Hydrogen sulfide: an agent of stability at the microbiome-mucosa interface

Abstract

A diverse range of effects of the intestinal microbiota on mucosal defense and injury has become increasingly clear over the past decade. Hydrogen sulfide (H₂S) has emerged as an important mediator of many physiological functions, including gastrointestinal mucosal defense and repair. Hydrogen sulfide is produced by gastrointestinal tract tissues and by bacteria residing within the gut and can influence the function of a wide range of cells. The microbiota also appears to be an important target of hydrogen sulfide. H₂S donors can modify the gut microbiota, and the gastrointestinal epithelium is a major site of oxidation of microbial-derived H₂S. When administered together with nonsteroidal anti-inflammatory drugs, H₂S can prevent some of the dysbiosis those drugs induce, possibly contributing to the observed prevention of gastrointestinal damage. Exogenous H₂S can also markedly reduce the severity of experimental colitis and plays important roles in modulating epithelial cell-mucus-bacterial interactions in the intestine, contributing to its ability to promote resolution of inflammation and repair of tissue injury. In this paper we review recent studies examining the roles of H₂S in mucosal defense, the possibility that H₂S can damage the gastrointestinal epithelium, and effects of H₂S on the gut microbiota and on mucus and biofilm interactions in the context of intestinal inflammation.

Keywords: NSAID; bacteria; biofilm; colitis; epithelium; inflammatory bowel disease; intestine; microbiota; mucus.

Fig. 1.

Administration of an inhibitor of endogenous H₂S synthesis in healthy mice and mice with hapten-induced colitis exacerbates inflammation and markedly alters the intestinal microbiota biofilm. Fluorescent in situ hybridization (FISH) was performed on colonic sections from C57BL/6 mice 7 days after induction of colitis with dinitrobenzene sulfonic acid. Representative images (from a total of 5 mice per group) are shown for healthy controls (A), colitis treated daily with vehicle (B), and colitis treated daily with β-cyanoalanine (BCA; 50 mg/kg; C and D). BCA is an inhibitor of H₂S synthesis. Host nuclei are colored red while FISH-positive cells are green. Scale bars represent 25 µM (A and C) or 50 µM (B and D). Dashed lines indicate the limit of the mucosa. The asterisk denotes translocated bacteria in the lamina propria. DADS, diallyl disulfide. [From Motta et al. (30).]

Fig. 2.

Administration of an H₂S donor, diallyl disulfide (DADS), restored the biofilm in rats with hapten-induced colitis. After induction of colitis, groups of 4–5 rats each were treated daily with DADS (0.5 ml of 30 μM) or vehicle for 7 days. Fluorescent in situ hybridization was performed on colonic sections from the rats. The images shown are representative of what was observed in all rats receiving the treatments: healthy controls (A) and colitis treated daily with vehicle (B and C) or DADS (D). Scale bars represent 50 µM. Dashed lines indicate the limit of the mucosa. The asterisks denote translocated bacteria in the lamina propria. DNBS, dinitrobenzene sulfonic acid. [From Motta et al. (30).]

Fig. 3.

A: naproxen treatment markedly increased the cytotoxic effects of bile on intestinal epithelial cells (IEC-6; ***P < 0.001). Bile collected from rats that had been cotreated with naproxen and an H₂S donor [diallyl disulfide (DADS)] exhibited reduced cytotoxicity, in a dose-dependent manner (^ψP < 0.05; ^ψψψP < 0.001). The rats were treated orally twice daily for 2 days with naproxen at 20 mg/kg and with vehicle or DADS. B: denaturing gradient gel electrophoresis analysis of intestinal microbiota samples from rats treated with naproxen (20 mg/kg) plus vehicle or DADS (30 mmol/kg). Treatment with DADS (blue) caused a marked shift in microbiota relative to vehicle-treated rats (black). C: using a resampling technique (majority unweighted-pair-group method with arithmetic mean algorithm), the dendrogram clustering observed in B was confirmed, indicating a robust difference in microbiota composition between groups (black, vehicle-treated rats; blue, DADs-treated rats). Each group consisted of five rats. Data were analyzed with Dunnett’s multiple-comparison test (cytotoxicity). [From Blackler et al. (5).]