An obesogenic diet increases atherosclerosis through promoting microbiota dysbiosis-induced gut lymphocyte trafficking into the periphery
Ludivine Laurans,
Nirmala Mouttoulingam,
Mouna Chajadine,
Aonghus Lavelle,
Marc Diedisheim,
Emilie Bacquer,
Laura Creusot,
Nadine Suffee,
Bruno Esposito,
Nada Joe Melhem,
Wilfried Le Goff,
Yacine Haddad,
Jean-Louis Paul,
Dominique Rainteau,
Alain Tedgui,
Hafid Ait-Oufella,
Laurence Zitvogel,
Harry Sokol,
Soraya Taleb
Affiliations
Ludivine Laurans
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France
Nirmala Mouttoulingam
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France
Mouna Chajadine
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France
Aonghus Lavelle
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, 75012 Paris, France; Paris Centre for Microbiome Medicine (PaCeMM) FHU, Paris, France
Marc Diedisheim
Clinique Saint Gatien Alliance (NCT+), 37540 Saint-Cyr-sur-Loire, France; Institut Necker-Enfants Malades (INEM), Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, 75015 Paris, France
Emilie Bacquer
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France
Laura Creusot
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, 75012 Paris, France; Paris Centre for Microbiome Medicine (PaCeMM) FHU, Paris, France
Nadine Suffee
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France; INSERM UMRS1166, ICAN-Institute of Cardiometabolism and Nutrition, Sorbonne University, 75013 Paris, France
Bruno Esposito
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France
Nada Joe Melhem
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France
Wilfried Le Goff
INSERM UMRS1166, ICAN-Institute of Cardiometabolism and Nutrition, Sorbonne University, 75013 Paris, France
Yacine Haddad
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France; Gustave Roussy, Villejuif, France; Institut National de la Santé et de la Recherche Médicale, Gustave Roussy, UMR1015, Villejuif, France
Jean-Louis Paul
Université Paris-Sud, Equipe d’Accueil 4529, UFR de Pharmacie, Chatenay-Malabry, France and Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
Dominique Rainteau
Paris Centre for Microbiome Medicine (PaCeMM) FHU, Paris, France; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Clinical Metabolomics Department, 75012 Paris, France
Alain Tedgui
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France
Hafid Ait-Oufella
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France
Laurence Zitvogel
Gustave Roussy, Villejuif, France; Institut National de la Santé et de la Recherche Médicale, Gustave Roussy, UMR1015, Villejuif, France; Université Paris-Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France; Center of Clinical Investigations BIOTHERIS, INSERM CIC1428, Gustave Roussy, Villejuif, France
Harry Sokol
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital, Gastroenterology Department, 75012 Paris, France; Paris Centre for Microbiome Medicine (PaCeMM) FHU, Paris, France; INRAe, Micalis & AgroParisTech, Jouy en Josas, France
Soraya Taleb
Université Paris Cité, INSERM, Paris Cardiovascular Research Center, 75015 Paris, France; Corresponding author
Summary: Although high-fat diet (HFD)-induced gut microbiota dysbiosis is known to affect atherosclerosis, the underlying mechanisms remain to be fully explored. Here, we show that the progression of atherosclerosis depends on a gut microbiota shaped by an HFD but not a high-cholesterol (HC) diet and, more particularly, on low fiber (LF) intake. Mechanistically, gut lymphoid cells impacted by HFD- or LF-induced microbiota dysbiosis highly proliferate in mesenteric lymph nodes (MLNs) and migrate from MLNs to the periphery, which fuels T cell accumulation within atherosclerotic plaques. This is associated with the induction of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) within plaques and the presence of enterotropic lymphocytes expressing β7 integrin. MLN resection or lymphocyte deficiency abrogates the pro-atherogenic effects of a microbiota shaped by LF. Our study shows a pathological link between a diet-shaped microbiota, gut immune cells, and atherosclerosis, suggesting that a diet-modulated microbiome might be a suitable therapeutic target to prevent atherosclerosis.
