[Functional abdominal pain]

Functional abdominal pain is an inhomogeneous group of disorders concerning aetiology and clinical presentation. Support for classification is provided by the ROME-Foundation with its criteria catalogue, ROME-III being the most recent one. However, basic approach consists of exclusion of somatic or psychiatric as well as psychosomatic disorders that are sharply defined and readily diagnosable. This article outlines a pragmatic gastroenterological approach by exemplary means of dyspepsia and irritable bowel syndrome. Dyspepsia includes a broad complex of mainly epigastric located symptoms, whereas irritable bowel syndrome is symptomatic with altered bowel habits and mid-abdominal pain in the majority. Gastreoenterologic therapy modalities are mainly based on empirical and symptomatic grounds, more than on precisely explaining pathophysioligic understanding.

Severity of mucosal inflammation as a predictor for alterations of visceral sensory function in a rat model

Transient inflammation is known to alter visceral sensory function and frequently precede the onset of symptoms in a subgroup of patients with irritable bowel syndrome (IBS). Duration and severity of the initial inflammatory stimulus appear to be risk factors for the manifestation of symptoms. Therefore, we aimed to characterize dose-dependent effects of trinitrobenzenesulfonic acid (TNBS)/ethanol on: (1) colonic mucosa, (2) cytokine release and (3) visceral sensory function in a rat model. Acute inflammation was induced in male Lewis rats by single administration of various doses of TNBS/ethanol (total of 0.8, 0.4 or 0.2 ml) in test animals or saline in controls. Assessment of visceromotor response (VMR) to colorectal distensions, histological evaluation of severity of inflammation, and measurement of pro-inflammatory cytokine levels (IL-2, IL-6) using enzyme-linked immunosorbent assay (ELISA) were performed 2h and 3, 14, 28, 31 and 42 days after induction. Increased serum IL-2 and IL-6 levels were evident prior to mucosal lesions 2h after induction of colitis and persist up to 14 days (p<0.05 vs. saline), although no histological signs of inflammation were detected at 14 days. In the acute phase, VMR was only significantly increased after 0.8 ml and 0.4 ml TNBS/ethanol (p<0.05 vs. saline). After 28 days, distension-evoked responses were persistently elevated (p<0.05 vs. saline) in 0.8 and 0.4 ml TNBS/ethanol-treated rats. In 0.2 ml TNBS/ethanol group, VMR was only enhanced after repeated visceral stimulation. Visceral hyperalgesia occurs after a transient colitis. However, even a mild acute but asymptomatic colitis can induce long-lasting visceral hyperalgesia in the presence of additional stimuli.

Antibodies to flagellin indicate reactivity to bacterial antigens in IBS patients

One of the several possible causes of irritable bowel syndrome (IBS) is thought to be low-grade mucosal inflammation. Flagellin, the primary structural component of bacterial flagellae, was shown in inflammatory bowel disease patients to activate the innate and adaptive immunity. It has not yet been conclusively established if IBS patients show reactivity to luminal antigens. In 266 patients [112 IBS, 61 Crohn's disease (CD), 50 ulcerative colitis (UC) and 43 healthy controls (HC)], we measured antibodies to flagellin (FAB, types A4-Fla2 and Fla-X), anti-Saccharomyces cerevisiae antibodies (ASCA) (both ELISA), antipancreas antibodies (PAB) and perinuclear antineutrophil cytoplasmatic antibodies (p-ANCA) (both IF). All IBS patients had normal fecal calprotectin (mean 21 microg mL(-1), SD 6.6) and fulfilled the ROME II criteria. Frequencies of antibodies in patients with IBS, CD, UC and HC, respectively, are as follows (in per cent): antibodies against A4-Fla2: 29/48/8/7; antibodies against Fla-X: 26/52/10/7; ASCA: 6/59/0/2; p-ANCA: 0/10/52/0; and PAB: 0/28/0/0. Antibodies against A4-Fla2 and Fla-X were significantly more frequent in IBS patients than in HC (P = 0.004 and P = 0.009). Antibodies to A4-Fla2 and Fla-X were significantly more frequent in IBS patients with antecedent gastroenteritis compared to non-postinfectious IBS patients (P = 0.002 and P = 0.012). In contrast to ASCA, PAB and p-ANCA, antibodies against A4-Fla2 and Fla-X were found significantly more often in IBS patients, particularly in those with postinfectious IBS, compared to HC. This observation supports the concept that immune reactivity to luminal antigens has a putative role in the development of IBS, at least in a subset of patients.

Persisting abdominal symptoms after travelers' diarrhea: Is there a genetic predisposition?

Functional gastrointestinal disorders (FGIDs) are defined as ailments of the mid or lower gastrointestinal tract which are not attributable to any discernable anatomic or biochemical defects.1 FGIDs include functional bowel disorders, also known as persisting abdominal symptoms (PAS). Irritable bowel syndrome (IBS) is one of the most common illnesses classified under PAS.2,3 This is the first prospective study that looks at the etiology and pathogenesis of post-infectious PAS in the context of environmental exposure and genetic susceptibility in a cohort of US travelers to Mexico. Our objective was to identify infectious, genetic and environmental factors that predispose to post infectious PAS. ^ Methods. This is a secondary data analysis of a prospective study on a cohort of 704 healthy North American tourists to Cuernavaca, Morelos and Guadalajara, Jalisco in Mexico. The subjects at risk for Travelers' diarrhea were assessed for chronic abdominal symptoms on enrollment and six months after the return to the US. ^ Outcomes. PAS was defined as disturbances of mid and lower gastrointestinal system without any known pathological or radiological abnormalities, or infectious, or metabolic causes. It refers to functional bowel disease, category C of functional gastrointestinal diseases as defined by the Rome II criterion. PAS was sub classified into Irritable bowel syndrome (IBS) and functional abdominal disease (FAD). ^ IBS is defined as recurrent abdominal pain or discomfort present at least 25% and associated with improvement with defecation, change in frequency and form of stool. FAD encompasses other abdominal symptoms of chronic nature that do not meet the criteria for IBS. It includes functional diarrhea, functional constipation, functional bloating: and unspecified bowel symptoms. ^ Results. Among the 704 travelers studied, there were 202 cases of PAS. The PAS cases included 175 cases of FAD and 27 cases of IBS. PAS was more frequent among subjects who developed traveler's diarrhea in Mexico compared to travelers who remained healthy during the short term visit to Mexico (52 vs. 38; OR = 1.8; CI, 1.3–2.5, P < 0.001). A statistically significant difference was noted in the mean age of subjects with PAS compared to healthy controls (28 vs. 34 yrs; OR = 0.97, CI, 0.95–0.98; P < 0.001). Travelers who experienced multiple episodes, a later onset of diarrhea in Mexico and passed greater numbers of unformed stools were more likely to be identified in PAS group at six months. Participants who developed TD caused by enterotoxigenic E.coli in Mexico showed a 2.6 times higher risk of developing FAD (P = 0.003). Infection with Providencia ssp. also demonstrated a greater risk to developing PAS. Subjects who sought treatment for diarrhea while in Mexico also displayed a significantly lower frequency of IBS at six months follow up (OR = 0.30; CI, 0.10–0.80; P = 0.02). ^ Forty six SNPs belonging to 14 genes were studied. Seven SNPs were associated with PAS at 6 months. These included four SNPs from the Caspase Recruitment Domain-Containing Protein 15 gene (CARD15), two SNPs from Surfactant Pulmonary-Associated Protein D gene (SFTPD) and one from Decay-Accelerating Factor For Complement gene (CD55). A genetic risk score (GRS) was composed based on the 7 SNPs that showed significant association with PAS. A 20% greater risk for PAS was noted for every unit increase in GRS. The risk increased by 30% for IBS. The mean GRS was high for IBS (2.2) and PAS (1.1) compared to healthy controls (0.51). These data suggests a role for these genetic polymorphisms in defining the susceptibility to PAS. ^ Conclusions. The study allows us to identify individuals at risk for developing post infectious IBS (PI-IBS) and persisting abdominal symptoms after an episode of TD. The observations in this study will be of use in developing measures to prevent and treat post-infectious irritable bowel syndrome among travelers including pre-travel counseling, the use of vaccines, antibiotic prophylaxis or the initiation of early antimicrobial therapy. This study also provides insights into the pathogenesis of post infectious PAS and IBS. (Abstract shortened by UMI.)^

Long-term gastrointestinal complications of Clostridium difficile associated diarrhea (CDAD)

Background. The incidence of Clostridium difficile -associated diarrhea (CDAD) is increasing worldwide likely because of increased use of broad spectrum antibiotics and the introduction of a clonal hyper-virulent strain called the BI strain. Short-term complications of CDAD include recurrent disease, requirement for colectomy, and persistent disease. However, data on the long-term consequences of CDAD are scarce. Among other infectious diseases (Shigella, Salmonella, and Campylobacter), long-term consequences such as irritable bowel syndrome (IBS), chronic dyspepsia/diarrhea, and other GI effects have been noted. Since the mechanism of action of these agents is similar to C.difficile, we hypothesized that patients with CDAD have greater likelihood of developing IBS and other functional gastrointestinal disorders (FGIDs) in the long-term as compared to a general sample of recently hospitalized patients. ^ Objective. To evaluate the long-term gastrointestinal complications of CDAD, (IBS, functional diarrhea, functional abdominal bloating, functional constipation and functional abdominal pain syndrome). ^ Methods. The current study was a secondary analysis of a previously completed observational case-control outcome study. Adult CDAD patients at St. Luke's Episcopal Hospital, Houston (SLEH) were followed up and interviewed by telephone six months after the initial diagnosis thereafter evaluated for the development of IBS and other FGIDs. A total of 46 patients with CDAD infection were recruited at SLEH between May-November 2007. The comparators were patients hospitalized in SLEH within one month before or after the admission of the reference case, hospital length of stay within one week longer or shorter than reference case, and age within 10 years more or less than the reference case. Cases and comparators were compared using Fisher's exact test. A p<0.05 was considered significant. ^ Results. Thirty CDAD patients responded to the questionnaires and were compared to 40 comparators. No comparator developed a FGID, while 3 (10%) CDAD patients developed new onset IBS (p=0.07), 4 (13.3%) developed new onset Functional Diarrhea (p=0.03), and 3 (10%) developed new onset Functional Constipation (p=0.07). No patient developed Functional Abdominal Bloating and Functional Abdominal Pain Syndrome. ^ Conclusion. In this study, new onset functional diarrhea was significantly more common in patients CDAD within six months after initial infection compared to matched controls.^

The impact of antibiotic associated diarrhea on health related quality of life in hospitalized patients

Objective. To determine the impact of antibiotic associated diarrhea (AAD) on health related quality of life (HRQOL) in hospitalized patients compared to matched controls without diarrhea. ^ Methods. This is a hospital-based, matched case-control study using secondary data from a prospective cohort trial of patients receiving broad-spectrum antibiotics. One hundred and seventy-eight patients were recruited of whom 18 (10%) reported having antibiotic associated diarrhea. Two non-diarrhea controls were selected for each case with diarrhea giving a final sample of 18 cases and 36 controls. Responses from Short Form (SF) 36 questionnaire were aggregated into eight domains including physical functioning (PF), role-functioning physical (RP), bodily pain (BP), general health (GH), social functioning (SF), vitality (VT), role-functioning emotional (RE), and mental health (MH). The eight domains were compared between cases and controls. A GI targeted HRQOL measure was administered to 13 patients with AAD. Responses from the disease-specific instrument were combined in eight subscale scores: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sex, and relationships. ^ Results. The sample consisted of 41 females (75.9%) and 13 males (24.1%) aged 53.5 ± 14.4 years (range: 21-76 years). Twenty five patients (46%) were Caucasian, 15 (27%) were African American, 13(24%) were Hispanic and 1(2%) was Asian. In univariate analysis, no significant differences in quality of life outcomes were observed in each of the SF36 domains between the case patients and matched controls. There were trends for decreased scores on the role-functioning physical, bodily pain, general health, social functioning, mental health, and mental summary domains. In total, 7 of 8 domain scores were lower in patients with AAD and 5 of 8 domain scores were lower by more than 5 points (considered clinically significant). Controlling for age, patients with antibiotic associated diarrhea had significantly lower general health, vitality, and mental health scale scores (p<0.05 each). The disease-specific scores were significantly lower in patients with AAD than those in published norms for irritable bowel syndrome patients. ^ Conclusion. In this small sample, several areas of decreased QOL in patients with AAD compared to matched controls were noted. A larger sample size to validate these results is necessary.^

Susceptibility to travelers' diarrhea and histo-blood group antigens

Histo-blood group antigens (HBGAs) have been associated with susceptibility to enteric pathogens including noroviruses (NoVs), enterotoxigenic Escherichia coli (ETEC), Campylobacter jejuni, and Vibrio cholerae. We performed a retrospective cohort study to evaluate the relationship between traveler HBGA phenotypes and susceptibility to travelers' diarrhea (TD) and post-infectious complications. 364 travelers to Guadalajara, Mexico were followed prospectively from June 1 - September 30, 2007 and from June 7–July 28, 2008 for the development of TD and at 6 months for post-infectious irritable bowel syndrome (PIIBS). Noroviruses were detected from illness stool specimens with RT-PCR. Diarrheal stool samples were also assayed for enterotoxigenic and enteroaggregative E. coli, Salmonella species, Shigella species, Vibrio species, Campylobacter jejuni, Yersinia enterocolitica, Aeromonas species, and Plesiomonas species. Diarrheal stools were evaluated for inflammation with fecal leukocytes, mucus, and occult blood. Phenotyping for ABO and Lewis antigens with an ELISA assay and FUT2 gene PCR genotyping for secretor status were performed with saliva. 171 of 364 (47%) subjects developed TD. HBGA typing for the travelers revealed O (62.9%), A (34.6%), B (1.6%), and AB (0.8%) phenotypes. There were 7% nonsecretors and 93% secretors among the travelers. AB phenotypes were more commonly associated with Cryptosporidium species (P=0.04) and ETEC ( P=0.08) as causes of TD. AB and B phenotype individuals were more likely to experience inflammatory diarrhea, particularly mucoid diarrhea ( P=0.02). However, there were relatively few individuals with AB and B phenotypes. GI and GII NoV and Cryptosporidium species infections and PI-IBS were identified only in secretors, but these differences were not statistically significant, (P=1.00), (P=1.00), and (P=0.60), respectively. Additional studies are needed to evaluate whether AB phenotype individuals may be more susceptible to developing TD associated with Cryptosporidium species or ETEC, and whether AB and B phenotype individuals may be more likely to develop inflammatory TD. Further studies are needed to investigate whether nonsecretor travelers may be at less risk for developing infections with NoVs and Cryptosporidium species and PI-IBS.^

Special issue : The Human Intestinal Microbiota

Peer reviewed

Genome analysis and characterisation of the exopolysaccharide produced by Bifidobacterium longum subsp. longum 35624™

The Bifibobacterium longum subsp. longum 35624™ strain (formerly named Bifidobacterium longum subsp. infantis) is a well described probiotic with clinical efficacy in Irritable Bowel Syndrome clinical trials and induces immunoregulatory effects in mice and in humans. This paper presents (a) the genome sequence of the organism allowing the assignment to its correct subspeciation longum; (b) a comparative genome assessment with other B. longum strains and (c) the molecular structure of the 35624 exopolysaccharide (EPS624). Comparative genome analysis of the 35624 strain with other B. longum strains determined that the sub-speciation of the strain is longum and revealed the presence of a 35624-specific gene cluster, predicted to encode the biosynthetic machinery for EPS624. Following isolation and acid treatment of the EPS, its chemical structure was determined using gas and liquid chromatography for sugar constituent and linkage analysis, electrospray and matrix assisted laser desorption ionization mass spectrometry for sequencing and NMR. The EPS consists of a branched hexasaccharide repeating unit containing two galactose and two glucose moieties, galacturonic acid and the unusual sugar 6-deoxy-L-talose. These data demonstrate that the B. longum 35624 strain has specific genetic features, one of which leads to the generation of a characteristic exopolysaccharide.

Peptide Therapeutics and the Pharmaceutical Industry: Barriers Encountered Translating from the Laboratory to Patients

Peptides are receiving increasing interest as clinical therapeutics. These highly tunable molecules can be tailored to biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. Despite challenges regarding up-scaling and licensing of peptide products, their vast clinical potential is reflected in the 60 plus peptide-based therapeutics already on the market, and the further 500 derivatives currently in developmental stages. Peptides are proving effective for a multitude of disease states including: type 2 diabetes (controlled using the licensed glucagon-like peptide-1 receptor liraglutide); irritable bowel syndrome managed with linaclotide (currently at approval stages); acromegaly (treated with octapeptide somostatin analogues lanreotide and octreotide); selective or broad spectrum microbicidal agents such as the Gram-positive selective PTP-7 and antifungal heliomicin; anticancer agents including goserelin used as either adjuvant or for prostate and breast cancer,and the first marketed peptide derived vaccine against prostate cancer, sipuleucel-T. Research is also focusing on improving the biostability of peptides. This is achieved through a number of mechanisms ranging from replacement of naturally occurring L-amino acid enantiomers with D-amino acid forms, lipidation, peptidomimetics, N-methylation, cyclization and exploitation of carrier systems. The development of self-assembling peptides are paving the way for sustained release peptide formulations and already two such licensed examples exist, lanreotide and octreotide. The versatility and tunability of peptide-based products is resulting in increased translation of peptide therapies, however significant challenges remain with regard to their wider implementation. This review highlights some of the notable peptide therapeutics discovered to date and the difficulties encountered by the pharmaceutica lindustry in translating these molecules to the clinical setting for patient benefit, providing some possible solutions to the most challenging barriers. 

Diet therapy with fodmaps restriction has benefits in fibromyalgia

The effects of a diet restriction in FODMAPs (Fermentable oligo-di-monosaccharides polyols) is being studied on the symptoms of Fibromyalgia (FM) and its impact on quality of life (QOL) besides the effect on gastrointestinal (GI) symptoms. High prevalence of functional GI disorders is found in FM and Low FODMAP Diet has growing scientific evidence as IBS (Irritable Bowel Syndrome) therapy.

Implication of gut microbiota in nonalcoholic fatty liver disease

International audience

Management of the clinical issue of constipation with abdominal complaints in adults: a national survey of Primary Care physicians and gastroenterologists

Irritable bowel syndrome and functional constipation represent a relevant and common health issue. However, real-world clinical practice includes patients with constipation who may or may not have other abdominal complaints (pain, bloating, abdominal discomfort) with variable frequency. The goal of the present study was to obtain information on the workload entailed by patients with constipation and associated abdominal complaints, predominant clinical behaviors, education needs, and potential daily practice aids both in Primary Care and gastroenterology settings. The clinical behavior of doctors is generally similar at both levels, despite differences in healthcare approach: use of empiric therapies and clinically guided diagnostic tests, with some differences in colonoscopy use (not always directly accessible from Primary Care). Regarding perceptions, general support and osmotic laxatives are most valued by PC doctors, whereas osmotic laxatives, combined laxatives, and linaclotide are most valued by GE specialists. Furthermore, over half of respondents considered differentiating both diagnoses as challenging. Finally, considerable education needs are self-acknowledged at both levels, as is a demand for guidelines and protocols to help in managing this issue in clinical practice. A strength of this study is its providing a joint photograph of the medical approach and the perceptions of constipation with abdominal discomfort from a medical standpoint. Weaknesses include self-declaration (no formal validation) and a response rate potentially biased by professional motivation.