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JMG, Mice, Animals, Verrucomicrobia, Gastrointestinal Microbiome, Akkermansia, Phenotype

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Nat Microbiol. 2023;8(3):424-40.







This work was supported by National Institutes of Health (NIH) grants DK108259 (F.E.R.), HL144651 (F.E.R. and A.J.L.), HL148577 (F.E.R. and A.J.L.), DK101573 (A.D.A.), GM131817 (H.E.B.), GM070683 (K.W.B. and G.A.C.); NIH National Center for Quantitative Biology of Complex Systems grant P41108538 (J.J.C.); NIH National Institute of Allergy and Infectious Diseases grant T32AI55397 (J.H.K.); NLM Computation and Informatics in Biology and Medicine Postdoctoral Fellowship 5T15LM007359 (L.L.T.) and T32DK007665 (L.L.T.) and NIH Chemistry-Biology Interface Training Grant T32 GM008505 (T.J.P.). This work was also supported by Fondation Leducq 17CVD01 (F.E.R.). V.L. was supported by the Foundation for Polish Science (MAB/2017/2 and START 064.2022), the European Molecular Biology Organization EMBO (Postdoctoral Fellowship ALTF 474-2021) and the National Science Centre, Poland (SONATINA 5 2021/40/C/NZ3/00283). The ‘Regenerative Mechanisms for Health - ReMedy’ project (MAB/2017/2) is carried out within the International Research Agendas Programme of the Foundation for Polish Science co-financed by the European Union under the European Regional Development Fund.


The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in vitro and in vivo studies revealed that A. muciniphila is a major source of these lipids in the gut, provided evidence that ornithine lipids have immunomodulatory effects and identified intestinal transcripts co-regulated with these traits including Atf3, which encodes for a transcription factor that plays vital roles in modulating metabolism and immunity. Collectively, these results suggest that ornithine lipids are potentially important for A. muciniphila-host interactions and support the role of host genetics as a determinant of responses to gut microbes.


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