Sulfate-reducing bacteria and their contribution to intestinal epithelial disorders.

摘要

Ulcerative colitis (UC) and colon cancer are complex and enigmatic diseases, thought to originate from a similar interplay between genetic predisposition and environmental insults. Intestinal hydrogen sulfide (H₂S), produced by commensal sulfate-reducing bacteria (SRB), may represent such an environmental insult, as this compound is highly toxic for aerobic organisms. Little is known about the intestinal ecology of SRB or the contributions of exogenous sulfate from diet or drinking water to H₂S production. We developed a PCR-based technique that targets the SRB enzyme adenosine phosphosulfate reductase to study SRB populations in C57BL/6J mice. This technique revealed SRB throughout the intestine in adult mice with densest SRB populations in the cecum and colon. An additional study measured intestinal sulfate and H ₂S concentrations in mice exposed to sulfate-supplemented (16.8 mM) drinking water for 1 yr. Neither sulfate nor H₂S concentrations were affected by exogenous sulfate, which indicates that endogenous rather than exogenous sources of sulfate may modulate SRB populations. Hydrogen sulfide concentrations (0.2−>1 mM) in the mouse large intestine were found to exceed the toxic threshold of 50 μM. Exposure of rat IEC-18 crypt epithelial cells to these physiological H₂S concentrations caused acute hypoxia, which increased steady-state c-Jun mRNA concentrations after 30 min, and triggered early cell cycle traverse after 4h. This H₂S-induced mitogenic response was mediated by mitogen-activated protein kinases (MAPK) ERK and p38, as revealed by kinase inhibition studies. Microarray analysis using an Affymetrix Rat Array™ confirmed that exposure to H₂S (90 min) caused acute hypoxia, as indicated by increased expression of hypoxia-response genes and genes encoding glycolytic enzymes. The up-regulation of genes contributing to the MAPK signaling pathway and those associated with proliferation is consistent with the observation that H₂S induced a mitogenic response in IEC-18 cells mediated by MAPK. These findings are the first to identify H₂S as a potential etiological factor in the development of UC or colon cancer via its ability to induce early cell cycle traverse in non-transformed intestinal epithelial cells. Thus, it becomes crucial to understand how host genetic background may affect disease outcome in response to the bacterial-derived environmental insult H₂S.