Transcriptomics profiles in intestinal sulfide overproduction, small intestinal bacterial overgrowth, and intestinal methanogen overgrowth

ABSTRACT Despite advances in identifying distinct microbial profiles linked to intestinal sulfide overproduction (ISO), small intestinal bacterial overgrowth (SIBO), and intestinal methanogen overgrowth (IMO), differences in host small bowel (SB) gene expression remain unexplored. Therefore, we compared host gene transcriptomics in SB biopsies from subjects with IMO, ISO, and SIBO. Separately, SB transcriptomics in rats gavaged with hydrogen sulfide (H 2 S) producers were also analyzed. ISO subjects exhibited unique transcriptomics profiles. ISO (≥1.5 parts per million [ppm] H 2 S) broadly affected genes linked to H₂S toxicity, such as electron transport chain and redox balance genes, while there were fewer significant effects on gene expression in IMO and SIBO. Rat data supported ISO findings, including dysregulation of mitochondrial respiration, redox balance, water homeostasis, immune response, and gut motility. IMPORTANCE Intestinal sulfide overproduction (ISO), intestinal methanogen overgrowth (IMO), and small intestinal bacterial overgrowth (SIBO) are conditions associated with higher levels of breath hydrogen sulfide and methane, respectively, and higher bacterial colony counts on small bowel aspirate cultures. While these conditions correlate with gastrointestinal symptoms, the cellular mechanisms involved when analyzed either separately or concomitantly are not well understood. Here, we aimed to explore changes in human small bowel transcriptomics in ISO, IMO, and/or SIBO, and to investigate if changes in ISO reflect those seen in models of rats gavaged with known hydrogen sulfide producers. The results demonstrate that each condition is unique and has its own transcriptomics profile, with ISO showing a greater effect on the host, which was partially validated by transcriptomic analyses in the small bowel of rats gavaged with hydrogen sulfide-producing bacteria. This study supports the need for individualized therapeutic strategies for each condition in the future.