Mitochondrial dysfunction-associated microbiota establishes a transmissible refractory response to anti-TNF therapy during ulcerative colitis

Gut Microbes. 2023 Dec;15(2):2266626. doi: 10.1080/19490976.2023.2266626. Epub 2023 Oct 16.


Anti-TNF therapy can induce and maintain a remission status during intestinal bowel disease. However, up to 30% of patients do not respond to this therapy by mechanisms that are unknown. Here, we show that the absence of MCJ, a natural inhibitor of the respiratory chain Complex I, induces gut microbiota changes that are critical determinants of the lack of response in a murine model of DSS-induced inflammation. First, we found that MCJ expression is restricted to macrophages in human colonic tissue. Therefore, we demonstrate by transcriptomic analysis of colon macrophages from DSS-induced mice that MCJ-deficiency is linked to the expression of genes belonging to the FcγR signaling pathway and contains an anti-TNF refractory gene signature identified in ulcerative colitis patients. The gut microbial composition changes observed upon DSS treatment in the MCJ-deficient mice revealed the increased presence of specific colitogenic members, including Ruminococcus gnavus and Oscillospira, which could be associated with the non-response to TNF inhibitors. Further, we show that the presence of a microbiota associated resistance to treatment is dominant and transmissible to responsive individuals. Collectively, our findings underscore the critical role played by macrophage mitochondrial function in the gut ecological niche that can substantially affect not only the severity of inflammation but also the ability to successfully respond to current therapies.

Keywords: FcγR signaling; IBD; anti-TNF therapy; complex I; microbiota; mitochondriopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis* / chemically induced
  • Colitis, Ulcerative* / drug therapy
  • Colitis, Ulcerative* / metabolism
  • Colon / metabolism
  • Dextran Sulfate / adverse effects
  • Disease Models, Animal
  • Gastrointestinal Microbiome* / physiology
  • Humans
  • Inflammation / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microbiota*
  • Tumor Necrosis Factor Inhibitors / adverse effects
  • Tumor Necrosis Factor Inhibitors / metabolism


  • Tumor Necrosis Factor Inhibitors
  • Dextran Sulfate

Grants and funding

This work was supported by grant [RTI2018-096494-B-100 and PID2021-124328OBI00 to JA] from the Spanish Ministry of Economy and Competitiveness co-financed with FEDER funds, the V Grant from GETECCU-MSD (Grupo Español de Trabajo en Enfermedad de Crohn y Colitis ulcerosa to LA), Basque Government project for health [number 2015111117 to LA] and Research Committee from OSI Barrualde-Galdakao (2018-2-2 to IRL and LA). APC was a fellow of the University of the Basque Country (UPV/EHU) and is currently a postdoctoral fellow funded by the Basque Government. Support was provided by the Basque Department of Industry, Tourism and Trade (Etortek and Elkartek Programs) and the Innovation Technology Department of Bizkaia County. CIC bioGUNE thanks MINECO for the Severo Ochoa Excellence Accreditation [SEV-2016-0644].