https://orcid.org/0000-0003-3855-6664
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ABSTRACT
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.
GRAPHICAL ABSTARCT
Abbreviations
| DSS | = | Dextran sulfate sodium |
| FcγR | = | Fc gamma receptor |
| HRP | = | Horseradish Peroxidase |
| IBD | = | Inflammatory bowel disease |
| IFX | = | Infliximab |
| MCJ | = | Methylation-controlled J protein |
| OTU | = | Operational taxonomic unit |
| SCFA | = | Short-chain fatty acid |
| TACE | = | Tumor necrosis factor α-converting enzyme |
| TIMP3 | = | Tissue inhibitor of metalloproteinase 3 |
| TNF | = | Tumour necrosis factor |
| UC | = | Ulcerative colitis |
Acknowledgments
We thank Estibaliz Atondo for technical support.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Authors’ contributions
Conception and design of the study (LA), data collection (APC, JC, MAPI, VGJ, AP, DB, APa and LA), data analysis (APC, JLL, MGL, MAPI, MF, IS, AMA, JLL and LA), drafting the manuscript (APC, JA and LA), manuscript revision (HR and MLMC), statistical analysis (APC, JLL and LA), obtained funding (AF, IRL, JA, and LA), and technical support (LB and IMR). All authors approved the final version for publication.
Data availability statement
Raw sequences used for metagenomics analysis were made available at European Nucleotide Archive (ENA www.ebi.ac.uk/ena) under the project number PRJEB33422 for dysbiosis and PRJEB41595 for infliximab experiment. Raw sequences used to perform the transcriptomic analysis were uploaded to GEO (Gene Expression Omnibus) database under project accession code GSE135033 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?&acc=GSE135033).
Ethics approval
Animal protocols were approved by the Animal Research Ethics Board of CIC bioGUNE (Spain; permit number CBBA-0615). Collection of colon samples from IBD patients were approved by the Clinical Research Ethics Board of Euskadi (CEIC-E; code 16-12).
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2266626.