Hydrogen sulfide (H2S), generated through various endogenous enzymatic and non-enzymatic pathways, is emerging as a regulator of physiological and pathological events throughout the body. Bacteria in the gastrointestinal tract also produce significant amounts of H2S that regulates microflora growth and virulence responses. However, the impact of the microbiota on host global H2S bioavailability and metabolism remain unknown. To address this question, we examined H2S bioavailability in its various forms (free, acid labile or bound sulfane sulfur), cystathionine gamma lyase (CSE) activity and cysteine levels in tissues from germ free versus conventionally housed mice. Free H2S levels were significantly reduced in plasma and gastrointestinal tissues of germ free mice. Bound sulfane sulfur levels were decreased by 50–80% in germ free mouse plasma, adipose and lung tissues. Tissue CSE activity was significantly reduced in many organs from germ free mice, whereas tissue cysteine levels were significantly elevated compared to conventional mice. These data reveal that the microbiota profoundly regulates systemic bioavailability and metabolism of H2S.

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BackgroundInorganic nitrate and nitrite have emerged as alternative substrates for nitric oxide (NO) generation in the gastrointestinal tract, and have shown to be protective against drug-induced gastric injury. The aim of this study was to investigate the preventive and therapeutic effects of nitrate and nitrite in a model of experimental colitis.MethodsColitis was induced in mice by administrating dextran sulfate sodium (DSS) with concurrent administration of nitrite (1 mM) or nitrate (10 mM) in the drinking water for 7 days. A therapeutic approach was also investigated by initiating nitrite treatment 3 days after DSS-induced colitis. Clinical and inflammatory markers were assessed and the colonic mucus thickness was measured in vivo. The effect of nitrite on wound healing was evaluated using colon epithelial cells.ResultsConcurrent administration of DSS and nitrite (1 mM) alleviated inflammation as determined by reduced disease activity index score (DAI) and increased colon length, while nitrate (10 mM) only reduced the DAI-score. Nitrite also displayed therapeutic effects by ameliorating established colonic inflammation with reduced colonic expression of iNOS and improving histopathology. DSS-induced decrease in colonic mucus thickness was completely prevented by nitrite administration. In addition, goblet cell abundance was lower by DSS treatment, but was increased by addition of nitrite. Further studies using colon epithelial cells revealed an NO-dependent improvement in wound healing with nitrite administration.ConclusionNitrite exerts both preventive and therapeutic effects in colonic inflammation. The protective effects involve preservation of an intact adherent mucus layer and regulation of epithelial cell restitution.

SCFA are important end products formed during colonic fermentation of dietary fibre (DF). It has been suggested that propionic and butyric acids affect metabolic parameters, low-grade systemic inflammation, insulin resistance and obesity. The aim of the present study was to investigate whether the various SCFA profiles observed after fermentation in the caecum of rats fed pectin, guar gum and fructo-oligosaccharides (FOS) were also represented in hepatic portal and aortic serum. The SCFA in serum were extracted using hollow fibre-supported liquid membrane extraction before GLC analysis. The concentrations of acetic, propionic and butyric acids in caecal content correlated well with those in portal serum (P,0·001) for all the three diets. A weaker correlation was found for propionic and butyric acids between the caecal content and aortic serum (P,0·05). Butyric acid concentration in caecal content was also reflected in the aortic serum (P¼0·019) of rats fed FOS. FOS gave rather low amounts of the SCFA, especially butyric acid, but caecal tissue weight was higher with FOS than with the other two diets. This may be explained by rapid fermentation and quick utilisation/absorption of the SCFA. The present study also showed that propionic acid was metabolised/utilised to a higher extent than butyric acid by colonocytes before reaching the liver. We conclude that the formation of propionic and butyric acids in the caecum is reflected by increased concentrations in the aortic blood. This approach may therefore simplify the evaluation and study of SCFA from DF in human subjects.

A central event in inflammatory bowel disease is the disruption of the mucosal homeostasis. Trefoil peptides [(TFF)] are emerging as key mediators in the defense and repair of the gastrointestinal mucosa. Here, we demonstrate induction of TFF by CLA with therapeutic antiinflammatory effects in a mouse model of inflammatory bowel disease. SW480 cells were treated with linoleic acid or CLA (0-2.5 μmol/L) in the absence or presence of the PPARγ inhibitor GW9662. Cells treated with CLA showed an upregulation of the intestinal trefoil factor, which was prevented by pretreatment with GW9662. Dextran sulfate sodium (2%) was used to induce colitis in mice and they were simultaneously fed with a standard or a CLA-supplemented (100 mg · kg(-1) · d(-1)) diet for 7 d. The CLA-enriched diet prevented the colon shortening induced by DSS and markedly reduced the disease activity index and the colonic expression of inducible NO synthase and NF-κB. Immunohistochemistry revealed an increase in PPARγ and TFF3 expression after CLA administration. Altogether, these results indicate that dietary CLA protects against DSS-induced colitis in a process involving induction of PPARγ and TFF3.