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The intestinal microbiota fuelling metabolic inflammation

Abstract

Low-grade inflammation is the hallmark of metabolic disorders such as obesity, type 2 diabetes and nonalcoholic fatty liver disease. Emerging evidence indicates that these disorders are characterized by alterations in the intestinal microbiota composition and its metabolites, which translocate from the gut across a disrupted intestinal barrier to affect various metabolic organs, such as the liver and adipose tissue, thereby contributing to metabolic inflammation. Here, we discuss some of the recently identified mechanisms that showcase the role of the intestinal microbiota and barrier dysfunction in metabolic inflammation. We propose a concept by which the gut microbiota fuels metabolic inflammation and dysregulation.

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Fig. 1: Gut barrier breach in metabolic diseases in mouse models.
Fig. 2: Multiple ‘gastrointestinal hits’ contribute to metabolic diseases.

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Acknowledgements

The authors thank members of the Tilg and Elinav laboratories for discussions and apologize to authors whose work was not included due to space constraints. H.T. is supported by the Excellence Initiative (Competence Centres for Excellent Technologies — COMET) of the Austrian Research Promotion Agency FFG: Research Centre of Excellence in Vascular Ageing Tyrol, VASCage (K-Project No. 843536) funded by BMVIT, BMWFW, Wirtschaftsagentur Wien and Standortagentur Tirol. N.Z. is supported by a Gilead Biosciences Fellowship. T.E.A. is grateful for the support from the Austrian Science Fund (FWF, P 29379-B28), the Austrian Society of Gastroenterology and Hepatology (ÖGGH), and the European Crohn’s and Colitis Organization (ECCO). E.E. is supported by Y. and R. Ungar, the Abisch Frenkel Foundation for the Promotion of Life Sciences, the Gurwin Family Fund for Scientific Research, the Leona M. and Harry B. Helmsley Charitable Trust, the Crown Endowment Fund for Immunological Research, the estate of J. Gitlitz, the estate of L. Hershkovich, the Benoziyo Endowment Fund for the Advancement of Science, the Adelis Foundation, J.L. and V. Schwartz, A. and G. Markovitz, A. and C. Adelson, the French National Centre for Scientific Research (CNRS), D. L. Schwarz, the V. R. Schwartz Research Fellow Chair, L. Steinberg, J. N. Halpern, A. Edelheit, grants funded by the European Research Council, a Marie Curie Integration grant, the German–Israeli Foundation for Scientific Research and Development, the Israel Science Foundation, the Minerva Foundation, the Rising Tide Foundation, the Helmholtz Foundation, and the European Foundation for the Study of Diabetes. E.E. is a senior fellow of the Canadian Institute of Advanced Research (CIFAR) and an international scholar of the Bill and Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI).

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All authors researched data for the article, made substantial contribution to discussion of content, and wrote, reviewed and edited the manuscript.

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Correspondence to Herbert Tilg or Eran Elinav.

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E.E. is a paid consultant for DayTwo and BiomX. The other authors declare no competing interests.

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Nature Reviews Immunology thanks K. Clément, B. Jabri and O. Pedersen for their contribution to the peer review of this work.

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Glossary

ob/ob mice

A mouse model of metabolic dysregulation and obesity that arises from increased appetite due to a leptin mutation (that renders these mice functionally leptin deficient).

Metabolic endotoxaemia

A state that favours the translocation of microbial components (such as lipopolysaccharide) to the bloodstream, which promotes metabolic disease.

Chylomicrons

Transport vesicles (so-called lipoprotein particles) for absorbed dietary lipids.

Berberine

A plant-derived alkaloid of an ancient Chinese herb, Coptis chinensis.

Low-density lipoprotein receptor-deficient mice

A mouse model of atherosclerosis caused by a targeted deletion of the gene encoding the low-density lipoprotein receptor (LDLR). In humans, homozygous mutations in LDLR cause familial hypercholesterolaemia, a disease characterized by pronounced hyperlipidaemia and accelerated atherosclerotic cardiovascular disease.

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Tilg, H., Zmora, N., Adolph, T.E. et al. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol 20, 40–54 (2020). https://doi.org/10.1038/s41577-019-0198-4

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