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Gut microbial metabolites as multi-kingdom intermediates

Abstract

The gut microbiota contributes to host physiology through the production of a myriad of metabolites. These metabolites exert their effects within the host as signalling molecules and substrates for metabolic reactions. Although the study of host–microbiota interactions remains challenging due to the high degree of crosstalk both within and between kingdoms, metabolite-focused research has identified multiple actionable microbial targets that are relevant for host health. Metabolites, as the functional output of combined host and microorganism interactions, provide a snapshot in time of an extraordinarily complex multi-organism system. Although substantial work remains towards understanding host–microbiota interactions and the underlying mechanisms, we review the current state of knowledge for each of the major classes of microbial metabolites with emphasis on clinical and translational research implications. We provide an overview of methodologies available for measurement of microbial metabolites, and in addition to discussion of key challenges, we provide a potential framework for integration of discovery-based metabolite studies with mechanistic work. Finally, we highlight examples in the literature where this approach has led to substantial progress in understanding host–microbiota interactions.

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Fig. 1: Fermentation of microbial-accessible carbohydrates and proteins by the colonic gut microbiota.
Fig. 2: Host–microbiota interactions during tryptophan metabolism.
Fig. 3: Gut microbiota–host interactions in one-carbon metabolism.

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Acknowledgements

K.A.K acknowledges support from the Fulbright United States Scholar Program (US Fulbright Scholar Award) and the Human Frontier Science Program (HFSP; Long-term Fellowship LT000195/2018-L). Work in the Bäckhed laboratory is supported by Transatlantic Networks of Excellence Award from the Leducq Foundation (17CVD01), JPI (A healthy diet for a healthy life; 2017-01996_3), AFA insurances, the Swedish Research Council (2019-01599), the Swedish Heart Lung Foundation (20180600), the Knut and Alice Wallenberg Foundation (2017.0026), the Novo Nordisk Foundation (NNF19OC0057271, NNF17OC0028232 and NNF15OC0016798), grants from the Swedish state under the agreement between the Swedish government and the county councils, and the ALF-agreement (ALFGBG-718101). F.B. is Torsten Söderberg Professor in Medicine and recipient of an ERC Consolidator Grant (European Research Council; Consolidator grant 615362-METABASE).

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All authors contributed substantially to the conceptualization and writing of the manuscript, focusing on the following sections: Introduction (K.A.K and F.B.), Fermentable substrates (K.A.K. and F.B.), Amino acids and their derivatives (K.A.K. and F.B.), Bile acids as gut microbial messengers (K.A.K. and F.B), Vitamins and one-carbon metabolites (K.A.K. and F.B.), Perspectives (K.A.K., J.F., and F.B.), Box 1 (K.A.K., J.F., and F.B.) and Box 2 (K.A.K. and F.B.)

Corresponding author

Correspondence to Fredrik Bäckhed.

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F.B. receives research support from Biogaia AB and is founder and shareholder in Implexion pharma AB. All other authors declare no competing interests.

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Nature Reviews Microbiology thanks P. Dorrestein, E. Gentry and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Mucosa

An epithelial layer comprising epithelial cells and mucus-secreting cells, among other specialized cell types, that lines multiple body surfaces (gastrointestinal tract, oropharynx, airways and vaginal tract) and functions as an innate barrier.

Fermentation

The chemical breakdown of organic substrates (for example, carbohydrates and amino acids) by various enzymes in the absence of molecular oxygen.

Gas chromatography–mass spectrometry

(GC-MS). An analytical method that couples chromatographic separation of complex biological samples in the gas phase to mass spectrometry for the identification and quantification of the compounds that comprise the sample.

Liquid chromatography–mass spectrometry

(LC-MS). An analytical method that couples chromatographic separation of complex biological samples in the liquid phase to mass spectrometry for the identification and quantification of the compounds that comprise the sample.

Desorption electrospray ionization mass spectrometry

A soft electrospray ionization technique that relies on solvent extraction directly on the sample under ambient conditions that is primarily used on tissues for imaging mass spectrometry.

Raman spectroscopy

A vibrational spectroscopy technique wherein a biological sample is subjected to a beam of light and differences in photon scatter (based on the molecular composition of the sample) are used to produce a unique chemical fingerprint.

Carbohydrate-active enzymes

(CAZymes). A collective term for enzymes that can synthesize or break down saccharides.

Microbial accessible carbohydrates

(MACs). Complex polysaccharides and oligosaccharides that are available to the gut microbiome’s vast repertoire of carbohydrate-active enzymes.

Mucus

A gel-like layer(s) secreted by and resting on top of the mucosa comprising mucins and functions as an essential barrier between the environment and the mucosal layer.

Mucins

Large, heavily decorated proteins characterized by proline-rich, serine-rich and threonine-rich tandem repeats (PTS domains) that are modified by complex O-glycans and form large polymeric protein networks that function as the building blocks of mucus in the intestinal tract.

Exoglycosidases

Enzymes that hydrolyse the glycosidic bond at the terminal monosaccharide in a polysaccharide or oligosaccharide.

Polysaccharidases

Enzymes that hydrolyse polysaccharides to form smaller saccharide chains.

Glycosidases

A general term for enzymes that hydrolyse glycosidic bonds in polysaccharides and oligosaccharides.

Chromatin

A highly structured nucleoprotein complex in eukaryotes that consists of the nucleic acids and histone proteins around which double-stranded genomic DNA winds to ultimately form chromosomes.

Germ-free mice

Mice born and raised in the complete absence of any microorganisms, frequently in a laminar flow glovebox isolator or IsoCage setting

Conventionally raised mice

Mice born and raised in a normal (‘conventional’) mouse colony setting with exposure to normal environmental microorganisms from birth onwards.

Bile salt hydrolases

Microbial enzymes that hydrolyse the amide bond in taurine and glycine-conjugated primary bile acids to yield a deconjugated bile acid.

Nuclear magnetic resonance spectroscopy

An analytical method frequently used in structural, quantitative and imaging applications wherein unique spectra are obtained for biomolecules based on nuclear resonance transitions that occur when atomic nuclei are immersed in a magnetic field and then subjected to specific magnetic energy levels.

Faecal microbiota transplantation

Delivery of processed stool from a donor into the intestinal tract of a recipient with the goal of stable engraftment.

Enterotypes

Variants in human microbial community composition based on empirical population measurements that are dominated by a single genus (for example, Bacteroides, Ruminococcus or Prevotella).

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Krautkramer, K.A., Fan, J. & Bäckhed, F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol 19, 77–94 (2021). https://doi.org/10.1038/s41579-020-0438-4

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