Gut Microbial Metabolites of Aromatic Amino Acids as Signals in Host–Microbe Interplay

Type 2 diabetes (T2D) is a worldwide prevalent metabolic disorder defined by high blood glucose levels due to insulin resistance (IR) and impaired insulin secretion. Understanding the mechanism of insulin action is of great importance to the continuing development of novel therapeutic strategies for the treatment of T2D. Disturbances of gut microbiota have been widely found in T2D patients and contribute to the development of IR. In the present article, we reviewed the pathological role of gut microbial metabolites including gaseous products, branched-chain amino acids (BCAAs) products, aromatic amino acids (AAAs) products, bile acids (BA) products, choline products and bacterial toxins in regulating insulin sensitivity in T2D. Following that, we summarized probiotics-based therapeutic strategy for the treatment of T2D with a focus on modulating gut microbiota in both animal and human studies. These results indicate that gut-microbial metabolites are involved in the pathogenesis of T2D and supplementation of probiotics could be beneficial to alleviate IR in T2D via modulation of gut microbiota.

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

Nature Microbiology ◽

10.1038/s41564-021-00970-4 ◽

2021 ◽

Author(s):

Martin F. Laursen ◽

Mikiyasu Sakanaka ◽

Nicole von Burg ◽

Urs Mörbe ◽

Daniel Andersen ◽

...

Keyword(s):

Amino Acids ◽

Gut Microbiota ◽

Immune Responses ◽

Early Life ◽

Bifidobacterium Longum ◽

Aromatic Amino Acids ◽

Dependent Manner ◽

Microbial Metabolites ◽

Phenyllactic Acid ◽

Lactic Acids

AbstractBreastfeeding 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.

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Metabolomic analysis revealed that green tea polyphenols decreased the formation of microbial metabolites of aromatic amino acids in humans

10.3390/iecm-3-05846 ◽

2018 ◽

Author(s):

Chi Chen ◽

Yuyin Zhou ◽

Ningning Zhang ◽

Andrea Arikawa

Keyword(s):

Amino Acids ◽

Green Tea ◽

Aromatic Amino Acids ◽

Tea Polyphenols ◽

Green Tea Polyphenols ◽

Microbial Metabolites ◽

Metabolomic Analysis

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Breastmilk-promoted bifidobacteria produce aromatic amino acids in the infant gut

10.1101/2020.01.22.914994 ◽

2020 ◽

Cited By ~ 6

Author(s):

Martin F. Laursen ◽

Mikiyasu Sakanaka ◽

Nicole von Burg ◽

Urs Mörbe ◽

Daniel Andersen ◽

...

Keyword(s):

Amino Acids ◽

Lactate Dehydrogenase ◽

Gut Microbiota ◽

Immune Responses ◽

Early Life ◽

Aromatic Amino Acids ◽

Dependent Manner ◽

Microbial Metabolites ◽

Stool Samples ◽

Lactic Acids

ABSTRACTBreastfeeding profoundly shapes the infant gut microbiota, which is critical for early life immune development. However, few breastmilk-dependent microbial metabolites mediating host-microbiota interactions are currently known. We here demonstrate that breastmilk-promoted Bifidobacterium species convert aromatic amino acids (tryptophan, phenylalanine and tyrosine) into their respective aromatic lactic acids (indolelactate, phenyllactate and 4-hydroxyphenyllactate) via a previously unrecognised aromatic lactate dehydrogenase. By longitudinal profiling of the gut microbiota composition and metabolome of stool samples of infants obtained from birth until 6 months of age, we show that stool concentrations of aromatic lactic acids are determined by the abundance of human milk oligosaccharide degrading Bifidobacterium species containing the aromatic lactate dehydrogenase. We demonstrate that stool concentrations of Bifidobacterium-derived indolelactate, the most abundant aromatic lactic acid in vivo, are associated with the capacity of infant stool samples to activate the aryl hydrocarbon receptor (AhR), a receptor important for controlling intestinal homeostasis and immune responses. Finally, we show that indolelactate 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 (HCAR3). Our findings reveal that breastmilk-promoted Bifidobacterium produce aromatic lactic acids in the gut of infants and suggest that these microbial metabolites may impact immune function in early life.

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Inhibitory Effects of Green Tea Polyphenols on Microbial Metabolism of Aromatic Amino Acids in Humans Revealed by Metabolomic Analysis

Metabolites ◽

10.3390/metabo9050096 ◽

2019 ◽

Vol 9 (5) ◽

pp. 96 ◽

Cited By ~ 6

Author(s):

Yuyin Zhou ◽

Ningning Zhang ◽

Andrea Y. Arikawa ◽

Chi Chen

Keyword(s):

Amino Acids ◽

Green Tea ◽

Aromatic Amino Acids ◽

Microbial Metabolism ◽

Tea Polyphenols ◽

Green Tea Polyphenols ◽

Rrna Gene ◽

Microbial Metabolites ◽

Metabolomic Analysis ◽

Potential Health

The bioactivities and potential health benefits of green tea polyphenols (GTP) have been extensively investigated, but the metabolic impact of chronic GTP intake on humans is not well defined. In this study, fecal and urine samples from postmenopausal female subjects taking a GTP supplement or placebo for 12 months were compared by liquid chromatography-mass spectrometry-based metabolomic analysis. The GTP-derived and GTP-responsive metabolites were identified and characterized by structural elucidation and quantitative analysis of the metabolites contributing to the separation of control and treatment samples in the multivariate models. Major GTP and their direct sulfate and glucuronide metabolites were absent in feces and urine. In contrast, GTP-derived phenyl-γ-valerlactone and phenylvaleric acid metabolites were identified as the most abundant GTP-derived metabolites in feces and urine, suggesting extensive microbial biotransformation of GTP in humans. Interestingly, GTP decreased the levels of microbial metabolites of aromatic amino acids (AAA), including indoxyl sulfate, phenylacetylglutamine, and hippuric acid, in urine. However, it did not affect the levels of AAA, as well as other microbial metabolites, including short-chain fatty acids and secondary bile acids, in feces. 16S rRNA gene sequencing indicated that the fecal microbiome was not significantly affected by chronic consumption of GTP. Overall, microbial metabolism is responsible for the formation of GTP metabolites while GTP metabolism may inhibit the formation of AAA metabolites from microbial metabolism. Because these GTP-derived and GTP-responsive metabolites have diverse bioactivities, microbial metabolism of GTP and AAA may play important roles in the beneficial health effects of green tea consumption in humans.

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The role of bacterial metabolites derived from aromatic amino acids in non-alcoholic fatty liver disease

Almanac of Clinical Medicine ◽

10.18786/2072-0505-2020-48-066 ◽

2020 ◽

Vol 48 (6) ◽

pp. 375-386

Author(s):

E. S. Shcherbakova ◽

T. S. Sall ◽

S. I. Sitkin ◽

T. Ya. Vakhitov ◽

E. V. Demyanova

Keyword(s):

Amino Acids ◽

Liver Disease ◽

Gut Microbiota ◽

Fatty Liver Disease ◽

Liver Steatosis ◽

Aromatic Amino Acids ◽

Microbial Metabolites ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

The review deals with the role of aromatic amino acids and their microbial metabolites in the development and progression of non-alcoholic fatty liver disease (NAFLD). Pathological changes typical for NAFLD, as well as abnormal composition and/or functional activity of gut microbiota, results in abnormal aromatic amino acid metabolism. The authors discuss the potential of these amino acids and their bacterial metabolites to produce both negative and positive impact on the main steps of NAFLD pathophysiology, such as lipogenesis and inflammation, as well as on the liver functions through regulation of the intestinal barrier and microbiota-gut-liver axis signaling. The review gives detailed description of the mechanism of biological activity of tryptophan and its derivatives (indole, tryptamine, indole-lactic, indole-propyonic, indole-acetic acids, and indole-3-aldehyde) through the activation of aryl hydrocarbon receptor (AhR), preventing the development of liver steatosis. Bacteria-produced phenyl-alanine metabolites could promote liver steatosis (phenyl acetic and phenyl lactic acids) or, on the contrary, could reduce liver inflammation and increase insulin sensitivity (phenyl propionic acid). Tyramine, para-cumarate, 4-hydroxyphenylacetic acids, being by-products of bacterial catabolism of tyrosine, can prevent NAFLD, whereas para-cresol and phenol accelerate the progression of NAFLD by damaging the barrier properties of intestinal epithelium. Abnormalities in bacterial catabolism of tyrosine, leading to its excess, stimulate fatty acid synthesis and promote lipid infiltration of the liver. The authors emphasize a close interplay between bacterial metabolism of aromatic amino acids by gut microbiota and the functioning of the human body. They hypothesize that microbial metabolites of aromatic amino acids may represent not only therapeutic targets or non-invasive biomarkers, but also serve as bioactive agents for NAFLD treatment and prevention.

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