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Mitochondrial dysfunction promotes microbial composition that negatively impacts on ulcerative colitis development and progression.

ABSTRACT: Recent evidence demonstrates potential links between mitochondrial dysfunction and inflammatory bowel diseases (IBD). In addition, bidirectional interactions between the intestinal microbiota and host mitochondria may modulate intestinal inflammation. We observed previously that mice deficient in the mitochondrial protein MCJ (Methylation-controlled J protein) exhibit increased susceptibility to DSS colitis. However, it is unclear whether this phenotype is primarily driven by MCJ^-/- associated gut microbiota dysbiosis or by direct effects of MCJ-deficiency. Here, we demonstrate that fecal microbiota transplantation (FMT) from MCJ-deficient into germ-free mice was sufficient to confer increased susceptibility to colitis. Therefore, an FMT experiment by cohousing was designed to alter MCJ-deficient microbiota. The phenotype resulting from complex I deficiency was reverted by FMT. In addition, we determined the protein expression pathways impacted by MCJ deficiency, providing insight into the pathophysiology of IBD. Further, we used magnetic activated cell sorting (MACS) and 16S rRNA gene sequencing to characterize taxa-specific coating of the intestinal microbiota with Immunoglobulin A (IgA-SEQ) in MCJ-deficient mice. We show that high IgA coating of fecal bacteria observed in MCJ-deficient mice play a potential role in disease progression. This study allowed us to identify potential microbial signatures in feces associated with complex I deficiency and disease progression. This research highlights the importance of finding microbial biomarkers, which might serve as predictors, permitting the stratification of ulcerative colitis (UC) patients into distinct clinical entities of the UC spectrum.

SUBMITTER: Pena-Cearra A

PROVIDER: S-EPMC10560208 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Mitochondrial dysfunction promotes microbial composition that negatively impacts on ulcerative colitis development and progression.

Peña-Cearra Ainize A Song Deguang D Castelo Janire J Palacios Ainhoa A Lavín Jose Luis JL Azkargorta Mikel M Elortza Felix F Fuertes Miguel M Pascual-Itoiz Miguel Angel MA Barriales Diego D Martín-Ruiz Itziar I Fullaondo Asier A Aransay Ana M AM Rodríguez Hector H Palm Noah W NW Anguita Juan J Abecia Leticia L

NPJ biofilms and microbiomes 20231007 1

Recent evidence demonstrates potential links between mitochondrial dysfunction and inflammatory bowel diseases (IBD). In addition, bidirectional interactions between the intestinal microbiota and host mitochondria may modulate intestinal inflammation. We observed previously that mice deficient in the mitochondrial protein MCJ (Methylation-controlled J protein) exhibit increased susceptibility to DSS colitis. However, it is unclear whether this phenotype is primarily driven by MCJ<sup>-/-</sup> a ...[more]

PMID: 37805634

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Project description:BackgroundAccumulating evidence reveals mitochondrial dysfunction exacerbates intestinal barrier dysfunction and inflammation. Despite the growing knowledge of mitochondrial dysfunction and ulcerative colitis (UC), the mechanism of mitochondrial dysfunction in UC remains to be fully explored.MethodsWe integrated 1137 UC colon mucosal samples from 12 multicenter cohorts worldwide to create a normalized compendium. Differentially expressed mitochondria-related genes (DE-MiRGs) in individuals with UC were identified using the "Limma" R package. Unsupervised consensus clustering was utilized to determine the intrinsic subtypes of UC driven by DE-MiRGs. Weighted gene co-expression network analysis was employed to investigate module genes related to UC. Four machine learning algorithms were utilized for screening DE-MiRGs in UC and construct MiRGs diagnostic models. The models were developed utilizing the over-sampled training cohort, followed by validation in both the internal test cohort and the external validation cohort. Immune cell infiltration was assessed using the Xcell and CIBERSORT algorithms, while potential biological mechanisms were explored through GSVA and GSEA algorithms. Hub genes were selected using the PPI network.ResultsThe study identified 108 DE-MiRGs in the colonic mucosa of patients with UC compared to healthy controls, showing significant enrichment in pathways associated with mitochondrial metabolism and inflammation. The MiRGs diagnostic models for UC were constructed based on 17 signature genes identified through various machine learning algorithms, demonstrated excellent predictive capabilities. Utilizing the identified DE-MiRGs from the normalized compendium, 941 patients with UC were stratified into three subtypes characterized by distinct cellular and molecular profiles. Specifically, the metabolic subtype demonstrated enrichment in epithelial cells, the immune-inflamed subtype displayed high enrichment in antigen-presenting cells and pathways related to pro-inflammatory activation, and the transitional subtype exhibited moderate activation across all signaling pathways. Importantly, the immune-inflamed subtype exhibited a stronger correlation with superior response to four biologics: infliximab, ustekinumab, vedolizumab, and golimumab compared to the metabolic subtype.ConclusionThis analysis unveils the interplay between mitochondrial dysfunction and the immune microenvironment in UC, thereby offering novel perspectives on the potential pathogenesis of UC and precision treatment of UC patients, and identifying new therapeutic targets.

Project description:BackgroundDisturbed bile acid homeostasis associated with a rise of primary and a decline of secondary bile acids is a consistent finding in inflammatory bowel diseases (IBDs). Whether fecal bile acids may emerge as biomarkers for IBD diagnosis and disease severity is less clear. Our study aimed to identify associations of 18 fecal bile acid species with IBD entity and disease activity.MethodsStool samples of 62 IBD patients and 17 controls were collected. Eighteen fecal bile acid species were quantified by LC-MS/MS using stable isotope dilution. Lipid levels normalized to a dry weight of the fecal homogenates and ratios of single bile acid species to total bile acid levels were used for calculations.ResultsIBD patients exhibited altered primary and secondary bile acid ratios in stool, with notable distinctions between ulcerative colitis (UC) compared to Crohn's disease (CD) and healthy controls. Fecal calprotectin was negatively correlated with glycolithocholic acid (GLCA) and hyodeoxycholic acid (HDCA) in UC. These bile acids were reduced in stool of UC patients with fecal calprotectin levels > 500 µg/g compared to UC patients with low calprotectin levels. Moreover, negative associations of six secondary bile acids with C-reactive protein (CRP) existed in UC. In CD patients, fecal bile acids did not correlate with CRP or fecal calprotectin. Diarrhoea is common in IBD, and UC patients with diarrhoea had reduced deoxycholic acid (DCA), glycine conjugated DCA (GDCA) and lithocholic acid in stool in contrast to patients with normal stool consistency. Fecal bile acid levels were not associated with diarrhoea in CD patients. UC patients treated with mesalazine had increased levels of fecal GDCA whereas no such changes were observed in CD patients. Bile acid levels of CD and UC patients treated with biologicals or corticosteroids did not change. Relative levels of GHDCA (specificity: 79%, sensitivity: 67%) and glycochenodeoxycholic acid (specificity: 74%, sensitivity: 63%) were the most specific to distinguish UC from CD.ConclusionDisrupted fecal bile acid homeostasis is associated with disease severity and disease symptoms in UC but not in CD, potentially aiding in distinguishing IBD subtypes and classifying the pathophysiology of diarrhoea in UC.

Dataset Information

Mitochondrial dysfunction promotes microbial composition that negatively impacts on ulcerative colitis development and progression.

Publications

Mitochondrial dysfunction promotes microbial composition that negatively impacts on ulcerative colitis development and progression.

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