环境中的氢作为电⼦供体，⽽不是甲基氧化途径产⽣的还原当量。

有趣的是，仅限于此变种的产甲烷菌被发现与肠道环境有关。

最后，很少有与甲烷菌属有关的古细菌能够利⽤⼄酸作为产甲烷的底物。

甲基辅酶M还原酶（MCRI或MCRII同功酶）负责CH3-S-CoM和H-S-CoM中CH4的形成，是所有产甲烷菌共有的。

A review of the species of protozoan epibionts on crustaceans-11

A REVIEW OF THE SPECIES OF PROTOZOAN EPIBIONTS ONCRUSTACEANS.I.PERITRICH CILIATESBYGREGORIO FERNANDEZ-LEBORANS and MARIA LUISA TATO-PORTODepartamento de Biologia Animal I(Zoologia),Facultad de Biologia,Pnta9a,Universidad Complutense,E-28040Madrid,SpainABSTRACTAn updated inventory of the peritrich(Protozoa,Ciliophora)epibiont species on crustaceans has been carried out.Data concerning268epibiont species,their taxonomic position,and the various crustacean basibionts were considered.The overview comprised in this study may be of use in further surveys of protozoan-crustacean epibiosis.RESUMENSe ha realizado un inventario actualizado de las especies de peritricos(Protozoa,Ciliophora) epibiontes en crustáceos.Se han considerado los datos concernientes a268especies epibiontes,su posición taxonómica,y los diferentes crustáceos visión general que comprende este estudio puede ser utilizada en futuras investigaciones sobre la epibiosis protozoos-crustáceos.INTRODUCTIONEpibiosis is a facultative association of two organisms:the epibiont and the basibiont(Wahl,1989).The term“epibiont”includes organisms that,during the sessile phase of their life cycle,are attached to the surface of a living substratum, while the basibiont lodges and constitutes a support for the epibiont(Threlkeld et al.,1993).Both concepts describe ecological functions(Wahl,1989).Several crustacean groups,cladocerans,copepods,cirripedes,isopods,amphi-pods,and decapods,include forms that are hosts for macroepibiont invertebrates (Ross,1983),and for protozoan microepibionts of the phylum Ciliophora:apos-tomatids,chonotrichids,suctorians,peritrichs,and heterotrichs(Corliss,1979; Small&Lynn,1985).The study of ciliate epibionts on crustaceans began in the last century.Bütschli(1887-89)made a compilation from former publications.After-wards,other authors(Keiser,1921;Kahl,1934,1935;Precht,1935;Raabe,1947; c®Koninklijke Brill NV,Leiden,2000Crustaceana73(6):643-683644G.FERNANDEZ-LEBORANS&M.L.TATO-PORTONenninger,1948)not only described epibiont species,but proposed explanations for the processes of epibiosis.A review of the protozoan epibionts found on de-capod crustaceans was carried out by Sprague&Couch(1971).Green(1974), in a study of the epibionts living on cladocerans,pays considerable attention to protozoan species.Ho&Perkins(1985)have focused on the epibionts found on copepods.In other contemporary and also earlier works,the following aspects have been taken into account:(1)speci city between ciliates and their crustacean basi-bionts(Evans et al.,1981;Batisse,1986,1992;Clamp,1991);(2)the morpholog-ical and physiological adaptations of the epibionts(D’Eliscu,1975;Batisse,1986, 1994;Fenchel,1987;Clamp,1991;Lom&De Puytorac,1994);(3)the effects pro-duced by the epibionts on the crustaceans(Herman et al.,1971;Turner et al.,1979; Kankaala&Eloranta,1987;Nagasawa,1988);(4)the possible use of epibionts for the assessment of water quality(Antipa,1977;Henebry&Ridgeway,1979;Scott &Thune,1986);(5)the implications of protozoan epibionts on cultures of vari-ous species of crustaceans(Overstreet,1973;Johnson,1977,1978;Lightner,1977, 1988;Couch,1978;Scott&Thune,1986;V ogelbein&Thune,1988;Camacho& Chinchilla,1989);and(6)the organization of the epibiont communities on plank-tonic crustaceans(Threlkeld et al.,1993).Despite the fact that there is a considerable amount of information about the protozoan epibionts on crustaceans,since the works of Sprague&Couch(1971), Green(1974),and Ho&Perkins(1985),which relate to speci c crustacean groups, no further general reviews have appeared.Several new species of protozoan ciliate epibionts have recently been described(Dovgal,1985;Batisse,1992;Fernandez-Leborans&Gomez del Arco,1996;Zhadan&Mikrjukov,1996;Fernandez-Leborans et al.,1996,1997),and some of these are peritrich ciliates(Matthes& Guhl,1973;Bierhof&Roos,1977;Jankowski,1986;Dale&Blom,1987;Clamp, 1990,1991;Threlkeld&Willey,1993;Hudson&Lester,1994;Stoukal&Matis, 1994;Foissner,1996).The purpose of this work is to provide an up-to-date review of the peritrich ciliates living as epibionts on crustaceans:268species have been considered in this compilation,which may contribute data for studies of epibiosis in crustaceans.CRUSTACEAN PROTOZOAN EPIBIONTS,I.PERITRICH CILIATES645RESULTS1)Phylum CILIOPHORA Do ein,1901Class OLIGOHYMENOPHOREA De Puytorac,Batisse,Bohatier,Corliss, Deroux,Didier,Dragesco,Fryd-Versavel,Grain,Grolière,Hovasse,Iftode,Laval,Roque,Savoie&Tuffrau,1974Subclass P ERITRICHIA Calkins,1933Order S ESSILIDA Kahl,1933Family Epistylididae Kahl,1935Genus Rhabdostyla Kent,1880( g.1)R.bosminae Levander,1907.On the cladoceran Bosmina sp.R.conipes Kahl,1935.On the cladoceran Daphnia sp.Fresh water.On the cladocerans Daphnia magna,D.longispina and Scapholeberis mucronata (cf.Green,1957,1974).R.cyclopis Kahl,1935.On the copepod Cyclops sp.Fresh water.R.cylindrica Stiller,1935.On the cladoceran Leptodora ke Balaton (Hungary).On the cladoceran Leptodora kindtii.Denmark(Green,1974).R.hungarica Stiller,1931.On the cladoceran Leptodora ke Balaton (Hungary).R.globularis Stokes,1890.On the cladoceran Bosmina longirostris and on Diaphanosoma brachyurum.Germany(Nenninger,1948).R.invaginata Stokes,1886.On the ostracod Cypris sp.R.sessilis Penard,1922.On the copepod Cyclops sp.Fresh water.R.pyriformis Perty,1852(cf.Kahl,1935;on Entomostraca).On the clado-ceran Daphnia longispina(cf.Nenninger,1948).On the cladoceran Daph-nia hyalina(cf.Sommer,1950).On Daphnia pulex and Ceriodaphnia reticu-lata(cf.Hamman,1952).On Daphnia magna,D.pulex,D.cucullata,Simo-cephalus vetulus,Ceriodaphnia reticulata,and Leptodora kindtii(cf.Green, 1953).On Daphnia magna(cf.Green,1955).On Daphnia magna andD.longispina(cf.Green,1957).On Daphnia atkinsoni,D.hyalina,D.lon-gispina,D.curvirostris,D.obtusa,Ceriodaphnia laticaudata,and C.pulchel-la(cf.Green,1974).R.vernalis Stokes,1887.On the copepod Eucyclops agilis(cf.Henebry& Ridgeway,1979).1)For authors and dates of species of Crustacea mentioned herein,see separate section,below.646G.FERNANDEZ-LEBORANS&M.L.TATO-PORTOFigs.1-2.1,Rhabdostyla(R.pyriformis,after Green,1957);2,Epistylis(E.gammari,after Precht,1935).Rhabdostyla sp.Bierhof&Roos,1977.Between the spines at the end of the telson on Gammarus tigrinus.Germany.Rhabdostyla sp.Weissman et al.,1993.On the copepod Acartia hudsonica. Genus Epistylis Ehrenberg,1832( g.2)E.anastatica(Linnaeus,1767)(cf.Kent,1881).Syn.:Vorticella anastatica L.,1767.On Entomostraca and freshwater plants.On cyclopoid copepods and Daphnia pulex(cf.Green,1974).E.astaci Nenninger,1948.Fresh water.On the gills of the decapod Astacusastacus(as A. uviatilis)(Germany).On A.leptodactylus(cf.Stiller,1971).On the gills of Austropotamobius torrentium(cf.Matthes&Guhl,1973).E.bimarginata Nenninger,1948.Fresh water.On the appendages of Astacusastacus(as A. uviatilis).Germany.E.branchiophila Perty,1852.Syn.:E.formosa Nenninger,1948.On theparasitic copepod Lernaea cyprinacea,in freshwater environments of South Africa(Van As&Viljoen,1984).E.breviramosa Stiller,1931.On the antennal lament of the cladoceran Daph-nia ke Balaton(Hungary).On the copepod Cyclops sp.,Czechoslovakia (Srámek-Husek,1948).On the cladocerans Bosmina longirostris and Alona af nis(cf.Green,1974).E.cambari Kellicott,1885.On the gills of the decapod Cambarus sp.(NE ofU.S.A.).On the maxillae of the cray sh Astacus leptodactylus(fresh water) (cf.Matthes&Guhl,1973).E.crassicollis Stein,1867.On freshwater Entomostraca and on the pleopodsand gills of cray sh.On the gills of Astacus astacus(as A. uviatilis),andCRUSTACEAN PROTOZOAN EPIBIONTS,I.PERITRICH CILIATES647 the maxillae,maxillipeds,and gills of A.leptodactylus,in Europe(Matthes& Guhl,1973).E.cyprinaceae Van As&Viljoen,1984.On the parasitic copepod Lernaea cyprinacea(fresh water,South Africa).E.daphniae Fauré-Fremiet,1905.On the cladoceran Daphnia sp.On Daphnia magna(cf.Nenninger,1948).On the copepod Boeckella triarticulata(New Zealand)(Xu&Burns,1990).On the cladoceran Moina macrocopa in an urban stream.E.diaptomi Fauré-Fremiet,1905.On the copepod Diaptomus sp.E.digitalis Ehrenberg,1838.On the copepod Cyclops sp.E.epibarnimiana Van As&Viljoen,1984.On the parasitic copepod Lernaea barnimiana(fresh water,South Africa).E.fugitans Kellicott,1887.On the cladoceran Sida crystallina.North America.E.gammari Precht,1935.On the antennae of the gammarid Gammarus sp. (Kiel channel).On the proximal part of the rst antenna and,less commonly, on the second antenna of Gammarus oceanicus and G.salinus.In the Baltic Sea and areas of Norway(Fenchel,1965).On the rst antenna of Gammarus tigrinus(cf.Stiller,1971).E.halophila Stiller,1942.On the cladocerans Daphnia longispina and D.pulex (Lake Cserepeser,Hungary).E.harpacticola Kahl,1933.On harpacticoid copepods in the Kiel channel. E.helenae Green,1957.On the cladocerans Daphnia pulex,D.magna,D.ob-tusa,D.longispina,D.curvirostris,Ceriodaphnia pulchella,C.reticulata, ticaudata,Moina macrocopa,M.micrura,Chydorus sphaericus,Simo-cephalus serrulatus,and S.vetulus(cf.Green,1957,1974).On Daphnia magna(cf.Nenninger,1948).On Ceriodaphnia reticulata and Simocephalus vetulus(cf.Matthes,1950).E.humilis Kellicott,1887.On the gammarid Gammarus sp.and other Ento-mostraca.custris Imhoff,1884.On the pelagic copepod Cyclops sp.On the buccal appendages of the branchiopod Lepidurus apus(freshwater areas near Vienna, Austria)(Foissner,1996).E.magna V an As&Viljoen,1984.On the parasitic copepod Lernaea cypri-nacea(fresh water,South Africa).E.niagarae Kellicott,1883.On the body surface of cray sh(Niagara River, U.S.A.).On the antennae and body of the European cray sh Astacus lep-todactylus,on Austropotamobius torrentium,and on Orconectes limosus(as Cambarus af nis)(cf.Matthes&Guhl,1973).On the surface of the copepod648G.FERNANDEZ-LEBORANS&M.L.TATO-PORTOEucyclops serrulatus,and on the cladocerans Daphnia pulex,D.rosea,Cerio-daphnia reticulata,and Scapholeberis mucronata(lakes of Colorado,U.S.A.) (Willey&Threlkeld,1993).E.nitocrae Precht,1935.On the third pereiopod of Gammarus tigrinus(cf.Bierhof&Roos,1977).E.nympharum Engelman,1862.On cladocerans(Nenninger,1948).On Cy-clops sp.(cf.Foissner&Schiffman,1974).On the branchiuran Dolops ra-narum(cf.Van As&Viljoen,1984).E.ovalis Biegel,1954.On the gnathopods of Gammarus tigrinus.On the thirdpereiopod of the gammarid Gammarus pulex,and on the spines at the end of the third uropod of Gammarus tigrinus(cf.Bierhof&Roos,1977).E.plicatilis Ehrenberg,1838.On the copepods Eucyclops agilis,Cyclopsvernalis,and C.bicuspidatus(Ashmore Lake,Illinois,U.S.A.)(Henebry& Ridgeway,1979).E.salina Stiller,1941.On the rst and second antennae,coxae,and gills of thegammarid Gammarus pulex(cf.Bierhof&Roos,1977).E.thienemanni Sommer,1951.On the gills of Gammarus tigrinus(cf.Bierhof&Roos,1977).E.zschokkei(Keiser,1921).Syn.:Opercularia zschokkei Keiser,1921.On thegnathopods of the gammarid Gammarus tigrinus and on other Entomostraca.On the cladoceran Acantholeberis curvirostris(cf.Nenninger,1948).Epistylis sp.Hutton,1964.On the decapod Penaeus duorarum(Florida,U.S.A.).Between the setae of the rst antenna of Gammarus tigrinus(cf.Bierhof& Roos,1977).Epistylis sp.Hutton,1964.On the decapod Ploeticus robustus(Daytona Beach, Florida,U.S.A.).Epistylis sp.Viljoen&Van As,1983.Two species on the thoracic appendages of a freshwater brachyuran,apparently erroneously identi ed as“Potamon sp.”(South Africa)[the genus Potamon does not occur in southern Africa].Epistylis sp.Pearse,1932.On the gills of the decapods Coenobita clypeatus, Geograpsus lividus,and Pachygrapsus transversus(Florida,U.S.A.).Epistylis sp.Hudson&Lester,1994.On the gills of the decapod Scylla serrata (Moreton Bay,Queensland,Australia).Epistylis sp.Turner et al.,1979.On the estuarine copepods Acartia tonsa andA.clausi(Escambia Bay,Florida,U.S.A.).Epistylis sp.Villarreal&Hutchings,1986.Fresh water.On the maxillipeds, pereiopods,and ventral portion of the abdomen of the decapod Cherax tenuimanus(Australia).CRUSTACEAN PROTOZOAN EPIBIONTS,I.PERITRICH CILIATES649 Family Lagenophryidae Bütschli,1889Genus Lagenophrys Stein,1852( g.3)L.aegleae Mouchet-Bennati,1932.Fresh water.On the branchial laments of the anomurans Aegla sp.,Aegla castro,and Aegla franca.Arroyo Miguelete, (Uruguay)and Parana River(Brazil).L.ampulla Stein,1851.Fresh water.On the gills of species of the genus Gammarus.L.andos(Jankowski,1986)(cf.Clamp,1991).Syn.:Circolagenophrys andos Jankowski,1986.Fresh water.On the decapod Parastacus chilensis(Chile).L.anticthos Clamp,1988.Fresh water.On the branchial laments of the decapods Parastacus pugnax,P.defossus,and P.saffordi(Chile,Brazil, Uruguay).L.aselli Plate,1886.On the branchial surface of the isopod Asellus aquaticus (Hamburg,Germany).L.awerinzewi Abonyi,1928.On the gills of the decapod Potamon uviatilis(as Telphusa uviatilis)(Africa).L.bipartita Stokes,1890.On the cladoceran Daphnia sp.(fresh water,U.S.A.).L.branchiarum Nie&Ho,1943.Fresh water.On the gills of the caridean shrimp Macrobrachium nipponense(as Palaemon nipponense)(Japan).L.callinectes Couch,1967.Marine and in estuaries.On the gills of the decapods Callinectes sapidus,C.bocourti,and C.maracaiboensis(Chesapeake Bay, Maryland,Virginia,and Gulf of Mexico).mensalis Swarczewsky,1930.Fresh water.On gammarids(Lake Baikal).L.darwini Kane,1965.On the branchial laments of the decapod Cherax quadricarinatus(stream near Darwin,Australia).L.dennisi Clamp,1987.Fresh water.On the decapods Orconectes illinoiensis, Cambarus bartonii bartonii,and C.chasmodactylus(North America).L.deserti Kane,1965.Fresh water.On the gills of the decapods Cherax tenuimanus and C.quinquecarinatus(SW rivers,Australia).L.diogenes(Jankowski,1986).Syns.:Circolagenophrys diogenes Jankowski, 1986,Lagenophrys incompta Clamp,1987.Fresh water.On the gills of the decapods Orconectes illinoiensis and Cambarus diogenes(Illinois,U.S.A.).L.discoidea Kellicott,1887(cf.Clamp,1990).Syns.:Lagenophrys labiata Wallengren,1900(a junior homonym of biata Stokes,1887(cf.Clamp, 1990));L.wallengreni Abonyi,1928;Circolagenophrys entocytheris Jankow-ski,1986.Fresh water.On ostracods.On the cray sh Cambarus sp.,C.chas-modactylus,C.bartonii bartonii,and Orconectes illinoiensis(Ontario,Canada and U.S.A.).650G.FERNANDEZ-LEBORANS&M.L.TATO-PORTOFigs.3-7.3,Lagenophrys(L.eupagurus,after Clamp,1989);4,Clistolagenophrys(C.primitiva, after Swarczewsky,1930);5,Setonophrys(munis,after Clamp,1991);6,Operculigera (O.asymmetrica,after Clamp,1991);7,Usconophrys(U.aperta,after Clamp,1991).L.dungogi Kane,1965.On the branchial laments of the decapod Euastacus sp.(stream near Dungog,Australia).L.engaei Kane,1965.On the branchial laments,basal areas of the gills, branchiostegite membrane and,more rarely,on the pleopods of the decapods Engaeus victoriensis and Austroastacus hemicirratulus(Victoria,Tasmania, and Melbourne,Australia).L.eupagurus Kellicott,1893(cf.Clamp,1989).Syns.:Lagenophrys lunatus Imamura,1940;Lagenophrys articularis Nie&Ho,1943.Marine,in estu-arine areas and fresh water.On the decapods Litopenaeus setiferus(as Pe-CRUSTACEAN PROTOZOAN EPIBIONTS,I.PERITRICH CILIATES651 naeus s.)(Penaeidea,Penaeidae),on the surface of the body,Litopenaeus van-namei(as Penaeus v.),on the surface of the body,Macrobrachium nipponense (Caridea,Palaemonidae)on antennae and pleopods,Macrobrachium ohione, on the surface of the middle of the pleura,Macrobrachium rosenbergii,on the gills,Palaemon paucidens(Caridea,Palaemonidae),Palaemonetes inter-medius(Caridea,Palaemonidae),Palaemonetes kadiakensis,Palaemonetes paludosus,Palaemonetes pugio,Palaemonetes varians,on the whole body, except on the gills,Palaemonetes vulgaris,Upogebia af nis(Thalassinidea, Upogebiidae),and Pagurus longicarpus(Anomura,Paguridae),on the gills (U.S.A.,Japan,Venezuela,Thailand).L.foxi Clamp,1987.Fresh water.On the gills of the gammarids Gammarus pseudolimnaeus,G.troglophilus,G.minus,and Gammarus sp.(Missouri, U.S.A.).L.in ata Swarczewsky,1930.On the distal areas of pleopods of the gammarid Gmelinoides fasciata(Lake Baikal).L.jacobi(Kane,1969).Syn.:Stylohedra jacobi Kane,1969.On freshwater decapods in Australia.L.johnsoni Clamp,1990.Syn.:Lagenophrys labiata Stokes,1887(partim). Fresh water.On the appendages and the surface of the carapace of the gammarids Gammarus fasciatus,G.daiberi,G.tigrinus,and Crangonyx gracilis(New Jersey,Michigan,and North Carolina,U.S.A.).biata Stokes,1887(cf.Clamp,1990).Fresh water.On the appendages and on the surface of the carapace of the gammarids Gammarus fasciatus, G.daiberi,G.tigrinus,and Cangronyx gracilis(New Jersey,Michigan,and North Carolina,U.S.A.).L.leniusculus(Jankowski,1986).Syns.:Circolagenophrys leniusculus Jan-kowski,1986;L.oregonensis Clamp,1987.Fresh water.On the carapace, gills,ventral surface of the abdomen,uropods,pereiopods,and pleopods of the decapod Pacifastacus leniusculus leniusculus,and on the gills of P.leniusculus trowbridgii and P.connectens(North America).L.lenticula(Kellicott,1885)(cf.Clamp,1991).Syns.:Stylohedra lenticula Kellicott,1885;S.lenticulata Kahl,1935;Lagenophrys lenticulata(Kahl, 1935)(cf.Thomsen,1945).Fresh water.Setae of the sixth and seventh pereiopods of the gammarids Hyalella azteca and H.curvispina(U.S.A., Canada,Mexico,and Uruguay).L.limnoria Clamp,1988.Syn.:Circolagenophrys circularis Jankowski,1986 (cf.Clamp,1991).On the isopod Limnoria lignorum.L.macrostoma Swarczewsky,1930.Fresh water.On gammarids(Lake Baikal). L.matthesi Schödel,1983.On the maxillipeds of the gammarids Gammarus pulex and Carinogammarus roeselii.652G.FERNANDEZ-LEBORANS&M.L.TATO-PORTOL.metopauliadis Corliss&Brough,1965.Fresh water.On the gills of the brachyuran Metopaulias depressus(endemic on Jamaica).L.monolistrae Stammer,1935.On the pleopods of the isopod Monolistra sp.L.nassa Stein,1852.Fresh water.On the pleopods of the gammarid Gammarus pulex.L.oblonga Swarczewsky,1930.On the antennae of the gammarid Gammarus hyacinthinus(Lake Baikal).L.orchestiae Abonyi,1928.On the amphipod Orchestia cavimana(Lake Balaton,Hungary).L.ornata Swarczewsky,1930.Fresh water.On ke Baikal.L.ovalis Swarczewsky,1930.Fresh water.On the thoracic appendages of ke Baikal.L.parva Swarczewsky,1930.On ke Baikal.L.patina Stokes,1887(cf.Clamp,1990).Syn.:Lagenophrys labiata Stokes, 1887(cf.Shomay,1955).(Corliss&Brough,1965;Clamp,1973).Fresh water.On the pereiopods and gills of the gammarids Gammarus sp.and Hyalella azteca.American continent.L.rugosa Kane,1965.Fresh water.On the gills of the decapod Geocharax falcata(Victoria,Australia).L.similis Swarczewsky,1930.On ke Baikal.L.simplex Swarczewsky,1930.On ke Baikal.L.solida Swarczewsky,1930.On ke Baikal.L.stammeri Lust,1950.On ostracods.Germany.(Lust,1950a).L.stokesi Swarczewsky,1930.On ke Baikal.L.stygia Clamp,1990.Syn.:Lagenophrys labiata Stokes,1887(cf.Jakschik, 1967).Subterranean water.On the gills of the cave-dwelling amphipod Bactrurus mucronatus(Illinois,U.S.A.).L.tattersalli Willis,1942.On European copepods.L.turneri Kane,1969.On freshwater decapods in Australia.L.vaginicola Stein,1852.Syn.:Lagenophrys obovata Stokes,1887.On the genital setae and thoracopods of the copepods Cyclops miniatus and Cantho-camptus sp.L.verecunda Felgenhauer,1982.On the decapod Palaemonetes kadiakensis (Illinois,U.S.A.).L.willisi Kane,1965.Fresh water.On the gills of the decapods Cherax destructor,C.albidus,and C.rotundus(Melbourne,New South Wales(e.g., Newcastle),and NW Australia).Genus Clistolagenophrys Clamp,1991( g.4)C.primitiva(Swarczewsky,1930)(cf.Clamp,1991).Syn.:Lagenophrys primi-tiva Swarczewsky,1930.On pereiopods and pleopods of the gammarid Pallasea cancellus(Lake Baikal).Genus Setonophrys Jankowski,1986(cf.Clamp,1991)( g.5)S.bispinosa(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys bispinosa Kane,1965.On pereiopods of the decapod Cherax rotundus setosus.Stream near Newcastle(N.S.W.,Australia).munis(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys communis Kane,1965.On the body surface(telson,pleopods,pereiopods,carapace...) of the decapod Cherax destructor.On the gills of the decapods C.rotundus,C.albidus,C.quadricarinatus,Euastacus armatus,and Engaeus marmoratus(Victoria,Melbourne,and Tasmania,Australia).S.lingulata(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys lingulata Kane,1965.On the branchial laments and branchiostegite membrane of the decapods Cherax destructor, C.albidus,and C.rotundus(Victoria, Melbourne,and coastal and central areas of Australia).S.nivalis(Kane,1969)(cf.Clamp,1991).Syn.:Lagenophrys nivalis Kane, 1969.On freshwater decapods in Australia.S.occlusa(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys occlusa Kane, 1965.On the anterior zone of the branchial cavity of the decapods Cherax destructor,C.albidus,and C.rotundus(Victoria and New South Wales, Australia).S.seticola(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys seticola Kane, 1965.On the setae of the decapods Engaeus fultoni and Geocharax falcata (Victoria,Melbourne,and Templestowe,Australia).S.spinosa(Kane,1965)(cf.Clamp,1991).Syn.:Lagenophrys spinosa Kane, 1965.On the pleopods,carapace,and telson of the decapod Cherax destructor (Victoria,Melbourne,and Heathcote,Australia).S.tricorniculata Clamp,1991.On the pleopods of the decapod Geocharax falcata(Victoria,Grampian Mountains,and Wannon River,Australia). Genus Operculigera Kane,1969( g.6)O.asymmetrica Clamp,1991.On the base of the gills of the freshwater decapods Parastacus pugnax and Samastacus spinifrons(Concepción and Talcahuano,Chile).O.insolita Clamp,1991.On the base of the gills of the freshwater decapod Parastacus pugnax(Concepción,Talcahuano,Malleco,and Puren,Chile).O.montanea Kane,1969.On the freshwater decapod Colubotelson sp.(Aus-tralia).O.obstipa Clamp,1991.Pleopods of the isopod Metaphreatoicus australis (New South Wales,Australia).O.parastacis Jankowski,1986.On the base of the gills of the decapod Parastacus nicoleti(Isla Teja,Valdivia,Chile).O.seticola Clamp,1991.On the setae at the base of gills of the decapod Parastacus pugnax(Concepción,Chile).O.striata Jankowski,1986.On the decapod Parastacus chilensis.Chile.O.taura Clamp,1991.On the branchial laments of the freshwater decapod Parastacus pugnax(Concepción,Malleco,and Puren,Chile).O.velata Jankowski,1986.On the gills of the anomuran Aegla laevis.Chile.O.zeenahensis Kane,1969.On freshwater decapods in Australia.Family Usconophryidae Clamp,1991Genus Usconophrys Jankowski,1985(cf.Clamp,1991)( g.7)U.aperta(Plate,1889)(cf.Clamp,1991).Syns.:Lagenophrys aperta Plate, 1889;Usconophrys dauricus Jankowski,1986.On the gills and pleopods of the isopod Asellus aquaticus(Marburg and Hessen,Germany;North Carolina, U.S.A.;Brittany,Finisterre,Plougarneau,Pont-Menou,and Douron River, France).U.rotunda(Precht,1935)(cf.Clamp,1991).Syn.:Lagenophrys rotunda Precht,1935.On ostracods.Germany.Family Operculariidae Fauré-Fremiet,1979(in Corliss,1979)Genus Opercularia Stein,1854( g.8)O.allensi Stokes,1887.Syn.:O.ramosa Stokes,1887.On several living and inert substrata.On the body of the cray sh Astacus leptodactylus(cf.Matthes &Guhl,1973).O.asellicola Kahl,1935.On the isopod Asellus sp.Germany.O.coarctata Claparède&Lachmann,1858.On crabs(Buck,1961).O.crustaceorum Biegel,1954.On the gills of the cray sh Astacus astacus(asA. uviatilis).On the maxillae,maxillipeds,and pleopods of Austropotamo-bius torrentium(cf.Matthes&Guhl,1973).O.cylindrata Wrzesniowski,1807.On the copepod Cyclops sp.O.gammari Fauré-Fremiet,1905.Pereiopods of the gammarid amphipod Gammarus sp.O.lichtensteini Stein,1868.On various crabs and molluscs.O.nutans Ehrenberg,1838.Syn.:O.microstoma Stein,1854.On Entomostraca.On the cladoceran Alona af nis(cf.Matthes,1950).On the maxillipeds of the European cray sh Astacus leptodactylus(cf.Matthes&Guhl,1973).O.protecta Penard,1922.On the setae of pereiopods of the gammarid amphi-pod Gammarus pulex.O.reichelei Matthes&Guhl,1973.Found exclusively on the maxillipeds of the cray sh Astacus leptodactylus.O.stenostoma Stein,1868.On the isopod Asellus aquaticus.Genus Orbopercularia Lust,1950(cf.Lust,1950b)( g.9)O.astacicola(Matthes,1950)(cf.Matthes&Guhl,1973).Syn.:Opercularia astacicola Matthes,1950.Maxillipeds and pleopods of the cray sh Aus-tropotamobius torrentium.Genus Propyxidium Corliss,1979( g.10)P.aselli Penard,1922.On the isopod Asellus sp.P.asymmetrica Matthes&Guhl,1973.On the European cray sh Astacus astacus(as A. uviatilis).P.bosminae Kahl,1935.On the cladoceran Bosmina sp.P.canthocampti Penard,1922.On the pereiopods of the harpacticoid copepod Canthocamptus sp.Fresh water.P.cothurnioide Kent,1880.On the ostracod Cypris sp.P.hebes Kellicott,1888.On the pereiopods of the isopod Asellus aquaticus.P.henneguyi(Fauré-Fremiet,1905)(cf.Kahl,1935).Syn.:Opercularia hen-neguyi Fauré-Fremiet,1905.On the rst abdominal segment of the copepod Cyclops sp.Genus Ballodora Dogiel&Furssenko,1921( g.11)B.dimorpha Dogiel&Furssenko,1921.On Porcellio sp.and other terrestrialisopods.Genus Nuechterleinella Matthes,1990( g.12)N.corneliae Matthes,1990.On the ostracod Cypria ophthalmica.Genus Bezedniella Stoukal&Matis,1994( g.13)B.prima Stoukal&Matis,1994.Fresh water.On the ostracod Cypria sp.(Slovakia).Figs.8-14.8,Opercularia(O.nutans,after Foissner et al.,1992);9,Orbopercularia(O.astacicola, after Matthes&Guhl,1973);10,Propyxidium(P.canthocampti,after Penard,1922);11,Ballodora (B.dimorpha,after Dogiel&Furssenko,1921);12,Nuechterleinella(N.corneliae,after Matthes, 1990);13,Bezedniella(B.prima,after Stoukal&Matis,1994);14,Rovinjella(R.spheromae,afterMatthes,1972).Family Rovinjellidae Matthes,1972Genus Rovinjella Matthes,1972( g.14)R.spheromae Matthes,1972.On the marine isopod Sphaeroma serratum. Family Scyphidiidae Kahl,1933Genus Scyphidia Dujardin,1841( g.15)Scyphidia sp.Henebry&Ridgeway,1979.On the cladocerans Scapholeberis kingi,Alona costata,and Pleuroxus denticulatus(Ashmore Lake,Illinois, U.S.A.).Family Vaginicolidae De Fromentel,1874Genus Platycola Kent,1881( g.16)P.baikalica(Swarczewsky,1930).Syn.:Vaginicola baicalica Swarczewsky, 1930.Fresh water.On the gills of the gammarids Brandtia lata,Pallasea grubei,and Echinogammarus fuscus(Lake Baikal).P.callistoma Hadzi,1940.Fresh water.On the cave-dwelling isopod Microlis-tra spinosissima(former Yugoslavia).P.circularis Dons,1940.Marine.On the uropods of the isopod Limnoria sp.P.decumbens(Ehrenberg,1830).Syns.:Vaginicola decumbens Ehrenberg, 1830;Platycola ampulla De Fromentel,1874;P.regularis De Fromentel, 1874;P.striata De Fromentel,1874;P.truncata De Fromentel,1874;P.longicollis Kent,1882;P.intermedia Kahl,1935;P.re exa Kahl,1935;P.amphora Swarcezwsky,1930;P.amphoroides Sommer,1951.Fresh water.On several vegetable and animal substrata.On the gills of the gammarid Brachiuropus sp.(Lake Baikal)(Swarczewsky,1930).geniformis Hadzi,1940.Fresh water.On the cave-dwelling isopod Micro-listra spinosissima(former Yugoslavia).P.pala Swarczewsky,1930.Syn.:Vaginicola pala Swarczewsky,1930.On the gills of the gammarid Palicarinus puzyllii(as Parapallesa pazill)(Lake Baikal).Genus Cothurnia Ehrenberg,1831(cf.Claparède&Lachmann,1858)( g.17)C.angusta Kahl,1933.Brackish or fresh water.On ostracods(Kiel,Germany).C.anomala Stiller,1951.Fresh water.On the amphipod Corophium curvispi-num(Lake Balaton,Hungary).C.antarctica(Daday,1911)(cf.Warren&Paynter,1991).Syn.:Cothurniopsisantarctica Daday,1911.Marine.Epibiont on the ostracod Philomedes lae-vipes(Antarctic areas).C.astaci Stein,1854.Fresh water.On the pleopods and gills of cray sh.On the maxillae,maxillipeds,and pleopods of the cray sh Astacus astacus。

微生态调节剂

治疗皮肤病 • 用痤疮丙酸杆菌和表皮葡萄球菌制剂治疗青春型痤疮和黄褐斑等皮肤病。有报告
服用乳杆菌制剂治疗青春型痤疮并取得良好疗效。
防治高胆固醇血症
• 研究表明，双歧杆菌、嗜乳酸杆菌制剂可使胆固醇转化为人体不吸收的粪甾醇。人体试验表明，食用含有保加利亚乳杆菌和嗜热链球菌的酸奶可降低血中胆固醇含量的5～10%，这对于治疗和缓解胆固醇血症具有一定的疗效。傅晓莉（1994）等经肠道分离一株屎肠球菌活菌对高胆固醇血症具有明显的预防和治疗作用。
谢谢！
抗生素相关性腹泻、真菌感染的防治
• 用益生菌制剂治疗临床大量使用抗生素引起的肠道菌群紊乱、念珠菌、肠球菌占优势，厌氧菌明显减少等引起的抗生素相关性腹泻，伪膜性结肠炎具有明显的作用，可以解除大量使用抗生素所造成的严重副作用。
•
多胺对肠管组织的成熟起不可缺的作用,它可由肠道细菌生成,故认作是
影响肠道内环境的至关重要物质。给高龄者投予酸奶(yogurt)试验结果证实
,确可使肠内多胺含量增加。此种作用的结果,由于肠道内环境获致改善,炎
症性细胞因子诱导受抑肠粘膜层康复遂使抗炎作用增加并取得强效的抗致
突变性(antimutagenicity)。
日比纪文等近年依基因技术制成的炎症性肠病(IBD)动物模型研究证实,在无菌状态下不会致病,即阐明发生IBD必需肠道细菌参与, 进一步研究发现,乳杆菌代谢产物酪酸可改善大肠上皮的能量平衡,促进细胞因子的生成而抑制可致炎症之转录因子NF κB。Gionchetti(2000～2003)应用乳杆菌与双歧杆菌等13株组合制剂 “VSL#3”对溃疡性结肠炎术后回肠美克尔憩室炎进行预防性治疗,取得了良好效果。
益生元（Prebiotics）是指能够选择性地促进宿主肠道内有的一种或几种有益细菌（益生菌）生长繁殖的物质，通过有益菌的繁殖增多，抑制有害细菌生长，从而达到调整肠道菌群，促进机体健康的目的。

每周只需注射一次,3个月即可轻松减掉10斤肥肉能让你管住嘴的减肥神药真的来了临床大发现

每周只需注射一次，3个月即可轻松减掉10斤肥肉。

能让你管住嘴的减肥神药真的来了临床大发现“管住嘴，迈开腿”简简单单六个字，就道出了减肥的真谛。

然而，面对那么多的美食诱惑，光这前三个字就足以让无数人的减肥大业半途而废了。

不过，好消息来了！最近，肥胖研究领域中的著名期刊《糖尿病，肥胖和代谢》杂志刊登的一项临床研究[1]显示，诺和诺德公司开发的索马鲁肽，可以抑制食欲，让你轻松“管住嘴”。

只需一周注射1次，连续注射12周后，就可减重10斤！而且，在这减轻的体重中，主要还是体内的脂肪组织，药物对除脂肪以外的去脂体重影响很小。

不光有效，还很安全！这项研究的通讯作者，来自英国利兹大学的John Blundell 教授表示，“索马鲁肽的作用是非常令人惊讶的，我们在12周内就观察到了其他减肥药物需要6个月才能达到的效果。

它减少了饥饿感和食欲，让患者能更好地控制饮食摄入。

”[2] John Blundell教授索马鲁肽（Semaglutide）本身是一款针对2型糖尿病的降糖药，主要成分为胰高血糖素样肽-1（GLP-1）类似物。

GLP-1是一种由小肠分泌的激素，在血液中葡萄糖水平升高时促进胰岛素的合成和分泌。

GLP-1进入人体后很容易被酶降解，天然的GLP-1半衰期仅有几分钟，所以，为了让它更长久的工作，研究人员会对它进行一些结构上的改造，在保留功能的同时不那么容易被酶降解。

这样得到的GLP-1类似物药物，比如大名鼎鼎的利拉鲁肽，可以将注射频率减缓到每天1~2次。

而索马鲁肽可以说是它们的“升级版”，在经过改造后，它的半衰期可延长至大约1周，因此注射一次的效果可以维持大约一周的时间[3]，对于患者来说更方便。

在不久前公布的全球大型III期临床试验中，索马鲁肽表现优秀，既能控制血糖，还可以保护心血管，这为它在上周赢得了FDA内分泌及代谢药物专家咨询委员会16:0的支持率，不出意外的话，索马鲁肽上市在即[4]。

不少分析人士预测它未来十年内的销售峰值将超百亿，成为治疗2型糖尿病中最好的降糖药。

Antibiotics for FGID

Case Studies of Antibiotic Therapy in the Management of Functional Gastrointestinal DisordersJ a n u a r y 2007e 3, I s s u e 1, S u p p l e m e n t 1w w w.c l i n i c a l a d v a n c e s .c o m V o l u m Commentary by Mark Pimentel, MD Cedars-Sinai Medical Center Los Angeles, CaliforniaSupported through an educational grant from Salix Pharmaceuticals, Inc.FacultyCharles Cattano, MDAnne Arundel Gastroenterology Associates Annapolis, Md .Jennifer Christie, MDMount Sinai School of Medicine New York, NYCharles Loewe, MDSarasota Center for Digestive Diseases Sarasota, Fla.Venkat Mohan, MDNorthwest Gastroenterology AssociatesBellevue, Wash.Th is publication is not intended to oﬀ er an opinion on the advisability of administering XIFAXAN (rifaximin) tablets 200 mg in a manner inconsistent with product labeling. Please consult the accompanying product information for full prescribing details or contact the Salix Medical Aﬀ airs Department (800-508-0024) with any questions.Maria T. Abreu, MDMount Sinai School of Medicine Nezam H. Afdhal, MDBeth Israel DeaconnessMedical CenterHarvard Medical SchoolRobert N. Baldassano, MD Children’s Hospital of Philadelphia University of Pennsylvania Theodore Bayless, MDJohns Hopkins HospitalManoop S. Bhutani, MD University of TexasMedical BranchThomas D. Boyer, MD University of ArizonaJoel V. Brill, MDPredictive Health, LLCRobert S. Brown, Jr., MD, MPH Columbia University Medical Center Stephen Brunton, MD Cabarrus Family Medicine Residency Brooks D. Cash, MDNational Naval Medical CenterLin Chang, MDDavid Geffen School of Medicine University of California,Los AngelesWilliam D. Chey, MD University of MichiganMedical CenterRussell D. Cohen, MD University of ChicagoScott J. Cotler, MDUniversity of Illinois at Chicago Douglas Dieterich, MDMount Sinai Medical CenterJack A. Di Palma, MD University of South Alabama Raymond DuBois, MD Vanderbilt UniversityGary W. Falk, MDCleveland Clinic Foundation Ronnie Fass, MDSouthern Arizona VAHealth Care SystemUniversity of Arizona HealthSciences CenterM. Brian Fennerty, MDOregon Health & ScienceUniversityRobert Gish, MDCalifornia Pacific Medical CenterTarek Hassanein, MDUniversity of California, San DiegoJorge Herrera, MDUniversity of South AlabamaColin W. Howden, MDNorthwestern UniversityFeinberg School of MedicineIra M. Jacobson, MDWeill Medical College ofCornell UniversityLennox J. Jeffers, MDUniversity of MiamiDavid A. Johnson, MDEastern VA Medical SchoolMaureen M. Jonas, MDChildren’s Hospital BostonSunanda V. Kane, MD, MSPHUniversity of ChicagoPhilip O. Katz, MDAlbert Einstein Medical CenterAsher Kornbluth, MDMount Sinai Medical CenterJoshua Korzenik, MDMassachusetts General HospitalBrian E. Lacy, MD, PhDDartmouth Hitchcock Medical CenterBret A. Lashner, MDCleveland Clinic FoundationAnthony J. Lembo, MDBeth Israel DeaconessMedical CenterRichard MacDermott, MDAlbany Medical CenterPhilip B. Miner Jr., MDOklahoma School of MedicineMark Pimentel, MD, FRCP(C)Cedars-Sinai Medical CenterPaul J. Pockros, MDScripps ClinicFred Poordad, MDCedars-Sinai Medical CenterDaniel H. PresentMount Sinai School of MedicineEamonn M. M. Quigley, MDNational University of Ireland, CorkK. Rajender Reddy, MDUniversity of PennsylvaniaDouglas K. Rex, MDIndiana University Medical CenterDavid T. Rubin, MDUniversity of ChicagoPaul Rutgeerts, MDKatholieke Universiteit LeuvenSeymour M. Sabesin, MDRush University Medical CenterRichard E. Sampliner, MDUniversity of ArizonaR. Balfour Sartor, MDUniversity of North Carolina,Chapel HillPhilip S. Schoenfeld, MD, MEd, MScUniversity of MichiganBo Shen, MDThe Cleveland ClinicMitchell Shiffman, MDVirginia CommonwealthUniversityDaniel Shouval, MDHadassah University HospitalJerome H. Siegel, MDBeth Israel Medical CenterMark Sulkowski, MDJohns Hopkins UniversitySchool of MedicineNicholas J. Talley, MD, PhDMayo ClinicNizar Zein, MDCleveland Clinic FoundationEDITORIAL ADVISORY BOARDE d i t o r-i n-C h i e fGary R. Lichtenstein, MDDirector, Inflammatory BowelDisease ProgramProfessor of MedicineUniversity of PennsylvaniaS e c t i o n E d i t o r sJohn Baillie, MB ChB, FRCPProfessor of MedicineDirector of PancreatobiliaryDisorders ServiceWake Forest University HealthSciences CenterStephen B. Hanauer, MDProfessor of Medicineand Clinical PharmacologyDirector, Section ofGastroenterology and NutritionUniversity of ChicagoJoel E. Richter, MD, FACP, MACGProfessor of MedicineChairman, Department of MedicineTemple University School of MedicineEugene R. Schiff, MDProfessor of MedicineChief of the Division of HepatologyDirector of the Center for Liver DiseasesUniversity of Miami School of MedicineDisclaimerFunding for this case study compendium has been provided through an unrestricted educational grant from Salix Pharmaceuticals, Inc., Morrisville, NC. Sponsorship of this supplement does not imply the sponsor’s agreement with the views expressed herein. Every eﬀ ort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Gastro-Hep Communications, the sponsors, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.©2007 Gastro-Hep Communications. 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.Introduction: Antibiotics for Functional Gastrointestinal Symptoms4Ciprofloxacin in a Patient With Exacerbation of Functional Gastrointestinal Symptoms After an Episode of Gastroenteritis5Charles Cattano, MDRifaximin Therapy in a Patient With Constipation-predominant IBS6Jennifer Christie, MDRifaximin in a Patient With Relapsing Functional Gastrointestinal Symptoms7Venkat Mohan, MDRifaximin as Acute Therapy and Maintenance Treatment for Functional Gastrointestinal Symptoms9Charles Loewe, MD CommentaryMark Pimentel, MD10Table of ContentsCase Studies of Antibiotic Therapy in the Management of Functional Gastrointestinal DisordersC A S E S T UD IE SIntroduction: Antibiotics for Functional Gastrointestinal SymptomsI rritable bowel syndrome (IBS) is a substantial healthproblem, aﬀ ecting an estimated 10–20% of individuals in the United States.1 Symptoms commonly associated with IBS include bloating, abdominal pain, constipation, diarrhea, and ﬂ atulence.2Th e causes of IBS are not well deﬁ ned but appear to be multifaceted. Underlying factors contributing to IBS pathogenesis include visceral hypersen-sitivity, altered gastrointestinal motility, chronic inﬂ amma-tion, and small intestinal bacterial overgrowth (SIBO).3,4 Th ese factors are not mutually exclusive, and speciﬁ c gastro-intestinal symptoms may vary among patients. For instance, SIBO may account for the increased gas production that occurs in many patients with IBS, and methane production is strongly associated with constipation-predominant IBS.4 Many potential mechanisms have been proposed to explain the pathophysiologic symptoms of IBS, including genetic predisposition; food intolerance; social, environ-mental, or behavioral factors; and previous enteric infec-tion.3 Th e complex nature of IBS pathology makes optimal treatment challenging. T reatment options for IBS include bulking agents, 5-hydroxytryptamine–modifying agents, antidepressants, antispasmodics, antiinﬂ ammatory agents, laxatives, antidiarrheals, antibiotics, and probiotics. Notably, antibiotics have a favorable eﬃ cacy proﬁ le in the treatment of individuals with SIBO.5-9,11Th e cases included in this supplement provide examples of the pathogenic role of bacteria in IBS and suggest that therapeutic approaches that aﬀ ect gut bacteria and the respective host responses to these pathogens might allevi-ate symptoms in patients with functional gastrointestinal symptoms. Th is notion is supported by observations from several open-label investigations as well as randomized, double-blind, controlled studies that have characterized the therapeutic beneﬁ t of antibiotics in the treatment of func-tional gastrointestinal symptoms in patients with or without a diagnosis of IBS.5-12Th e cases described in this supplement also provide real-world examples of antibiotic treatment of functional gastrointestinal symptoms in clinical practice. Although no conclusions about the eﬃ cacy of antibiotics for functional gastrointestinal symptoms can be drawn on the basis of these cases alone, the present observations illustrate the potential applications of antibiotics for the treatment of functional gastrointestinal disorders and suggest areas for further investigation.References1. Saito YA, Schoenfeld P, Locke GR 3rd. Th e epidemiology of irritable bowel syndrome in North America: a systematic review. 2002;97:rol. 2Am J Gastroenterol1910-1915.2. Th ompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut. 1999;45:43-47.3. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108-2131.4. Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292:852-858.5. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing cor-relates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. . 2003;98:412-419.rol. 20Am J Gastroenterol6. Di Stefano M, Malservisi S, Veneto G, et al. Rifaximin versus chlortetracycline in the short-term treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Th er. 2000;14:551-556.7. Lauritano EC, Gabrielli M, Lupascu A, et al. Rifaximin dose-ﬁ nding study for the treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Th er. 2005;22:31-35.8. T respi E, Ferrieri A. Intestinal bacterial overgrowth during chronic pancreatitis. Curr Med Res Opin. 1999;19:47-52.9. Corazza GR, Ventrucci M, Strocchi A, et al. T reatment of small intestine bacte-rial overgrowth with rifaximin, a non-absorbable rifamycin. J Int Med Res. 1988;16: 312-316.10. Di Stefano M, Strocchi A, Malservisi S, et al. Non-absorbable antibiotics for managing intestinal gas production and gas-related symptoms. Aliment Pharmacol Th er. 2000;14:1001-1008.11. Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and ﬂ atulence. Am J . 2006;101:326-333rol. 20Gastroenterol.12. Pimentel M, Park S, Mirocha J, et al. Th e eﬀ ect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557-563.4Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 2007M A N A G E M E N T O F F U N C T I O N A L G A S T R O I N T E S T I N A L D I S O R D E R S Ciprofloxacin in a Patient With Exacerbationof Functional Gastrointestinal Symptoms Afteran Episode of GastroenteritisDr. Cattano is a partner with Anne Arundel Gastroenterology Associates. A member of Mensa, he is Principal Investigator forMaryland Clinical Trials and is actively engaged in clinical trials involving both functional and inﬂ ammatory bowel disorders. Charles Cattano, MDA 50-year-old white woman presented with a 20-year his-tory of functional gastrointestinal symptoms, manifesting as recurrent abdominal cramps, excessive gas, and stool urgency without hematochezia or nocturnal stooling. Th e patient complained of severe diarrhea and moderate bloating, gas, and abdominal pain. Fatty meals exacerbated symptoms, and abdominal pain and bloating improved following bowel movements. A previous evaluation in 2004 resulted in a diagnosis of Rome II–positive, diarrhea-predominant IBS. Additionally, in August 2005, the patient’s symptoms ﬂ ared after an 8-day episode of acute viral gastroenteritis. Her medi-cal history included a longstanding history of anxiety, but no history of diabetes, thyroid disease, or neurologic issues. Her only surgery was hysterectomy for ﬁ broids, preceded by two uncomplicated childbirths. She denied tobacco use but admitted prior marijuana smoking. She has consumed alcohol socially. Her family history was notable for the pres-ence of “colitis” in her mother and sister, who had similar gastrointestinal symptoms.Current medications included dicyclomine 10 mg daily, which was initiated in June 2004. Previously the patient had been taking alprazolam as needed for restlessness but elected to discontinue use in order to “avoid addiction.” Her response to dicyclomine was rated as “50% better.” Th e patient also received a trial regimen of chlordiazepoxide 5 mg plus clidinium 2.5 mg twice daily (bid) with a reported 60% response, but discontinued the medication after 2 weeks due to oversedation. Th us, the patient was referred for gastroen-terology consultation for further evaluation and treatment.On physical examination, the patient weighed 142 lbs at a height of 5' 4". Her skin was nonicteric and lungs clear to posterior and anterior auscultation bilaterally. Heart sounds revealed S1S2 with a mitral click but no murmur. Her abdomen was scaphoid with mild tenderness in the right and left lower quadrants, without rebound. Bowel sounds were active in all four quadrants. Rectal examination revealed guaiac-negative brown stool and no digital tender-ness. Review of colonoscopic ﬁ ndings from August 2004 indicated diﬀ use spasm, but random biopsy was negative for inﬂ ammation. Results of complete blood count and blood chemistry tests provided by her referring primary care physi-cian were normal, as was the baseline level of serum thyreo-tropic hormone. Stool analysis proved negative for Giardia, enteric pathogens, and leukocytes. No breath test for bacte-rial overgrowth was available within our community.On the basis of her post-infectious symptoms, a diagnosis of SIBO was suspected. She received ciproﬂ oxa-cin 500 mg bid for 10 days. At a follow-up visit in August 2005, 3 weeks after discontinuing ciproﬂ oxacin treatment, her gastrointestinal symptoms were moderately improved and she reported no adverse eﬀ ects related to ciproﬂ oxa-cin treatment.Th e patient was lost to follow-up thereafter, due to a lack of interest in maintenance therapy. She telephoned again 6 months later to report recurrence of diarrhea without bleeding and requested a reﬁ ll of her ciproﬂ oxacin prescrip-tion. Based on available data, the patient was oﬀ ered a 14-day trial regimen of rifaximin 400 mg three times daily, with the expectation of consolidating symptom improve-ment. Her prior history of improvement with ciproﬂ oxacin provided support for a presumption of SIBO; however, formal breath testing was deferred. Tegaserod was initiated concomitantly with low-dose rifaximin 200 mg bid. Within 7 days on the combined regimen of tegaserod and rifaximin, the patient reported signiﬁ cant reduction in diarrhea (from 7 to 2 stools daily), as well as reductions in fecal urgency and abdominal cramping.DiscussionTh e merits of rifaximin treatment in IBS patients are under investigation, and preliminary data discussed else-where herein suggest beneﬁ t. Th e empiric use rifaximin in patients with SIBO symptoms, however, bears consid-eration, even without formal SIBO documentation. As noted in the case above, breath testing is not always readily ordered, and where available the cost of analysis is often substantial. Th erefore, empiric rifaximin treatment in IBS patients may be justiﬁ ed, particularly because, unlike with systemic antibiotics, the GI selectivity of rifaximin permits few side eﬀ ects and little expectation of signiﬁ cant bacterial resistance.1Reference1. Gerard L, Garey KW, DuPont HL. Rifaximin: a nonabsorbable rifamycin antibiotic for use in nonsystemic gastrointestinal infections. Expert Rev Anti Infect Th er. 2005;3:201-211.Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 20075C A S E S T UD IE SRifaximin Therapy in a Patient With Constipation-predominant IBSDr. Christie is an Assistant Professor and Director of the Womens’ Gastrointestinal Health and Motility Center in the Division of Gastroenterology at the Mount Sinai School of Medicine in New York City.Jennifer Christie, MDA 38-year-old Hispanic woman presented on August 10, 2005, with a 2-year history of postprandial bloating, gas, abdominal pain, and constipation, which was spontane-ous, intermittent, and self-limiting. Her medical history included migraine headaches and cholecystectomy. Medica-tions included sumatriptan as needed. Th e patient denied smoking, drinks alcohol socially, denied extraordinary stress, and had no known history of gastroenteritis and no known drug allergies.Functional gastrointestinal symptoms were refractory to treatment with simethicone (2-month course), alpha-galactosidase (Beano), and dietary modiﬁ cations, which included high-ﬁ ber foods and avoidance of lactose-con-taining products, raw vegetables, and beans. Th e patient reported worsening of gas and bloating. Another IBS drug was prescribed, which resulted in severe diarrhea. Upon presentation to the gastroenterologist, the patient was tak-ing no prescription medications.Upon physical examination, the patient appeared in no acute distress. Abdominal examination revealed mild dis-tention, a right upper quadrant surgical scar, positive bowel signs, mild diﬀ use tenderness, no rebound, and no guard-ing. Based on her symptoms of very severe bloating and gas, abdominal pain, and constipation, she was diagnosed with constipation-predominant IBS. Basic blood work consist-ing of metabolic panel and thyroid-stimulating hormone (TSH) was negative. A glucose breath test was negative for SIBO, based on hydrogen measures only. Despite her negative breath test but because of her symptom proﬁ le, the patient was administered rifaximin 400 mg three times daily for 10 days.T wo weeks later, the patient reported improvement in bloating and gas. However, she still complained of slight constipation. T egaserod 2 mg twice daily was prescribed with resolution of constipation. DiscussionIrritable bowel syndrome is commonly associated with symptoms of gas and bloating. Investigators have found that small bowel gas is found in excess in patients with IBS compared to controls.1Additionally, Pimentel and colleagues2found that treatment with oral antibiotics after a positive lactulose breath test was associated with improvement in IBS symptoms as well as normalization of breath test results. Interestingly, the hydrogen breath test using glucose in this patient was negative, yet the patient’s symptoms improved with empiric rifaximin treatment. Th is may have been due to the elimination of methane-producing intestinal bacteria that were not detected during the hydrogen breath test. In a study measuring methane production during lactulose breath testing, a 100% asso-ciation was found between constipation-predominant IBS and a methane-positive breath test.3 Breath testing may be falsely negative in patients with primarily methanogenic bacteria causing symptoms of IBS. Th erefore, we must consider methane to be an important intestinal gas in the production of gastrointestinal symptoms. References1. Koide A, Yamaguchi T, Odaka T, et al. Quantitative analysis of bowel gas using plain abdominal radiograph in patients with irritable bowel syndrome. Am J Gastro-enterol. 2000;95:1735-1741.2. Pimentel M, Chow E, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, random-ized, placebo-controlled study. . 2003;98:412-419.rol. 20Am J Gastroenterol3. Pimentel M, Mayer AG, Park S, et al. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig Dis Sci. 2003;48:86-92.6Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 2007M A N A G E M E N T O F F U N C T I O N A L G A S T R O I N T E S T I N A L D I S O R D E R S Rifaximin in a Patient With Relapsing Functional Gastrointestinal SymptomsDr. Mohan is a practicing gastroenterologist with Northwest Gastroenterology Associates in Bellevue, Washington, as wellas Clinical Assistant Professor of Medicine at the University of Washington in Seattle. His clinical interests include thetreatment of functional bowel and acid reﬂ ux disorders.Venkat Mohan, MDA 47-year-old white woman presented in December 2004 with a 10-year history of functional gastrointestinal symp-toms, including abdominal discomfort, loose stools, and a 2-year worsening of symptoms manifesting as excessive ﬂ atulence, bloating, and gas, without constipation or diar-rhea. Milk, cheese, and stress exacerbated her symptoms. Th e patient’s medical history indicated abdominal cramps and acid reﬂ ux, with no known history of gastroenteritis, neurologic disease, diabetes, or thyroid disease. Review of symptoms was unremarkable, with no weight loss, blood in the stool, or nausea. Her surgical history included appen-dectomy and hysterectomy. Her psychiatric history was noted for complaints of anxiety. In regard to related familial history, her father had colon cancer and her mother had diverticulosis. Her alcohol intake was reported as a once-weekly glass of wine. She was a nonsmoker.Gastrointestinal symptoms were refractory to dietary changes, which included replacement of dairy intake with soy products; consumption of small, low-fat meals; and avoidance of carbonated beverages, coﬀ ee, and artiﬁ cial sweeteners. Over-the-counter treatment with simethicone or alpha-galactosidase supplements provided only a mini-mal response. No speciﬁ c medications had been prescribed for treatment of her functional gastrointestinal symptoms, and the patient was not receiving medications for other disorders. Because of persistent symptoms, the patient was referred for gastroenterology consultation.On physical examination, the patient could be char-acterized as a pleasant, well-nourished female weighing 157 lbs at 5' 6". Cardiovascular, lung, and abdominal examinations were unremarkable. Results of routine screening laboratory tests for complete blood count, chemistry proﬁ le, TSH, erythrocyte sedimentation rate, and anti-endomysial antibody were normal. Stool test for fecal fat was normal. Breath tests were not performed. Results of a colonoscopy performed in November 2004 were negative. Based on symptom-based clinical data, the patient was diagnosed with functional bowel disorder and SIBO.Th e patient received rifaximin 400 mg twice daily (bid) for 10 days in combination with the probiotic Flora-Q once daily for 2 weeks and tegaserod 6 mg nightly for 2 months. She had a mild increase in loose bowel movements in the initial days of therapy due to the eﬀ ect of tegaserod, which ultimately normalized. At a follow-up visit 4 weeks after initiation of rifaximin adjunct therapy, the patient reported improved symptoms of bloating, gas, and abdominal dis-comfort, as well as normal stool consistency. At a routine follow-up oﬃ ce visit in May 2005, the patient reported that symptoms were greatly improved. No side eﬀ ects attributed to the treatment regimen were reported.No maintenance treatment was prescribed. Th e patient experienced a relapse in August 2005 and received rifaximin 400 mg bid for 2 weeks. Her symptoms of bloating, gas, and abdominal pain markedly improved. She was placed on a course of tegaserod 6 mg nightly for 2 months and currently remains symptom-free.DiscussionEmerging evidence supports the hypothesis that SIBO con-tributes to the pathogenesis of IBS.1 Many individuals with IBS also have SIBO, as indicated by reports of abnormal breath test results in up to 84% of individuals with IBS.2,3 Furthermore, multiple randomized, double-blind, placebo-controlled studies have demonstrated that patients who experienced normalization of breath test results following antibiotic treatment experience greater improvement of functional bowel symptoms.2-5 Speciﬁ cally, the nonsystemic antibiotic rifaximin has been shown to safely and eﬀ ectively eliminate bacterial overgrowth and improve global symp-toms of IBS.5,6Abnormal motility of the phase III “housekeeper” waves of the migrating motor complex in the small intestine may contribute to the development of SIBO in individuals with IBS.7 Th e recurrence of symptoms in this patient may be related to a lack of stimulation of this housekeeper wave. Th e administration of promotility agents such as tegaserodGastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 20077C A S E S T UD IE Smay help stimulate the phase III complex and prevent recurrence of SIBO. An additional agent administered to promote normal intestinal motility is oral erythromycin 50 mg daily.References1. Lin HC. Small intestinal bacterial overgrowth: a framework for understanding irritable bowel syndrome. JAMA. 2004;292:852-858.2. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial over-growth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol.2000; 95:3503-3506.3. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing cor-relates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. . 2003;98:412-419.rol. 20Am J Gastroenterol4. Di Stefano M, Strocchi A, Malservisi S, et al. Non-absorbable antibiotics for man-aging intestinal gas production and gas-related symptoms. Aliment Pharmacol Th er. 2000;14:1001-1008.5. Sharara AI, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and ﬂ atulence. Am J . 2006;101:326-333.rol. 20Gastroenterol6. Pimentel M, Park S, Mirocha J, et al. Th e eﬀ ect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann . 2006;145:557-563.Med. 20Intern Med7. Pimentel M, Soﬀ er EE, Chow EJ, et al. Lower frequency of MMC is found in IBS subjects with abnormal lactulose breath test, suggesting bacterial overgrowth. Dig Dis Sci. 2002;47:2639-2643.8Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 2007M A N A G E M E N T O F F U N C T I O N A L G A S T R O I N T E S T I N A L D I S O R D E R S Rifaximin as Acute Therapy and Maintenance Treatment for Functional Gastrointestinal Symptoms Charles Loewe, MDDr. Loewe has been in private practice in Sarasota, Florida, since 1982 and is the founder of the Sarasota Center for Digestive Diseases.He has performed over 40,000 procedures and maintains a keen interest in advanced endoscopic procedures.A 55-year-old white woman presented with a 10-year history of functional gastrointestinal symptoms, includ-ing mild diarrhea, severe constipation, abdominal pain, bloating, and gas. Symptoms were exacerbated by certain carbohydrates and alleviated only by not eating. A medi-cal consultation in 1998 resulted in a diagnosis of Rome II–positive, alternating-form IBS. Th e patient’s medical history was notable for recurrent episodes of diverticulitis, appendectomy, cholecystectomy, total abdominal hysterec-tomy, and a family history of colorectal cancer. Th e patient had no known history of gastroenteritis, diabetes, thyroid disease, neurologic disorder, or psychiatric problems, and reported no signiﬁ cant weight loss, no tobacco use, and only occasional consumption of alcohol. Symptoms were refractory to previous interventions, including oral dicyclo-mine 20 mg before meals, over-the-counter laxatives, and a high-ﬁ ber diet. Th e patient was referred to a gastroenterolo-gist for recurrent diverticulitis and alternating symptoms of constipation and diarrhea.On physical examination, the patient’s temperature was normal and her pulse rate was 75 bpm with a blood pressure of 120/75 mm Hg. Her height measured 5' 3" and weight 125 lbs. Abdominal examination revealed no hepatosplenomegaly, no abnormal mass, and slight tender-ness in the lower quadrants. Results of all stool studies were negative, with no detection of blood. Results of thyroid studies, complete blood count and C-reactive protein lev-els, and liver proﬁ le studies were normal. A 3-hour lactulose breath test revealed an abnormal hydrogen peak. Results of a colonoscopy performed in August 2004 revealed diver-ticulosis. A CT scan also showed evidence of diverticulosis with muscular hypertrophy.Based on clinical symptoms, the patient was adminis-tered oral rifaximin 400 mg twice daily for 10 days. A lactu-lose breath test administered after initiation of rifaximin treatment was normal. Following completion of rifaximin treatment, probiotic therapy and tegaserod 2 mg daily were administered as maintenance therapy. At her 3-month fol-low-up evaluation, the patient had not experienced symp-tom recurrence.DiscussionIrritable bowel syndrome is a very common chronic medi-cal condition with no known cause. Dr. Douglas Drossman ﬁ rst presented the biopsychosocial model of IBS,1which has gained much acceptance as a pathophysiologic cause, as have the application of symptom-based diagnostic criteria originally put forth by Manning and colleagues2 and further applied in the Rome diagnostic criteria. Research currently focuses on altered motility, neuroenteric signaling, visceral hypersensitivity, and brain-gut dysfunction.Irritable bowel syndrome is a complex gastrointestinal disorder characterized by a heterogeneous pathophysiology.A primary focus of recent research is the role of enteric bacteria in IBS pathogenesis, as demonstrated by the correlation between postinfectious IBS and a previous episode of bacterial gastroenteritis (eg, travelers’ diarrhea). Pimentel and colleagues have utilized the lactulose breath test to identify a subset of IBS patients with SIBO.3 Th eir therapeutic method began with neomycin and has evolved into a rifaximin-based primary treatment to normalize the abnormal breath test and to achieve global improvement of IBS symptoms, including bloating, abdominal discomfort, diarrhea, and constipation.4References1. Drossman DA. Gastrointestinal illness and the biopsychosocial model. J Clin Gas-. 1996;22:252-254.rol. 19troenterol2. Manning AP, Th ompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. . 1978;2:653-654.d J. 19Br Med J3. Lee H-C, Pimentel M. Bacteria and irritable bowel syndrome: the evidence for small intestinal bacterial overgrowth. Curr Gastroenterol Rep. 2006;8:305-311.4. Pimentel M, Park S, Mirocha J, et al. Th e eﬀ ect of a nonabsorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145:557-563.Gastroenterology & Hepatology Volume 3, Issue 1, Supplement 1 January 20079。

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ported the presence of a breakdown of toler-ance to the normal commensal intestinal flora in active IBD 2-3. Reduction of microflora by antibiotics, bowel rest and fecal diversion de-creases inflammatory activity in Crohn’s dis-ease and to a lesser extent in ulcerative colitis (UC). The pathogenetic role of intestinal mi-croflora is further suggested by the observa-tion that experimental colitis, in germ-free or antibiotic treated animals, is less severe com-pared to that inducible in normal animals or at times is not inducible at all. Moreover, bac-terial products, such as N -formil-methionyl-leucyil-phenylalanine (FMLP), lipopolysac-charidase (LPS) and peptidoglycan-polysac-charidase (LPS), can induce and perpetuate experimental colitis 4-8.Pouchitis, a non-specific inflammation of the ileal reservoir (pouch) mucosa, is the ma-jor long-term complication encountered after proctocolectomy and ileo-anal anastomosis for UC. The etiology and pathophysiology of pouchitis are not well understood, and a vari-ety of hypotheses have been proposed to ex-plain this inflammatory condition. Among this, a major role has been attributed to fecal stasis and bacterial overgrowth, recurrent UC,misdiagnosed Crohn’s disease and mucosal is-chemia of the pouch 9. However, pouchitis most likely seems to be the result of a com-plex interaction between a genetical or im-munological susceptibility of the patient and the morphological and functional modifica-tions of the ileal-pouch, due to the fecal stasis and consequent bacterial overgrowth 10-11.Several trials have been carried-out on the use of antibiotic treatment in patients with ac-Abstract. –The etiology of inflammatorydisease is still unknown, but a body of evidence from clinical and experimental observation indi-cates a role for intestinal microflora in the pathogenesis of this disease. Reduction of mi-croflora using antibiotics, bowel rest and fecal diversion decreases activity in Crohn’s disease and in ulcerative colitis. Several trials have been carried out on the use of antibiotic treatment in patients with active ulcerative colitis with con-trasting results. A number of trials have been carried out using Rifaximin, a non-absorbable broad-spectrum antibiotic, confirming the ab-sence of systemic bioavalaibility of the drug even when administered at very high doses and for prolonged periods. It may therefore be useful in treatment of ulcerative colitis and pouchitis,since its absorption through inflamed mucosa is negligible, it maintains a topical action without systemic effects and the lack of resistant bacte-rial strains may allow prolonged and repeated treatments.Key Words:Rifaximin, Antibiotic, IBD, Ulcerative colitis.IntroductionThe ethiology of inflammatory bowel dis-ease (IBD) remains unknown, but a body of evidence from clinical and experimental ob-servations indicates a pathogenetic role among others for intestinal microflora 1. The distal ileum and the colon are the areas with the highest intraluminal bacterial concentra-tion, and represent the sites of primary in-flammation in IBD. Recent studies have re-Review – Antibiotic treatment ininflammatory bowel disease: rifaximin, a new possible approachP.GIONCHETTI, F. RIZZELLO, A. VENTURI, F. UGOLINI *, M. ROSSI **,P. BRIGIDI **, R. JOHANSSON, A.FERRIERI ***, G.POGGIOLI *, M.CAMPIERIClinica Medica I, Nuove Patologie, Bologna University (Italy)*Istituto di Clinica Chirurgica II, Bologna University (Italy)**Dipartimento di Scienze Farmaceutiche, Bologna University (Italy)***Direzione Medica Alfa Wassermann, Bologna (Italy)tive UC, with contrasting results. Intravenous metronidazole was not found to be superior to placebo when used in association with cor-ticosteroids in severe UC12, while oral van-comicyn showed a certain efficacy, that how-ever did not reach statistical significance13. Favorable results have been obtained with tobramicyn, an aminoglycoside active against Gram negative bacteria, administered togeth-er with standard steroid treatment; 74% of patients achieved a complete symptomatic re-mission compared with only 43% in the place-bo treated group14. However, a more recent trial with cyprofloxacin has not been able to demonstrate a favourable effect of antibiotic treatment when compared to placebo15. Treatment of pouchitis remains empirical, and antibiotics are the mainstay of therapeu-tic regimens; metronidazole is the most com-mon administered first-line antibiotic, and most patients show remission of clinical symptons within a few days. One double-blind, placebo-controlled study utilizing metronidazole showed a significant reduction of bowel motions however without improve-ment of endoscopic appearance of the in-flammed intestinal tract or of the histological inflammatory activity16. Other antibacterial agents that have shown some positive results are ciprofloxacin, the association of amoxi-cyllin+clavulanic acid, tetracycline and ery-thromycin.No attempt has been made to compare metronidazole with other therapeutic regi-mens. About 15% of patients with pouchitis present a chronic inflammatory condition. In same cases, this inflammation is treatment-re-sponsive and requires maintainance metron-idazole therapy with a high incidence of side effects (dysgeusic nausea and peripheral neu-ropathy). In other cases pouchitis shows no response to antibiotic-treatment and is de-fined as treatment-resistant.Rifaximin is a non-absorbable antibiotic. Its mechanism of action is based on the inhi-bition of prokaryotic RNA-polymerase. The inhibition of this enzyme suppresses initiation of chain formation during RNA synthesis. The drug has bactericidal rather than bacte-riostatic property having a low ratio between bactericidal and inhibitory activity (1:1 to 4:1 in susceptible strains)17. It shares the same antibacterial spectrum with other rifamycins, covering all the main Gram positive and neg-ative, aerobic and anaerobic species associat-ed with gastro-intestinal infection17-18. Resistance to rifaximin has been demon-strated to occur either in vitro and in vivo in residual intestinal flora; drug resistance how-ever decreases rapidly after the end of the treatment, and disappeares completely after 1 to 2 weeks for anaerobic cocci, enterococci and Enterobacteriacee, and after 8 to 16 weeks for Clostridium and Bacteroides species. Therefore it appears that rifaximin resistant strains are unable to permanently colonize the gastro-intestinal tract19.Several experimental and clinical observa-tions have shown that rifaximin is virtually not absorbed. Recent experiments with 14C-rifaximin performed in rat and dog mod-els showed that, after intravenous administra-tion, plasma levels were detectable for 4 and 12 hours respectively, whereas after oral ad-ministration, serum radiolabelled product levels were very low and detectable only for 1 and 6 hours, respectively. Following oral ad-ministration in rats, after 48 hours the excre-tion of radioactivity in urine was about 0.7% of the dose, whereas in faeces the radiola-belled product was found in quantities that reached 90% or more of the oral dose; simi-lar results were observed in dogs. Following intravenous administration in dogs, within 24/48 hours most of the radioactivity was ex-creted in faeces (83% dose), whereas urinary excretion was about 6% of the administered dose; 168 hours after administration, radioac-tivity was totally excreted in faeces, possibly as a consequence of enterohepatic circulation of 14C-rifaximin or its metabolites20.Blood levels in healthy volunteers, after single oral administration of a dose of 400 mL, were undetectable in 50% of volunteers and below 5 ng/mL in the other 50%, using techniques with detection limit of 2 ng/mL. After 48 hours, urinary recovery of the drug did not exceed 0.025% of the administered dose (unpublished observation).More recently, in one study which investi-gated the systemic absorption of rifaximin af-ter single oral administration of 400 mg, in patients with mild to moderate ulcerative col-itis, urinary excretion was found to be negligi-ble, and plasma concentration was unde-tectable in almost all patients21.Largely variable amounts of rifaximin have been recovered in faeces, depending on massP.Gionchetti, F. Rizzello, A. Venturi, F. Ugolini, M. Rossi, P. Brigidi, R.Johansson et alof the faeces and transit time. In some cases up to 76% of the administered dose could be recovered in faeces in 24 hours. Therefore, independently from its poor absorption, ri-faximin is not distributed at a systemic level but undergoes a first pass removal by the liv-er and its behaviour is like rifamycin SV, which does not show any systemic absorp-tion, remaining in the enterohepatic circula-tion, and being subsequently almost totally excreted in faeces.Rifaximin has been used successfully in the treatment of hepatic encephalopathy, acute in-fectious diarrheal disease, preparation for colonic and biliary surgery and diverticulitis22-25. Because of its broad spectrum and its mainly topical activity, we recently conducted a pilot placebo-controlled study in a group of patients with severe UC refractory to steroid treatment using rifaximin as an adjunct to standard steroid treatment.Fourteen patients received rifaximin (800 mg/day) and 14 received an identical placebo. Overall nine patients (64.3%) receiving rifax-imin and five (41.7%) (p NS) receiving place-bo showed a positive response to the treat-ment, as defined by an improvement of the disease’s clinical activity from baseline to the l0th day, and tapered steroids gradually. Moreover rifaximin determined a significant reduction in stool frequency (p<0.02), rectal bleeding (p<0.05) and sigmoidoscopic score (p<0.01) compared with placebo. Twelve hours after the last dose of rifaximin, it was not possible to identify the drug in any of the plasma samples (2 ng/mL was the detection limit of the analytical method). The total amount of rifaximin excretion in 24-hrs urine after 10 days was 64,617.14 ±20,976.57 ng/mL (mean±SEM)26. These findings suggest that rifaximin may be useful in patients with steroid refractory UC. More recently we uti-lized rifaximin (1 g b.d.) in association with ciprofloxacin (500 mg b.d.), given for 15 days, in patients with chronic, antibiotic-resistant pouchitis. Eighteen patients, who failed to re-spond to metronidazole as well as to other commonly used treatments for pouchitis, en-tered the study. Sixteen of 18 treated patients (88.8%) either improved (n=10) or went into remission (n=6), with a decrease of the medi-an Pouchitis Disease Activity Index (PDAI) score from 12 (range 8-17) to 4 (range 0-16). Pharmacokinetic study of rifaximin showed the absence of the drug in any at the plasma samples 12 hrs after from the last dose, and the presence of negligible levels of the un-changed active principle in 24 hrs urine sam-ples. These data further confirm the absence of systemic bioavailability of the drug even when administered at very high dosage (2 g/day) and for a prolonged period27.It is possible to conclude that rifaximin may be useful in treatment of ulcerative coli-tis and pouchitis; its absorption through in-flamed mucosa is negligible as in normal mu-cosa. The drug maintains a topical action without systemic effects. 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