Gut-derived lactic acid enhances tryptophan to 5-hydroxytryptamine in regulation of anxiety via <i>Akkermansia muciniphila</i>

Abstract

The gut microbiota plays a pivotal role in anxiety regulation through pathways involving neurotransmitter production, immune signaling, and metabolic interactions. Among these, gut-derived serotonin (5-hydroxytryptamine, 5-HT), synthesized from tryptophan metabolism, has been identified as a key mediator. However, it remains unclear whether specific microbial factors regulate tryptophan metabolism to influence 5-HT production and anxiety regulation. In this study, we analyzed 110 athletes undergoing closed training and found that fecal lactate levels were significantly associated with anxiety indicators. We observed a significant negative correlation between <i>Akkermansia</i> abundance and anxiety levels in athletes. Co-supplementation with lactate and <i>Akkermansia muciniphila</i> (<i>A. muciniphila</i>) modulated tryptophan metabolism by increasing key enzyme TPH1 and reducing IDO1, thus shifting metabolism from kynurenine (Kyn) to 5-HT. In addition, lactate enhanced the propionate production capacity of <i>A. muciniphila</i>, potentially contributing to anxiety reduction in mice. Taken together, these findings suggest that enteric lactate and <i>A. muciniphila</i> collaboratively restore the imbalance in tryptophan metabolism, leading to increased 5-HT activity and alleviating anxiety phenotypes. This study highlights the intricate interplay between gut metabolites and anxiety regulation, offering potential avenues for microbiota-targeted therapeutic strategies for anxiety.