Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease
M Llopis
(1, 2, 3)
,
Anne-Marie Cassard
(4, 5, 6, 7, 8, 9, 1, 10, 11)
,
L Wrzosek
(1, 2)
,
L Boschat
(3)
,
A Bruneau
(3)
,
G Ferrere
(1, 2)
,
V Puchois
(1, 2)
,
J Martin
(12, 13, 14)
,
P Lepage
(15)
,
T Le Roy
(16)
,
L Lefèvre
(17)
,
B Langelier
(18, 19)
,
F Cailleux
(1, 2)
,
A González-Castro
(20)
,
S Rabot
(3)
,
F Gaudin
(21)
,
H Agostini
(22)
,
S Prévot
(23)
,
D Berrebi
(24)
,
D Ciocan
(1, 2, 25)
,
C Jousse
(26)
,
S Naveau
(9, 27, 28)
,
P Gérard
(3)
,
G Perlemuter
(9, 27, 28)
1
Cytokines, chimiokines et immunopathologie
2 DHU - Hepatinov
3 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé
4 Université Paris-Saclay
5 INSERM - Institut National de la Santé et de la Recherche Médicale
6 LERMIT - Laboratory of Excellence in Research on Medication and Innovative Therapeutics
7 U996 DHU Hépatinov
8 FHU PaCeMM - Paris Center for Microbiome Medicine
9 MI2 - Inflammation, microbiome, immunosurveillance
10 CREMD - Centre de recherche sur l'endocrinologie moléculaire et le développement
11 BIOTRAM - Biologie des Transporteurs Mitochondriaux et Métabolisme
12 IJL - Institut Jean Lamour
13 Labex DAMAS
14 LEM3 - Laboratoire d'Etude des Microstructures et de Mécanique des Matériaux
15 PNCA - Physiologie de la Nutrition et du Comportement Alimentaire
16 UNICANCER/Lille - Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille]
17 GABI - Génétique Animale et Biologie Intégrative
18 University of Waterloo [Waterloo]
19 Department of Materials Science and Engineering and Canadian Centre for Electron Microscopy, McMaster University
20 Vall d'Hebron University Hospital [Barcelona]
21 IPSIT - Ingénierie et Plateformes au Service de l'Innovation Thérapeutique de Paris Saclay
22 AP-HP, Hôpital Bicêtre, Unité de recherche clinique Paris-Sud,
23 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
24 AP-HP, Anatomie et de Cytologie Pathologiques, Hôpital Robert Debré
25 AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère
26 ICCF - Institut de Chimie de Clermont-Ferrand
27 DHU Hepatinov
28 AP-HP - Hôpital Antoine Béclère [Clamart]
2 DHU - Hepatinov
3 MICALIS - MICrobiologie de l'ALImentation au Service de la Santé
4 Université Paris-Saclay
5 INSERM - Institut National de la Santé et de la Recherche Médicale
6 LERMIT - Laboratory of Excellence in Research on Medication and Innovative Therapeutics
7 U996 DHU Hépatinov
8 FHU PaCeMM - Paris Center for Microbiome Medicine
9 MI2 - Inflammation, microbiome, immunosurveillance
10 CREMD - Centre de recherche sur l'endocrinologie moléculaire et le développement
11 BIOTRAM - Biologie des Transporteurs Mitochondriaux et Métabolisme
12 IJL - Institut Jean Lamour
13 Labex DAMAS
14 LEM3 - Laboratoire d'Etude des Microstructures et de Mécanique des Matériaux
15 PNCA - Physiologie de la Nutrition et du Comportement Alimentaire
16 UNICANCER/Lille - Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille]
17 GABI - Génétique Animale et Biologie Intégrative
18 University of Waterloo [Waterloo]
19 Department of Materials Science and Engineering and Canadian Centre for Electron Microscopy, McMaster University
20 Vall d'Hebron University Hospital [Barcelona]
21 IPSIT - Ingénierie et Plateformes au Service de l'Innovation Thérapeutique de Paris Saclay
22 AP-HP, Hôpital Bicêtre, Unité de recherche clinique Paris-Sud,
23 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
24 AP-HP, Anatomie et de Cytologie Pathologiques, Hôpital Robert Debré
25 AP-HP, Hepatogastroenterology and Nutrition, Hôpital Antoine-Béclère
26 ICCF - Institut de Chimie de Clermont-Ferrand
27 DHU Hepatinov
28 AP-HP - Hôpital Antoine Béclère [Clamart]
Anne-Marie Cassard
- Fonction : Auteur
- PersonId : 1420958
- IdHAL : anne-marie-cassard
- ORCID : 0000-0002-1813-5128
- IdRef : 096151781
G Perlemuter
- Fonction : Auteur correspondant
Résumé
Objective There is substantial inter-individual diversity in the susceptibility of alcoholics to liver injury. Alterations of intestinal microbiota (IM) have been reported in alcoholic liver disease (ALD), but the extent to which they are merely a consequence or a cause is unknown. We aimed to demonstrate that a specific dysbiosis contributes to the development of alcoholic hepatitis (AH).
Design We humanised germ-free and conventional mice using human IM transplant from alcoholic patients with or without AH. The consequences on alcohol-fed recipient mice were studied.
Results A specific dysbiosis was associated with ALD severity in patients. Mice harbouring the IM from a patient with severe AH (sAH) developed more severe liver inflammation with an increased number of liver T lymphocyte subsets and Natural Killer T (NKT) lymphocytes, higher liver necrosis, greater intestinal permeability and higher translocation of bacteria than mice harbouring the IM from an alcoholic patient without AH (noAH). Similarly, CD45+ lymphocyte subsets were increased in visceral adipose tissue, and CD4(+) T and NKT lymphocytes in mesenteric lymph nodes. The IM associated with sAH and noAH could be distinguished by differences in bacterial abundance and composition. Key deleterious species were associated with sAH while the Faecalibacterium genus was associated with noAH. Ursodeoxycholic acid was more abundant in faeces from noAH mice. Additionally, in conventional mice humanised with the IM from an sAH patient, a second subsequent transfer of IM from an noAH patient improved alcohol-induced liver lesions.
Conclusions Individual susceptibility to ALD is substantially driven by IM. It may, therefore, be possible to prevent and manage ALD by IM manipulation.