Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bo

[kiny]

http://gut.bmj.com/content/early/2012/09/18/gutjnl-2012-302578.short?g=w_gut_ahead_tab

Connecting dysbiosis, bile-acid dysmetabolism and gut inflammation in inflammatory bowel diseases

Service de Gastroentérologie et Nutrition, Hôpital St-Antoine, 184 rue du Faubourg St-Antoine, 75571 Paris Cedex 12, France

Published Online First 19 September 2012


Henri Duboc Sylvie Rajca1,2,3, Dominique Rainteau1,2,4, David Benarous5,
Marie-Anne Maubert1,2,4, Elodie Quervain1,2, Ginette Thomas1,2,4, Véronique Barbu4, Lydie Humbert1,2,4, Guillaume Despras2, Chantal Bridonneau6, Fabien Dumetz6, Jean-Pierre Grill1,2, Joëlle Masliah1,2,4, Laurent Beaugerie1,2,3, Jacques Cosnes1,2,3, Olivier Chazouillères7, Raoul Poupon7, Claude Wolf1, Jean-Maurice Mallet2, Philippe Langella6, Germain Trugnan1,2,4, Harry Sokol1,2,3, Philippe Seksik1,2,3



Abstract

Objective Gut microbiota metabolises bile acids (BA). As dysbiosis has been reported in inflammatory bowel diseases (IBD), we aim to investigate the impact of IBD-associated dysbiosis on BA metabolism and its influence on the epithelial cell inflammation response.

Design Faecal and serum BA rates, expressed as a proportion of total BA, were assessed by high-performance liquid chromatography tandem mass spectrometry in colonic IBD patients (42) and healthy subjects (29). The faecal microbiota composition was assessed by quantitative real-time PCR. Using BA profiles and microbiota composition, cluster formation between groups was generated by ranking models. The faecal BA profiles in germ-free and conventional mice were compared. Direct enzymatic activities of BA biotransformation were measured in faeces. The impact of BA on the inflammatory response was investigated in vitro using Caco-2 cells stimulated by IL-1β.

Results IBD-associated dysbiosis was characterised by a decrease in the ratio between Faecalibacterium prausntizii and Escherichia coli. Faecal-conjugated BA rates were significantly higher in active IBD, whereas, secondary BA rates were significantly lower. Interestingly, active IBD patients exhibited higher levels of faecal 3-OH-sulphated BA. The deconjugation, transformation and desulphation activities of the microbiota were impaired in IBD patients. In vitro, secondary BA exerted anti-inflammatory effects, but sulphation of secondary BAs abolished their anti-inflammatory properties.

Conclusions Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.

 

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correspondence



Dysbiosis modulates capacity for bile acid modification in the gut microbiomes of patients with inflammatory bowel disease: a mechanism and marker of disease?

Lesley A Ogilvie,
Brian V Jones



Centre for Biomedical and Health Science Research, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK

Correspondence to Dr Brian V Jones, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, UK; [email protected]

Contributors LAO and BVJ conceived the study, analysed the data and wrote the article.


The recently published article by Gadaleta and co-workers1 has demonstrated that activation of the bile acid (BA) nuclear receptor, Farnesoid X receptor α (FXR), affords multi-level protection against intestinal inflammation and inflammatory bowel disease (IBD) in mice. Of the numerous avenues of research into IBD diagnosis and treatment that are opened by these findings, the questions posed by Gadaleta and co-workers regarding the contribution of gut bacteria to FXR modulation and aetiology of IBD are of particular significance.

Bacteria resident in the human gastrointestinal tract collectively encode a distributed pathway of BA modification, the products of which are the natural ligands for FXR,2 and there is growing appreciation that this may be a key activity through which the gut microbiota integrates factors relating to diet and mucosal inflammation, to initiate or exacerbate disease.3 These modified BAs display altered binding profiles for BA receptors, with several secondary BAs being among the most potent agonists. Moreover, microbial transformation could also influence BA bioavailability for receptor binding.2 In conjunction with the protective role of FXR activation described by Gadaleta and co-workers,1 it is logical to hypothesise that the dysbiosis of the gut microbiota characteristic of IBD may alter capacity for BA modification in this community. In turn, such functional shifts may perturb BA-associated regulation of mucosal inflammatory processes, via alterations in FXR-mediated signalling.

To determine whether the capacity for BA modification is altered in the gut microbiomes of IBD patients, we embarked on an in silico analysis to determine the relative abundance of bile salt hydrolases (BSHs) in the gut microbiomes of IBD patients compared with healthy controls. Since BSH catalyses the ‘gateway’ reaction in microbial BA modification,4 the relative abundance of this function should be indicative of the capacity for BA modification in the gut microbiome.5

The amino acid sequences of 24 functional BSH ‘types’ were used to search human gut metagenomes constituting the MetaHIT (Metagenomics of the Human Intestinal Tract) dataset,6 which comprises the gut microbiomes of 124 individuals of varying disease status (99 healthy, 21 ulcerative colitis, 4 Crohn's disease). Sequences in the MetaHIT dataset producing valid hits (tBlastn: minimum 35% identity ≥50 amino acids, 1e−5) to these functional BSH types were retrieved, and encoded BSH-like homologues were affiliated with a phylogenetic division based on top hits (by bit-score) from subsequent BlastX searches of the non-redundant dataset. Affiliated hits were then used to construct non-redundant BSH relative abundance profiles for major phylogenetic divisions in the human gut microbiota (figure 1), as previously described.5

Figure 1

Bile salt hydrolase (BSH) relative abundance profiles for major phylogenetic divisions in the human gut microbiota. ACT, Actinobacteria; BACT, Bacteroidetes; FIRM, Firmicutes; TOTAL, BSH-like relative abundance in complete MetaHIT dataset regardless of phylogenetic affiliation. ALL MH, complete MetaHIT dataset, HEALTHY, healthy individuals only, UC, individuals with ulcerative colitis only, CD, individuals with Crohn's disease only. Error bars indicate SEM. Level of significance in χ2 distribution analysis: *p<0.01, **p<0.001. Inset table shows relative abundance, within complete MH dataset, for other phylogenetic divisions with which BSH-like homologues were affiliated. Brackets denote SEM.


he majority of BSH-like sequences identified were affiliated with the Firmicutes division followed by the Bacteroidetes and Actinobacteria, and their general distribution between divisions was congruent with the overall composition of the human gut microbiome.6 However, we observed distinct alterations in total and division-specific BSH relative abundance in individuals diagnosed with Crohn's disease (CD) and ulcerative colitis (UC), compared with healthy individuals (figure 1). Most notable were alterations in the CD group, where BSH relative abundance was significantly reduced in the Firmicutes affiliated sequences, but no significant alterations were observed in Bacteroidetes and Actinobacteria affiliated sequences. In addition to a reduction in total BSH relative abundance, the intestinal BA metabolic profile is also likely to be altered due to distinct differences in substrate ranges of BSH originating in the Bacteroidetes compared with Firmicutes and Actinobacteria.5



Overall, this initial in silico analysis provides evidence that shifts in population structure associated with IBD perturb functions of the gut microbiome involved in FXR-mediated signalling. In tandem with the work of Gadaleta and co-workers,1 this supports the hypothesis that variations in the capacity for BA modification in the gut microbiome may be a significant factor in the onset or progression of IBD. When considered against the host genetic background of immune dysregulation, believed to be key to IBD initiation, even small perturbations in systems controlling mucosal immune responses could be important in helping sustain the inappropriate inflammatory response that results in tissue damage. If so, this opens exciting possibilities for disease treatment, prophylaxis and diagnosis. Larger, more detailed studies should now be undertaken to confirm these initial observations, and explore the potential for manipulating and exploiting this facet of host–microbe interaction in the human gut.

 

[kiny]

Mentioned Faecalibacterium prausntizii many times, it disappears in many people with crohn's disease, but it's in no probiotic. After me and someoen for me talked to labs why, it's because first it wasn't easy to find it, second it's a bacteria that doesn't survive air, but most of all the reason now is that probiotics are considered medication, not food, and to get Faecalibacterium prausntizii approved for crohn is going to take a lot of money.

Also would like to ask authors if OmpC immunoglobulin reaction is related to dysbiosis, but had not much time.