Unveiling the gut’s hydrogen engine
Scientists have long known that the human gut is a bustling metabolic reactor. Carbohydrates are fermented by trillions of microbes, yielding energy, beneficial short-chain fatty acids, and a spectrum of gases. Among these gases, molecular hydrogen (H₂) plays a surprising and crucial role. Rather than being a mere byproduct, H₂ serves as a valuable energy source for other microbes that consume it, a process that can influence the efficiency and outcomes of gut fermentation. A new, multinational study now pinpoints the dominant enzyme that drives H₂ production in healthy guts and reveals how this hydrogen economy shifts in Crohn’s disease (CD).
The study at a glance
In a Nature Microbiology publication, researchers integrated genomic, transcriptomic, and biochemical analyses to identify the primary driver of fermentative H₂ production in healthy individuals. The team started with a broad computational sweep: analyzing 300 stool metagenomes and 78 metatranscriptomes to map the landscape of hydrogen-related genes and their expression in a healthy gut. To validate these findings, they examined 102 mucosal biopsy-enriched metagenomes from 42 donors and compared samples from different gut regions—terminal ileum, caecum, and rectum—to confirm consistency across the intestinal tract.
To demonstrate function, the researchers selected 19 diverse bacterial species from the human gut and grew them under anaerobic conditions that mimic the gut environment. Gas chromatography quantified H₂ production over time, linking genetic potential to actual hydrogen output. Biochemical assays on bacterial extracts then connected H₂ production to the pyruvate:ferredoxin oxidoreductase (PFOR) reaction, a central step in fermentation. The work combined AlphaFold2 modelling, heterologous expression, and spectroscopy/EPR evidence to validate the ferredoxin-like domain and catalytic role of the enzyme in question.
The main finding: a dominant hydrogen-producing enzyme
The study identifies the group B [FeFe]-hydrogenase as the most abundant and active hydrogen-producing gene in the healthy human gut. On average, group B genes occurred at about 0.75 copies per genome, roughly seven and a half times more than the previously emphasized group A1 hydrogenase. Activity assays corroborated these results, showing higher transcription levels for group B across metatranscriptomes. A striking and previously underappreciated finding was that Bacteroides—one of the most common gut genera—emerge as major users of group B enzymes, driving significant H₂ production. In contrast, a species like Bacteroides stercoris, which lacks hydrogenase genes, produced no H₂, aligning with the genetic data.
What changes in Crohn’s disease?
Comparing healthy individuals with 46 CD patients showed a marked shift in the gut’s hydrogen economy. The healthy group B hydrogenase code was significantly depleted in Crohn’s disease (P = 0.0023) and was replaced by other hydrogenases and pathways: group A1 hydrogenase rose about 2.8-fold, formate hydrogenlyase (group 4a) increased 5.2-fold, and group 1d [NiFe]-hydrogenase rose 2.6-fold. Genes involved in respiratory H₂ oxidation, particularly group 1d [NiFe]-hydrogenases, also rose, suggesting a restructured hydrogen economy in the inflamed gut. These findings imply that Crohn’s disease disrupts the balance between hydrogen production and consumption, potentially influencing microbial energy networks and gut inflammation.
Interpreting the numbers and next steps
While the combined [FeFe] hydrogenase subgroups did not differ significantly between CD and controls, the overall pattern points to correlative shifts rather than a proven causal mechanism in this study. The data suggest that respiratory hydrogenotrophs—microbes that consume H₂—likely dominate H₂ uptake in the gut, but direct activity measurements still need confirmation. The authors emphasize that the results illuminate not only who is producing H₂ but how the broader hydrogen economy may recalibrate in disease, offering new angles for diagnostics and potential microbiome-targeted therapies.
Why this matters for health and treatment
Understanding the gut’s hydrogen economy deepens our grasp of microbial energy flow and its impact on gut health. If group B [FeFe]-hydrogenase is the principal source of fermentative H₂ in a healthy gut, strategies that support this enzyme’s activity could sustain beneficial fermentation dynamics. Conversely, recognizing how Crohn’s disease shifts hydrogen production toward alternative enzymes and respiratory pathways highlights potential targets for restoring metabolic balance. Future research may explore dietary interventions, prebiotics, or microbiome therapies designed to support hydrogen-producing communities or modulate hydrogenotroph activity, with the aim of improving gut health and reducing inflammation.
Bottom line
A global research effort has pinpointed the primary driver of fermentative hydrogen production in the healthy human gut—the group B [FeFe]-hydrogenase—while revealing a disease-associated switch to other hydrogenases in Crohn’s disease. This work advances our understanding of gut metabolism and sets the stage for microbiome-informed approaches to inflammatory bowel disease management.
