Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy.

Date publication

juillet 2026

Journal

Cancer cell

Auteurs

Membres identifiés du Cancéropôle Est :
Pr GHIRINGHELLI François , Mme TRUNTZER Caroline

Tous les auteurs :
Mallard de La Varende AL, Tian AL, Thomas S, Lahmar I, Messaoudene M, Li S, Motiño O, Guillaume-Dit-Taunière H, Iebba V, Hurtado Y, Pham TN, Thélémaque C, Araujo-Voces M, Suissa D, Ly P, Reich E, Vitali G, Arlunno BT, Durand S, Aprahamian F, Leduc M, Forveille S, Kepp O, de la Calle-Fabregat C, Schippers A, Wagner N, Fournier PE, Honda K, Marmorino F, Cremolini C, Maleki Vareki S, Lenehan JG, Marabelle A, Danlos FX, Deligne M, Truntzer C, Ghiringhelli F, Ree AH, Bousquet PA, Meltzer S, Ginhoux F, Rummel D, Fu Y, Quinn RA, Alves Costa Silva C, Iacovelli R, Ciccarese C, Porcari S, Elkrief A, Routy B, Ianiro G, Derosa L, Kroemer G, Fidelle M, Zitvogel L

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/42526445

Résumé

Gut dysbiosis compromises cancer immunosurveillance by downregulating ileal mucosal addressin cell adhesion molecule 1 (MAdCAM-1), but the metabolic landscape associated with gut dysbiosis remains elusive. Here, we show that antibiotics (ABX) or ABX-associated Enterocloster species lead to the loss of secondary bile acids (BAs) including deoxycholic acid (DCA) and the accumulation of tauro-conjugated primary BAs (tauro-chenodeoxycholic acid [TCDCA] and tauro-β-muricholic acid [T-βMCA]) from the alternative pathway in the plasma of patients and mice. Fecal microbial transplantation (FMT), the ileum-specific farnesoid X receptor (FXR) agonist fexaramine, or glycodeoxycholic acid (GDCA) compensated dysbiosis-associated BA abnormalities and circumvent primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and T cell exhaustion in tumors. Subclinical cholestasis defined by elevation of γ-glutamyl transferase (γGT) correlated with increased TCDCA and decreased soluble MAdCAM-1 in plasma and predicted poor survival in multivariate analyses in six cohorts of patients who received immunotherapy. Hence, subclinical cholestasis accompanies gut dysbiosis, paving the way to immunoresistance.

Mots clés

MAdCAM-1, PD-1, antibiotics, bile acids, cancer, gut microbiota, immune checkpoint blockade, immunotherapy, microbiome, mucosal addressin cell adhesion molecule 1

Référence

Cancer Cell. 2026 07 29;: