Peer-reviewedCC BY-NC 4.0Cancer Cell
Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy
Abstract
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.
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BibTeX
@article{varende2026subclinical,
title = {{Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy}},
author = {Anne-Laure Mallard de la Varende and Ai-Ling Tian and Simon Thomas and Imran Lahmar and Meriem Messaoudene and Sijing Li and Omar Motiño and Hortense Guillaume-Dit-Taunière and Valerio Iebba and Yoan Hurtado and Thao-Nguyen Pham and Cassandra Thélémaque and Miguel Araujo-Voces and Deborah Suissa and Pierre Ly and Ella Reich and Giacomo Vitali and Bryan Thierry Arlunno and Sylvere Durand and Fanny Aprahamian and Marion Leduc and Sabrina Forveille and Oliver Kepp and Carlos de la Calle-Fabregat and Angela Schippers and Norbert Wagner and Pierre-Edouard Fournier and Kenya Honda and Federica Marmorino and Chiara Cremolini and Saman Maleki Vareki and John G Lenehan and Aurélien Marabelle and François-Xavier Danlos and Margaux Deligne and Caroline Truntzer and François Ghiringhelli and Anne H Ree and Paula A Bousquet and Sebastian Meltzer and Florent Ginhoux and Deklan Rummel and Yousi Fu and Robert A Quinn and Carolina Alves Costa Silva and Roberto Iacovelli and Chiara Ciccarese and Serena Porcari and Arielle Elkrief and Bertrand Routy and Gianluca Ianiro and Lisa Derosa and Guido Kroemer and Marine Fidelle and Laurence Zitvogel},
journal = {Cancer Cell},
year = {2026},
month = jul,
doi = {10.1016/j.ccell.2026.06.022},
url = {https://hal.science/hal-05738805v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Subclinical cholestasis is a hallmark of gut dysbiosis causing resistance to cancer immunotherapy
AU - Anne-Laure Mallard de la Varende
AU - Ai-Ling Tian
AU - Simon Thomas
AU - Imran Lahmar
AU - Meriem Messaoudene
AU - Sijing Li
AU - Omar Motiño
AU - Hortense Guillaume-Dit-Taunière
AU - Valerio Iebba
AU - Yoan Hurtado
AU - Thao-Nguyen Pham
AU - Cassandra Thélémaque
AU - Miguel Araujo-Voces
AU - Deborah Suissa
AU - Pierre Ly
AU - Ella Reich
AU - Giacomo Vitali
AU - Bryan Thierry Arlunno
AU - Sylvere Durand
AU - Fanny Aprahamian
AU - Marion Leduc
AU - Sabrina Forveille
AU - Oliver Kepp
AU - Carlos de la Calle-Fabregat
AU - Angela Schippers
AU - Norbert Wagner
AU - Pierre-Edouard Fournier
AU - Kenya Honda
AU - Federica Marmorino
AU - Chiara Cremolini
AU - Saman Maleki Vareki
AU - John G Lenehan
AU - Aurélien Marabelle
AU - François-Xavier Danlos
AU - Margaux Deligne
AU - Caroline Truntzer
AU - François Ghiringhelli
AU - Anne H Ree
AU - Paula A Bousquet
AU - Sebastian Meltzer
AU - Florent Ginhoux
AU - Deklan Rummel
AU - Yousi Fu
AU - Robert A Quinn
AU - Carolina Alves Costa Silva
AU - Roberto Iacovelli
AU - Chiara Ciccarese
AU - Serena Porcari
AU - Arielle Elkrief
AU - Bertrand Routy
AU - Gianluca Ianiro
AU - Lisa Derosa
AU - Guido Kroemer
AU - Marine Fidelle
AU - Laurence Zitvogel
PY - 2026
DA - 2026/07/29
JO - Cancer Cell
DO - 10.1016/j.ccell.2026.06.022
UR - https://hal.science/hal-05738805v1
AB - 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.
SN - 1535-6108
ER -