Abstract
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.
Highlights
Human breastmilk is a well-adapted nutritional supply for the infant[1]
Principal component analysis (PCA) of faecal aromatic amino acid metabolite concentrations (Supplementary Data 1e) suggested a minor separation by breastfeeding status, which was largely driven by three aromatic lactic acids, 4-hydroxyphenyllactic acid (4-OH-PLA), phenyllactic acid (PLA) and indolelactic acid (ILA) (Fig. 1c)
We identified an aromatic lactate dehydrogenase (ALDH), which catalyses the last step of the conversion of aromatic amino acids into their respective aromatic lactic acids in the infant gut
Summary
Breastfeeding provides the infant with important short-term protection against infections and may provide long-term metabolic and immunological benefits[1,2,3] These benefits may partly be mediated through the gut microbiota, since breastfeeding is the strongest determinant of gut microbiota composition and function during infancy[4,5,6]. Human breastmilk contains human milk oligosaccharides (HMOs), which are complex, highly abundant sugars serving as substrates for specific microbes including certain species of Bifidobacterium[7]. This co-evolution between bifidobacteria and the host, mediated by HMOs, to a large extent directs the colonization of the gut in early life, which has critical impact on the immune system[8]. Nature Microbiology breastmilk-promoted Bifidobacterium via production of aromatic lactic acids impact the immune system in early life
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