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We would like to thank Dr. Richard H. Barton for generating the 1H NMR spectra for the discovery cohort and validation cohort 1. This work was funded by ISCIII (PI20/01090) cofunded by ERDF, "A way to make Europe" (to J.M.-P) , and ISCIII (CP18/0009) cofunded by ESF, "Investing in your future" (to J.M.-P) . This work was also partially funded by Instituto de Salud Carlos III (ISCIII, Madrid, Spain) through the projects PI15/01934, PI18/01022, and PI21/01361 to J.M.F-R, Generalitat de Catalunya 2021 -SGR -01263 and 2022 -SGR -01556 and funding grant ACCIO-Eurecat (PRIV2020-EURHEPAD) (to X.E.) , and EU METACARDIS under agreement HEALTH-F4-2012-305312 and MRC MR/M501797/1 (to M.-E.D.) . L.H. received an MRC Intermediate Research Fellowship (MR/L01632X/1, UK Med-Bio) . N.B. and N.T. were supported by BBSRC through BB/R012504/1, BBS/E/F/000PR10349, BBS/E/F/00044509, and BB/R012490/1. F.H. was supported by ERC -H2020 StG (erc-stg-948219, EPYC) and BBSRC BB/r012490/1 and BBS/e/F/000Pr10355. S.Q.-V. was supported by the Vicente Lopez fellowship (Eurecat) . IDIBGI is a CERCA center from the CERCA Program/Generalitat de Catalunya.

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Potential therapeutic implications of histidine catabolism by the gut microbiota in NAFLD patients with morbid obesity

Publicated to:Cell Rep Med. 4 (12): - 2023-12-19 4(12), DOI: 10.1016/j.xcrm.2023.101341

Authors: Quesada-Vazquez, Sergio; Castells-Nobau, Anna; Latorre, Jessica; Oliveras-Canellas, Nuria; Puig-Parnau, Irene; Tejera, Noemi; Tobajas, Yaiza; Baudin, Julio; Hildebrand, Falk; Beraza, Naiara; Burcelin, Remy; Martinez-Gili, Laura; Chilloux, Julien; Dumas, Marc-Emmanuel; Federici, Massimo; Hoyles, Lesley; Caimari, Antoni; Bas, Josep M del; Escote, Xavier; Fernandez-Real, Jose-Manuel; Mayneris-Perxachs, Jordi

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Abstract

The gut microbiota contributes to the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Histidine is a key energy source for the microbiota, scavenging it from the host. Its role in NAFLD is poorly known. Plasma metabolomics, liver transcriptomics, and fecal metagenomics were performed in three human co-horts coupled with hepatocyte, rodent, and Drosophila models. Machine learning analyses identified plasma histidine as being strongly inversely associated with steatosis and linked to a hepatic transcriptomic signature involved in insulin signaling, inflammation, and trace amine-associated receptor 1. Circulating histidine was inversely associated with Proteobacteria and positively with bacteria lacking the histidine utilization (Hut) system. Histidine supplementation improved NAFLD in different animal models (diet-induced NAFLD in mouse and flies, ob/ob mouse, and ovariectomized rats) and reduced de novo lipogenesis. Fecal microbiota transplantation (FMT) from low-histidine donors and mono-colonization of germ-free flies with Enterobacter cloacae increased triglyceride accumulation and reduced histidine content. The interplay among microbiota, histidine catabolism, and NAFLD opens therapeutic opportunities.

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