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. 2025 Dec;17(1):2447834.
doi: 10.1080/19490976.2024.2447834. Epub 2025 Jan 9.

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

Miaomiao Pan  1 , Chenglang Qian  1 , Shaoye Huo  2 , Yuchen Wu  3 , Xinyi Zhao  4 , Yueming Ying  5 , Boyu Wang  1 , Hao Yang  1 , Anaguli Yeerken  1 , Tongyao Wang  1 , Mengwei Fu  1 , Lihong Wang  2 , Yuhuan Wei  2 , Yunhua Zhao  2 , Chunhai Shao  2   6 , Huijing Wang  3 , Chao Zhao  1   7
Affiliations

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

Miaomiao Pan et al. Gut Microbes. 2025 Dec.

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 Akkermansia abundance and anxiety levels in athletes. Co-supplementation with lactate and Akkermansia muciniphila (A. muciniphila) 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 A. muciniphila, potentially contributing to anxiety reduction in mice. Taken together, these findings suggest that enteric lactate and A. muciniphila 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.

Keywords: 5-hydroxytryptamine; Akkermansia muciniphila; Gut microbiome; competitive anxiety; lactic acid; propionic acid; tryptophan.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Anxiety associated with gut microbiome composition and fecal lactate.
Figure 2.
Figure 2.
Lactate enhanced the activity of 5-HT system in mice.
Figure 3.
Figure 3.
Lactate alleviated anxiety and modulated gut microbiota in mice.
Figure 4.
Figure 4.
Lactate redirected tryptophan metabolism through enzymatic regulation.
Figure 5.
Figure 5.
Lactate and A. muciniphila regulate the directional shift of tryptophan metabolism.
Figure 6.
Figure 6.
Lactate relies on gut microbiota to maintain intestinal barrier integrity.
Figure 7.
Figure 7.
Schematic illustration of the regulatory role of lactate and A. muciniphila on tryptophan metabolism.
See this image and copyright information in PMC

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Supplementary concepts