Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti-inflammatory effect both in vitro and in vivo. However, ...the chemical nature of the anti-inflammatory compounds has not yet been determined.
Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Anti-inflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice.
The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-κB pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS-induced colitis in mice.
A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-κB pathway in intestinal epithelial cells and to prevent colitis in an animal model.
Preventing postoperative recurrence after ileocolonic resection (ICR) for Crohn's disease (CD) is challenging. Defining the disturbances of the microbial composition and community structure after ICR ...and their link with early disease recurrence is crucial.
Microbiota composition (fingerprinting and 16S rDNA sequencing) and community structure (correlation networks of bacterial species) were assessed from ileal mucosa sampled in 20 patients undergoing ICR and 6 months later during endoscopy from above (neoterminal ileum) and below (subanastomotic colon) the surgical anastomosis.
ICR had a dramatic effect on gut microbial ecosystem. At surgery, CD mucosa harboured a dysbiotic microbiota with high proportions of α/β Proteobacteria and Bacilli. Six months later, half of the patients had recurrent lesions at ileocolonoscopy and presented higher numbers of Lachnospiraceae. Recurrence of endoscopic lesions was associated with enrichment in Enterococcus durans while patients in remission had increased proportions of Dorea longicatena and Bacteroides plebeius. Structural differences were striking between recurrence and remission microbiota; while the microbiota of patients with CD recurrence exhibited a loose community structure, the microbiota of patients in remission displayed communities that were robustly correlated to each other. Microbiota colonising the neoterminal ileum and subanastomotic colon 6 months after ICR only differed in patients with recurrence.
ICR modifies the gut microbiome. Remission after 6 months was associated with homogenous bacterial distribution around the anastomosis. Community structure and bacterial networks highlight target species, including Faecalibacterium prausnitzii and Ruminococcus gnavus, which may allow precise modulations of the overall microbial ecosystem towards remission pattern.
Background
Irritable bowel syndrome (IBS) physiopathology is multifactorial and roles for both microbiota and bile acid (BA) modifications have been proposed. We investigated role of dysbiosis, ...transit pattern and BA metabolism in IBS.
Methods
Clinical data, serum, and stool samples were collected in 15 healthy subjects (HS), 16 diarrhea‐predominant (IBS‐D) and 15 constipation‐predominant IBS (IBS‐C). Fecal microbiota composition was analyzed by real‐time PCR. Sera and fecal BA profiles, 7α‐C4 levels, and in vitro BA transformation activity by fecal microbiota were measured by mass spectrometry. Serum Fibroblast Growth Factor 19 (FGF19) was assayed by ELISA.
Keys Results
Dysbiosis was present in IBS patients with an increase in Escherichia coli in IBS‐D patients (p = 0.03), and an increase in Bacteroides (p = 0.01) and Bifidobacterium (p = 0.04) in IBS‐C patients. Sera primary and amino‐conjugated BA were increased in IBS‐D (63.5 ± 5.5%, p = 0.01 and 78.9 ± 6.3%, p = 0.03) and IBS‐C patients (55.9 ± 5.5%, p = 0.04 and 65.3 ± 6.5%, p = 0.005) compared to HS (37.0 ± 5.8% and 56.7 ± 8.1%). Serum 7α‐C4 and FGF19 levels were not different among all three groups. Fecal primary BA were increased in IBS‐D patients compared to HS, including chenodeoxycholic acid which has laxative properties (25.6 ± 8.5% vs 3.5 ± 0.6%, p = 0.005). Bile acid deconjugation activity was decreased in IBS‐D (p = 0.0001) and IBS‐C (p = 0.003) feces. Abdominal pain was positively correlated with serum (R = 0.635, p < 0.001) and fecal (R = 0.391, p = 0.024) primary BA.
Conclusions & Inferences
Different sera and fecal BA profiles in IBS patients could be secondary to dysbiosis and further differences between IBS‐C and IBS‐D could explain stool patterns. This study opens new fields in IBS physiopathology and suggests that modification of BA profiles could have therapeutic potential.
We demonstrated that in comparison to healthy subjects, IBS patients have different serum and fecal bile acid profiles that could be secondary to dysbiosis and altered metabolic functions. We also observed variation in bile acid profiles between IBS‐C and IBS‐D patients, which may explain differences in stool patterns. Bile acid profiles were also correlated with abdominal pain.
Summary
Background
Consequences of latent cytomegalovirus (CMV) infection reactivation on inflammatory bowel disease (IBD) flare, as a flare‐worsening factor or simple bystander, are debated. Impact ...of anti‐viral treatment on IBD course is poorly known.
Aim
To assess the impact of CMV reactivation on patients hospitalised for IBD flare and the effect of anti‐viral treatment on IBD flare in patients with CMV reactivation.
Methods
First, a population of UC patients from Saint‐Antoine hospital, in flare with positive blood CMV PCR without anti‐viral treatment (n = 26), were compared to matched patients with negative blood CMV PCR in a case–control study. Secondly, a total of 110 hospitalisations between October 2003 and May 2012 for IBD flare‐up with CMV reactivation (80 diagnosed on blood PCR, 33 on tissue PCR) were identified in three French referral centres. Evolution following CMV reactivation diagnosis was compared between patients receiving anti‐viral treatment and those who did not.
Results
In the case–control study, no differences were observed between the two groups regarding length of hospital stay and colectomy rate. Comparing treated and untreated patients, no differences were observed at inclusion regarding age, gender, IBD type, immunosuppressant, CRP and haemoglobin level. No differences were observed regarding CRP level decrease at 10 days and colectomy rate at 3 months. Anti‐viral treatment was associated with lower serum albumin level at inclusion and longer hospitalisation.
Conclusions
CMV reactivation does not appear to alter the course of IBD flare. CMV treatment does not seem to impact the course of IBD. These results should be confirmed prospectively.
Summary
Background
Recently, a new enteropathy has been described: olmesartan‐associated enteropathy. However, the association has been questioned: a phase 3 trial and a cohort study found no ...association between gastrointestinal events and olmesartan.
Aim
To collect French cases of sartan‐associated enteropathy to describe further this entity, confirm or refute causality, and determine if the association exists with other sartans.
Methods
French gastroenterologists were invited to report cases of sartan‐associated enteropathy and collect clinical, biological and histological data. Patients with diarrhoea and histological duodenal abnormalities were included.
Results
Thirty‐six patients with olmesartan‐associated enteropathy were reported, including 32 with villous atrophy and four without. There was only one patient with irbesartan‐associated enteropathy. None of the patients died. Patients with villous atrophy had diarrhoea, vomiting, renal failure, hypokalaemia, body weight loss and hypoalbuminaemia. Thirty‐one patients were hospitalised; four required intensive care. Anti‐transglutaminase and anti‐enterocyte antibodies were negative; anti‐nuclear antibodies were positive (9/11). Endoscopic duodenal biopsies showed villous atrophy (32/32) and polyclonal intra‐epithelial CD3+CD8+ lymphocytosis (11/11). Exactly, 14/15 patients responded to steroids and/or immunosuppressants, prescribed because of suspected autoimmune enteropathy. Ten olmesartan interruptions were followed by reintroductions before steroids or immunosuppressants. Interruptions were followed by remissions (9/10), but reintroductions were followed by relapses (9/9). Twenty‐nine patients were in remission since olmesartan interruption, including 26 without immunosuppressants. Patients with normal villi had similar clinical characteristics, but mild histological abnormalities (intra‐epithelial lymphocytosis and lamina propria lymphocytic infiltration).
Conclusions
Olmesartan causes a severe and immune‐mediated enteropathy, with or without villous atrophy. Enteropathy associated with other sartans seems to be very rare.
Background Irritable bowel syndrome (IBS) is a multifactorial disease for which a dysbiosis of the gut microbiota has been described. Bile acids (BA) could play a role as they are endogenous ...laxatives and are metabolized by gut microbiota. We compared fecal BA profiles and microbiota in healthy subjects (HS) and patients with diarrhea‐predominant IBS (IBS‐D), and we searched for an association with symptoms.
Methods Clinical features and stool samples were collected in IBS‐D patients and HS. Fecal BA profiles were generated using HPLC coupled to tandem mass spectrometry. The fecal microbiota composition was assessed by q‐PCR targeting dominant bacterial groups and species implicated in BA transformation.
Key Results Fourteen IBS‐D patients and 18 HS were included. The two groups were comparable in terms of age and sex. The percentage of fecal primary BA was significantly higher in IBS‐D patients than in HS, and it was significantly correlated with stool consistency and frequency. Fecal counts of all bacteria, lactobacillus, coccoides, leptum and Faecalibacterium prausnitzii were similar. There was a significant increase of Escherichia coli and a significant decrease of leptum and bifidobacterium in IBS‐D patients.
Conclusions & Inferences We report an increase of primary BA in the feces of IBS‐D patients compared to HS, correlated with stool consistency and frequency. A dysbiosis of different bacterial groups was detected, some of them involved in BA transformation. As the gut microbiota is the exclusive pathway to transform primary into secondary BA, this suggests a functional consequence of dysbiosis, leading to lower BA transformation.
Summary
We review the evidence that strongly suggests a role of the intestinal microbiota in the onset and perpetuation of inflammatory bowel disease (IBD).
Experimental studies consisted of ...suppressing micro‐organisms from the microbiota (using germ‐free or gnotoxenic animals or antibiotics), introducing new micro‐organisms or microbial components (e.g. probiotics, CpG‐DNA) or selectively increasing some endogenous bacteria (e.g. using prebiotics).
Intervention studies were performed in patients or animal models of spontaneous or chemically‐induced colitis.
Information was also obtained from observational studies that described the composition of the faecal and mucosal microbiota at various stages of the disease process and in controls. Many have used culture‐independent techniques that identify bacteria based on the nucleic acid sequence of ribosomal RNA molecules. Microbiota in patients with IBD seem to be characterized by high concentrations of bacteria in contact with the mucosa, instability, the presence of high numbers of unusual bacteria and sometimes a reduction in the biodiversity.
Studies searching for a generalized or localized dysbiosis in IBD are discussed, as well as those trying to identify bacterial molecules and receptors, which may be implicated in triggering the inflammatory process.
Summary
Background
The comparative efficacy of adalimumab (ADA) and infliximab (IFX) in Crohn's disease, and the benefit of initial combotherapy with an immunomodulator, are debated.
Aim
To assess ...the best anti‐TNF treatment regimens in Crohn's disease.
Methods
We included 906 biologic‐naïve Crohn's disease patients median age, 31 years (24–41) and performed a retrospective analysis of 1284 therapeutic exposures to ADA (n = 521) or IFX (n = 763) between 2006 and 2015. An immunomodulator was associated during the first 4–6 months (initial combotherapy) during 706 therapeutic exposures (55%). Median duration of anti‐TNF therapy was 39 months (IQR 17–67). Primary outcomes were 6‐month and 2‐year response rates and drug survival. Logistic regression with propensity scoring and Cox proportional hazard analysis determined variables associated with outcomes.
Results
The response rates at 6 months and 2 years were 64% and 44% on ADA mono, 86% and 70% on ADA combo, 72% and 45% on IFX mono, and 84% and 68% on IFX combotherapy, respectively. Differences between ADA and IFX were not significant, whereas combotherapy was superior to monotherapy (P < 0.001). Drug survival was longer with combotherapy vs. monotherapy adjusted hazard ratio 2.17 (1.72–2.70) and not significantly different between ADA and IFX. During subsequent anti‐TNF exposures, IFX combotherapy fared better than other groups regarding response rates, drug survival, disease activity, hospitalisations and abdominal surgery.
Conclusion
In this retrospective analysis of a large tertiary centre cohort of Crohn's disease patients, ADA and IFX had similar efficacy as first line treatment, while initial combotherapy with an immunomodulator improved all outcome measures.
Summary
Background
The safety of anti‐tumour necrosis factor (TNF) agents during pregnancy is a major concern for child‐bearing women and physicians.
Aim
To assess the impact of anti‐TNF therapy on ...adverse pregnancy and foetal outcomes in women with inflammatory bowel disease (IBD).
Methods
Pregnancies occurring during anti‐TNF treatment or less than 3 months after its cessation in IBD patients followed in GETAID centres were recorded from January 2009 to December 2010. Ninety‐nine pregnancies in women without anti‐TNF treatment were identified from the CESAME registry. We compared pregnancy and neonatal outcomes by a case–control study.
Results
In the 124 IBD patients followed, 133 pregnancies were reported. At the conception time, 23% of patients had active disease. Eighty‐eight per cent (n = 117) of the 133 pregnancies followed until delivery resulted in 118 liveborns (one twin pregnancy). Complications were observed in 47 (35%) women and 24 (20%) newborns. In multivariate analysis, factors associated with pregnancy complications were: current smoking (P = 0.004), a B2 (stenotic) phenotype in CD women (P = 0.004), occurrence of a flare during pregnancy (P = 0.006) and a past history of complicated pregnancy (P = 0.007). Current smoking was the only factor associated with severe (i.e. potentially lethal) pregnancy complications (P = 0.02). Having IBD for more than 10 years prior to conception was associated with newborn complications (P = 0.007). No difference was found with the control group for any of the pregnancy and neonatal outcomes.
Conclusion
In our series, the safety profile of anti‐TNF therapy during pregnancy and the neonatal period appears similar to control group of IBD women not treated with anti‐TNF therapy.
Previous studies of the endogenous microbiota in patients with ulcerative colitis (UC) have not taken bacterial activity into account, yet bacteria with high transcriptional activity might have a ...more important pathophysiological role than inactive bacteria. We therefore analyzed the biodiversity of active bacteria in the fecal microbiota of UC patients, in comparison with that of healthy subjects. Feces were collected from nine patients with active UC and from nine healthy controls. Total DNA and RNA were extracted, and 16S ribosomal DNA and RNA were amplified by PCR and reverse transcription-PCR, respectively. Amplification products were compared by means of temporal temperature gradient gel electrophoresis (TTGE). Bands of interest were excised, sequenced, and identified by comparison with the GenBank database (NCBI). The dominant-species diversity based on RNA-derived TTGE profiles was significantly lower for UC patients than for healthy controls (P = 0.01). The mean similarity index between the "present" and "active" microbiota was 74% ± 18% for UC patients. Comparison of the individual "active" microbiota identified a band that was present for eight UC patients and only two controls (89% versus 22%; P = 0.008). The band was sequenced for 6 patients and always corresponded to Escherichia coli. The biodiversity of active bacteria in the dominant fecal microbiota of patients with UC is lower than that of healthy subjects. E. coli is more represented in the active microbiota of UC patients. The possible pathophysiological role of this difference remains to be determined.
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