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

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 cholic acid-derived bile acids, BA (DCA) and the accumulation of tauro-conjugated primary BA (TCDCA, T-abo-MCA) in the plasma of patients and mice. DCA/GDCA (glyco-DCA) compensated dysbiosis bile acid abnormalities and circumvented primary resistance to PD-1 blockade. GDCA curtailed ABX-induced MAdCAM-1 downregulation and seemed to have an impact on anti tumor immunity. The single cell RNA sequencing in a mouse model of MCA205 fibrosarcoma helped us to characterize the effect of GDCA or DCA on anti tumor immunity and showed a decrease in T cell exhaustion in the TME.