Human gut-associated Bifidobacterium species salvage exogenous indole, a uremic toxin precursor, to synthesize indole-3-lactic acid via tryptophan

ABSTRACT

Indole in the gut is formed from dietary tryptophan by a bacterial tryptophan-indole lyase. Indole not only triggers biofilm formation and antibiotic resistance in gut microbes but also contributes to the progression of kidney dysfunction after absorption by the intestine and sulfation in the liver. As tryptophan is an essential amino acid for humans, these events seem inevitable. Despite this, we show in a proof-of-concept study that exogenous indole can be converted to an immunomodulatory tryptophan metabolite, indole-3-lactic acid (ILA), by a previously unknown microbial metabolic pathway that involves tryptophan synthase β subunit and aromatic lactate dehydrogenase. Selected bifidobacterial strains converted exogenous indole to ILA via tryptophan (Trp), which was demonstrated by incubating the bacterial cells in the presence of (2-¹³C)-labeled indole and l-serine. Disruption of the responsible genes variedly affected the efficiency of indole bioconversion to Trp and ILA, depending on the strains. Database searches against 11,943 bacterial genomes representing 960 human-associated species revealed that the co-occurrence of tryptophan synthase β subunit and aromatic lactate dehydrogenase is a specific feature of human gut-associated Bifidobacterium species, thus unveiling a new facet of bifidobacteria as probiotics. Indole, which has been assumed to be an end-product of tryptophan metabolism, may thus act as a precursor for the synthesis of a host-interacting metabolite with possible beneficial activities in the complex gut microbial ecosystem.

KEYWORDS:

• Indole
• indole-3-lactic acid
• tryptophan
• Bifidobacterium
• trpB
• aldh

Acknowledgments

We thank the late Professor Tohru Suzuki at Gifu University for providing pKKT427 and Aya Mizuno for helping with mutant construction.

Disclosure statement

B. longum BB536, B. breve MCC1274 and M-16 V, and B. infantis M-63 are commercialized strains. All authors except for AN, ToK, MS, TA, and TaK are employees of Morinaga Milk Industry Co., Ltd. Employment of MS at Kyoto University is in part supported by Morinaga Milk Industry Co., Ltd.

Author contributions

TO and TaK conceived the study. CCY, TO, and TaK designed the study. CCY and AN performed bacterial cultivation. EM, AH, and MS constructed mutants. CCY, TS, AN, and ToK performed the instrumental analysis. HK and TO performed the database search. CCY and TS analyzed the data. TA, JzX, TO, and TaK evaluated the data. CCY, TO, and TaK visualized the data. CCY, MT, and TO wrote the paper. TO and TaK edited the paper.

Supplemental material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2347728

Additional information

Funding

This study was partly supported by the JSPS-KAKENHI (21H02116 to TaK) and the JSPS Research Fellowship (23KJ1259 to AN).