Role of IM in ALD and the development of new therapeutic approaches

Home / Teams / Team III / Role of IM in ALD and the development of new therapeutic approaches

Alcoholic liver disease (ALD) is the leading cause of cirrhosis worldwide, with few therapeutic options other than alcohol withdrawal. Patients with chronic alcohol consumption are susceptible to developing severe alcoholic hepatitis and even hepatocellular carcinoma (HCC). Our previous studies have shown that this susceptibility is associated with specific microbiota profiles in both mice and humans. We demonstrated that soluble fiber (pectin) prevents and improves alcohol-induced liver injury in mice. We showed that pectin improves ALD by modulating bile acid metabolism and tryptophan derivatives. Tryptophan derivatives, including indoles, are produced by the gut microbiota and modulate the host homeostasis through the receptor for aryl hydrocarbon (AhR). Moreover, we demonstrated that the aryl hydrocarbon receptor (AhR) plays an important role in gut homeostasis by regulating anti-microbial peptide and mucus production by IL-22 which has been proven to improve ALD.

In our current studies, we are trying to decipher by which molecular mechanisms, indoles and AhR improve alcoholic liver injury.

We have also initiated clinical trials to study the role of microbiome modulation in alcohol use disorders.

  • Ciocan D, Spatz M, Trainel N, Hardonnière K, Domenichini S, Mercier-Nomé F, Desmons A, Humbert L, Durand S, Kroemer G, Lamazière A, Hugot C, Perlemuter G, Cassard AM. Modulation of the Bile Acid Enterohepatic Cycle by Intestinal Microbiota Alleviates Alcohol Liver Disease. Cells. 2022 Mar 11;11(6):968. doi: 10.3390/cells11060968.
  • Spatz M, Ciocan D, Merlen G, Rainteau D, Humbert L, Gomes-Rochette N, Hugot C, Trainel N, Mercier-Nomé F, Domenichini S, Puchois V, Wrzosek L, Ferrere G, Tordjmann T, Perlemuter G, Cassard AM. Bile acid-receptor TGR5 deficiency worsens liver injury in alcohol-fed mice through intestinal microbiota dysbiosis. JHEP Reports, 2021 Jan 19;3(2):100230. doi: 10.1016/j.jhepr.2021.100230.
  • Wrzosek L, Ciocan D, Hugot C, Spatz M, Dupeux M, Houron C, Lievin-Le Moal V, Puchois V, Ferrere G, Trainel N, Mercier-Nomé F, S. Domenichini, Durand S, Kroemer G, Voican CS, Emond P, Straube M, Sokol H, Perlemuter G, Cassard AM. Microbiota tryptophan metabolism induces aryl hydrocarbon receptor activation and improves alcohol-induced liver injury. Gut 2021, Jul;70(7):1299-1308. doi: 10.1136/gutjnl-2020-321565.
  • Ciocan D, Voican CS, Wrzosek L, Hugot C, Rainteau D, Humbert L, Cassard AM, Perlemuter G. Bile acid homeostasis and intestinal dysbiosis in alcoholic hepatitis. Aliment Pharmacol Ther. 2018 Nov;48(9):961-974. doi: 10.1111/apt.14949. Epub 2018 Aug 24.
  • Wrzosek L, Ciocan D, Borentain P, Spatz M, Puchois V, Hugot C, Ferrere G, Mayeur C, Perlemuter G, Cassard AM. Transplantation of human microbiota into conventional mice durably reshapes the gut microbiota. Sci Rep. 2018 May 1;8(1):6854. doi: 10.1038/s41598-018-25300-3.
  • Ciocan D, Rebours V, Voican CS, Wrzosek L, Puchois V, Cassard AM, Perlemuter G. Characterization of intestinal microbiota in alcoholic patients with and without alcoholic hepatitis or chronic alcoholic pancreatitis. Sci Rep. 2018 Mar 19;8(1):4822. doi: 10.1038/s41598-018-23146-3.
  • Llopis M, Cassard AM, Wrzosek L, Boschat L, Bruneau A, Ferrere G, Puchois V, Martin JC, Lepage P, Le Roy T, Lefevre L, Langelier B, Cailleux F, Gonzalez-Castro AM, Rabot S, Gaudin F, Agostini H, Prevot S, Berrebi D, Ciocan D, Jousse C, Naveau S, Gerard P, Perlemuter G. Intestinal microbiota contributes to individual susceptibility to alcoholic liver disease, Gut, 2016, 65, 830-839
  • Ratiner K, Ciocan D, Abdeen S.K, Elinav E. Utilization of the microbiome in personalized medicine. Nat. Rev. Microbiol. 2023, doi: 10.1038/s41579-023-00998-9.
  • Hu W, Cassard AM, Ciocan D. Pectin in Metabolic Liver Disease. Nutrients. 2022 Dec 29;15(1):157. doi: 10.3390/nu15010157.
  • Ciocan D, Cassard AM. In the quest for treating alcohol liver disease. EBioMedicine. 2022 May 27;81:104086. doi: 10.1016/j.ebiom.2022.104086. Online ahead of print.
  • Ciocan D, Cassard AM. Intestinal bacteria involved in nutritional liver disease killed by phagotherapy: a new therapeutic target. Med Sci (Paris). 2020 Apr;36(4):310-312.  doi: 10.1051/medsci/2020052.
  • Cassard AM., Houron C., Ciocan D. Intestinal microbiota and non alcoholic fatty liver disease. Nutrition clinique et métabolisme. Vol. 34, 2020. doi: 10.1016/j.nupar.2019.12.002
  • Ciocan D., Wrzosek L., Cassard AM., Perlemuter G. Microbiota and liver Diseases. Hépato-Gastro et Oncologie Digestive 2019 ; 26 : 402-408. doi : 10.1684/hpg.2019.1768
  • Perlemuter G. Circulating bugs in blood in alcoholic liver disease! Hepatology. 2018 Apr;67(4):1207-1209. doi: 10.1002/hep.29624.