Dominance of metabolically flexible fermenters drives intestinal gas production in Crohn's disease.

Abstract

Molecular hydrogen (H2) and hydrogen sulfide (H2S) are central gut metabolites that shape microbial metabolism and affect host health. In Crohn's disease (CD), the shift in microbiota composition ('dysbiosis') is associated with intestinal accumulation of these gases, but the responsible microbes remain poorly resolved. Here, we analysed 4,644 bacterial and archaeal species-level genomes from the Unified Human Gastrointestinal Genome Collection to identify H2-cycling microbes, assessed their prevalence in ca. 1,700 stool metagenomes from healthy and diseased individuals, and validated their activity using culture-based incubations of stool isolates and biopsy samples. Approximately half of all species encoded H2-producing abilities, with acetate- and propionate-forming fermenters such as Phocaeicola and Bacteroides dominating healthy cohorts, whereas comparatively few taxa, including Escherichia and Megamonas, encoded H2 consuming abilities. In CD, H2 producers became more abundant but less diverse, favouring species with multiple H2-evolving hydrogenases and more fermentation routes, especially Clostridium and Enterocloster species. Consistently, isolates enriched in CD produced H2 faster and at higher concentrations than health-associated isolates. Increased H2S-producing capacity in CD was driven mainly by these H2-producing fermenters carrying anaerobic sulfite reductases (Asr), rather than sulfate-reducing bacteria, and was supported by elevated H2S production in Asr-positive isolates, likely providing an additional electron sink. These findings provide a species-resolved view of gut gas metabolism and implicate metabolically flexible fermenters in excessive gas and sulfide production in gut disorders.Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.