Production of hydrogen sulfide by the intestinal microbiota and epithelial cells and consequences for the colonic and rectal mucosa.

Among bacterial metabolites, hydrogen sulfide (HS) has received increasing attention. The epithelial cells of the large intestine are exposed to two sources of HS. The main one is the luminal source that results from specific bacteria metabolic activity toward sulfur-containing substrates. The other source in colonocytes is from the intracellular production mainly through cystathionine β-synthase (CBS) activity. HS is oxidized by the mitochondrial sulfide oxidation unit, resulting in ATP synthesis, and, thus, establishing this compound as the first mineral energy substrate in colonocytes. However, when the intracellular HS concentration exceeds the colonocyte capacity for its oxidation, it inhibits the mitochondrial respiratory chain, thus affecting energy metabolism. Higher luminal HS concentration affects the integrity of the mucus layer and displays proinflammatory effects. However, a low/minimal amount of endogenous HS exerts an anti-inflammatory effect on the colon mucosa, pointing out the ambivalent effect of HS depending on its intracellular concentration. Regarding colorectal carcinogenesis, forced CBS expression in late adenoma-like colonocytes increased their proliferative activity, bioenergetics capacity, and tumorigenicity; whereas, genetic ablation of CBS in mice resulted in a reduced number of mutagen-induced aberrant crypt foci. Activation of endogenous HS production and low HS extracellular concentration enhance cancerous colorectal cell proliferation. Higher exogenous HS concentrations markedly reduce mitochondrial ATP synthesis and proliferative capacity in cancerous cells and enhance glycolysis but do not affect their ATP cell content or viability. Thus, it appears that, notably through an effect on colonocyte energy metabolism, endogenous and microbiota-derived HS are involved in the host intestinal physiology and physiopathology.