The role of gut microbiota in maintaining optimal brain and cognitive health is becoming increasingly appreciated in the field of neuroscience. Hydrogen sulfide (H₂S) is a potent and potentially lethal neurotoxin in high doses, yet it is produced endogenously at extremely low levels and is thought to serve important biological roles, such as regulation of cerebral vasculature. Nevertheless, elevated concentrations of H₂S can be introduced exogenously by sulfate reducing bacteria (SRB) in the gut microbiome. The neurocognitive implications of this gut-derived, systemically permeating H₂S remain relatively unknown. Preclinical evidence shows that introducing SRB to the gut leads to cognitive deficits – effects that can be reversed by subsequent neutralization of H₂S. However, no human study has evaluated the relationship between H₂S and cognitive performance. Here, we examined the effects of gut-derived systemic H₂S on cognitive function in humans.

Thirty-eight healthy participants (Age = 41 ± 16.9; 15 Males, 23 Females) underwent lactulose breath tests, which included measuring breath H₂S concentrations every 15 minutes for 3 hours after consuming lactulose – a non-digestible starch that is readily fermentable by gut bacteria. During this time, participants performed neuropsychological tests that included Trail Making Test A (TMT-A). The observed H₂S values were summed across the 3-hour period to obtain total detectable H₂S levels for each individual. An independent t-test was used to assess group differences in age-corrected TMT-A scores between participants who were H₂S-positive (H₂S+; N = 24) and H₂S-negative (H₂S-; N = 14), as some individuals had no detectable H₂S in their breath throughout testing. Subsequently, a regression analysis was used to evaluate the relationship between total H₂S levels and TMT-A scores within the H₂S+ group in order to examine a dose-dependent relationship between H₂S and cognitive performance.

The H₂S+ group performed significantly worse on TMT-A compared to the H₂S- group (t(36) = -3.010, p = 0.005). Within the H₂S+ group, the association between higher H₂S and worse performance on the TMT-A approached statistical significance (β = -0.366, t(22) = -1.847, p = 0.078). The relationship between age and H₂S levels was assessed to address a potential age confound, and was found to be non-significant (p = .349).

We observed that the systemic presence of exogenous, gut-derived H₂S was associated with significantly decreased performance on TMT-A in the absence of overt gastrointestinal or neuropsychiatric pathology. In addition, a trending negative relationship between H₂S levels and cognitive performance was detected. These findings add to our growing understanding regarding the specific processes through which the microbiome exerts its influence on neurocognitive functioning in humans. Further, we note that counterintuitive evidence has recently been emerging regarding the beneficial effects of H₂S and H₂S-based pharmacotherapies for some disorders. As such, our results provide an important contribution to the ongoing efforts to delineate the beneficial biological roles of H₂S from its toxic effects.