Bifidobacterium species associated with breastfeeding produce aromatic lactic acids in the infant gut

Martin F. Laursen, Mikiyasu Sakanaka, Nicole von Burg, Urs Mörbe, Daniel Andersen, Janne Marie Moll, Ceyda T. Pekmez, Aymeric Rivollier, Kim F. Michaelsen, Christian Mølgaard, Mads Vendelbo Lind, Lars O. Dragsted, Takane Katayama, Henrik L. Frandsen, Anne Marie Vinggaard, Martin I. Bahl, Susanne Brix, William Agace, Tine R. Licht, Henrik M. Roager

Research output: Contribution to journalArticlepeer-review

24 Citations (SciVal)


Breastfeeding profoundly shapes the infant gut microbiota, which is critical for early life immune development, and the gut microbiota can impact host physiology in various ways, such as through the production of metabolites. However, few breastmilk-dependent microbial metabolites mediating host–microbiota interactions are currently known. Here, we demonstrate that breastmilk-promoted Bifidobacterium species convert aromatic amino acids (tryptophan, phenylalanine and tyrosine) into their respective aromatic lactic acids (indolelactic acid, phenyllactic acid and 4-hydroxyphenyllactic acid) via a previously unrecognized aromatic lactate dehydrogenase (ALDH). The ability of Bifidobacterium species to convert aromatic amino acids to their lactic acid derivatives was confirmed using monocolonized mice. Longitudinal profiling of the faecal microbiota composition and metabolome of Danish infants (n = 25), from birth until 6 months of age, showed that faecal concentrations of aromatic lactic acids are correlated positively with the abundance of human milk oligosaccharide-degrading Bifidobacterium species containing the ALDH, including Bifidobacterium longum, B. breve and B. bifidum. We further demonstrate that faecal concentrations of Bifidobacterium-derived indolelactic acid are associated with the capacity of these samples to activate in vitro the aryl hydrocarbon receptor (AhR), a receptor important for controlling intestinal homoeostasis and immune responses. Finally, we show that indolelactic acid modulates ex vivo immune responses of human CD4+ T cells and monocytes in a dose-dependent manner by acting as an agonist of both the AhR and hydroxycarboxylic acid receptor 3 (HCA3). Our findings reveal that breastmilk-promoted Bifidobacterium species produce aromatic lactic acids in the gut of infants and suggest that these microbial metabolites may impact immune function in early life.

Original languageEnglish
Pages (from-to)1367-1382
Number of pages16
JournalNature Microbiology
Publication statusPublished - 2021

Bibliographical note

Funding Information:
We thank the children and families participating in the SKOTI study, which was supported by the Danish Directorate for Food, Fisheries and Agribusiness (grant no. 3304-FSE-06-0503), as well as the children and parents participating in the CIG cohort. Furthermore, we thank Aarstiderne A/S for providing a small gift for the CIG participants. We thank M. Danner Dalgaard at the Technical University of Denmark in-house facility (DTU Multi-Assay Core, DMAC) for performing the 16S rRNA gene sequencing, MS-Omics for performing the lactate analyses, Glycom A/S for kindly donating the HMOs and A. Schnipper for her efforts in supporting the work. We also thank S. Fukiya and A. Yokota (Research Faculty of Agriculture, Hokkaido University) for providing Bifidobacterium gene manipulation tools and for technical suggestions, Y. Sugiyama (Graduate School of Agriculture, Kyoto University) for helpful discussions on HPLC analysis, S. Maeda (Faculty of Bioresources and Environmental Sciences, Ishikawa Prefectural University) for technical support on enzyme purification, technician L. Buus Rosholm (Department of Biotechnology and Biomedicine, Technical University of Denmark) for performing the human monocyte experiments and technician B. Møller Plesning (National Food Institute, Technical University of Denmark) for running the AhR and HCAR-3 assays. We thank laboratory animal caretakers M. Danielsen, E. Erna Navntoft and K. Rene Worm (National Food institute, Technical University of Denmark). This work was supported by Augustinus Fonden (grant no. 17-2003 to H.M.R.); Hørslev Fonden (grant no. 203866 to H.M.R.); Beckett Fonden (grant no. 17-2-0551 to H.M.R.); Aase og Ejnar Danielsens Fond (grant no. 10-002019 to H.M.R.); the Innovation Fund Denmark (grant no. 11-116163/0603-00487B; Center for Gut, Grain and Greens to T.R.L.); JSPS-KAKENHI (18K14379 to M.S., 19K22277 to T.K.); JSPS Overseas Research Fellowships (201860637 to M.S.) and the Institute for Fermentation, Osaka (to M.S. and T.K.); ‘Diet-induced arrangement of the gut microbiome for improvement of cardiometabolic health’ (DINAMIC) under the Joint Programming Initiative, ‘A Healthy Diet for a Healthy Life’ (JPI-HDHL), supported by the Innovation Fund Denmark (grant no. 5195-00001B to L.O.D.); and ‘Biomarkers for infant fat mass development and nutrition’ under the ERA-HDHL joint transnational programme ‘Biomarkers for nutrition and health’, supported by the Innovation Fund Denmark (grant no. 4203-00005B to S.B.).

Publisher Copyright:
© 2021, The Author(s).

Subject classification (UKÄ)

  • Nutrition and Dietetics
  • Gastroenterology and Hepatology
  • Endocrinology and Diabetes
  • Microbiology in the medical area


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