The mitochondrial negative regulator MCJ modulates the interplay between microbiota and the host during ulcerative colitis

Abstract

Recent evidences indicate that mitochondrial genes and function are decreased in active ulcerative colitis (UC) patients, in particular, the activity of Complex I of the electron transport chain is heavily compromised. MCJ is a mitochondrial inner membrane protein identified as a natural inhibitor of respiratory chain Complex I. The induction of experimental colitis in MCJ-deficient mice leads to the upregulation of Timp3 expression resulting in the inhibition of TACE activity that likely inhibits Tnf and Tnfr1 shedding from the cell membrane in the colon. MCJ-deficient mice also show higher expression of Myd88 and Tlr9, proinflammatory genes and disease severity. Interestingly, the absence of MCJ resulted in distinct microbiota metabolism and composition, including a member of the gut community in UC patients, Ruminococcus gnavus. These changes provoked an effect on IgA levels. Gene expression analyses in UC patients showed decreased levels of MCJ and higher expression of TIMP3, suggesting a relevant role of mitochondrial genes and function among active UC. The MCJ deficiency disturbs the regulatory relationship between the host mitochondria and microbiota affecting disease severity. Our results indicate that mitochondria function may be an important factor in the pathogenesis. All together support the importance of MCJ regulation during UC.

Avian intestinal ultrastructure changes provide insight into the pathogenesis of enteric diseases and probiotic mode of action

“…The lack of ATP could have been a potential www.nature.com/scientificreports/ factor, as ATP is central for cell renewal 48 . Studies in humans (IBD) suggest that both mitochondrial dysfunction and increased gut permeability affect the overall competence of the intestinal epithelial barrier 41,49 , but the stimuli that initiate either process is not known. However, in the current study, enterocytes of NE & H57 birds were intact and with normal-appearing cytoplasm and mitochondria (Fig.…”

Single Donor FMT Reverses Microbial/Immune Dysbiosis and Induces Clinical Remission in a Rat Model of Acute Colitis

“…Changes in the Firmicutes-to-Bacteroidetes ratio are frequently used in the literature to indicate dysbiosis, possibly caused by disease state [ 41 , 42 ] and possibly due to their positive association with TNF-α and IL-1β production, which are critical cytokines involved in the regulation of immune cells [ 43 , 44 , 45 ]. In a recent study with DSS-induced colitis in mice, the microbial analysis indicated similar results with a large shift in microbiota favouring the presence of Firmicutes and suppressing Bacteroidetes due to decreased levels of unclassified genus from Bacteroidetes S24–7 family, Bacteroides and Prevotella [ 46 ]. The phylum Firmicutes includes Gram-positive bacteria with rigid or semi-rigid cell walls that are predominantly from the genera Clostridium , Bacillus , Enterococcus , Lactobacillus and Ruminicoccus .…”

Immunoglobulin A, an Active Liaison for Host-Microbiota Homeostasis

“…In addition, the MyD88 deficient mice displayed exacerbated colitis severity with gut dysbiosis highlighted by an overabundance of SFB and increased bacterial load, indicating MyD88 signaling is needed in IgA responses to IBD and gut dysbiosis [176,177]. Comparatively, deletion of methylation-controlled J protein (a mitochondrial inner membrane protein) caused a bloom in the IBD-associated bacterium Ruminococcus gnavus, but surprisingly increased SIgA levels [178]. Likewise, indoleamine 2,3-dioxygenase (IDO) knockout mice had higher basal levels of SIgA reactive toward Citrobacter rodentium and were resistant to Citrobacter-induced colitis [179].…”