Fusobacterium nucleatum Aggravates the Progression of Colitis by Regulating M1 Macrophage Polarization via AKT2 Pathway

Abstract

Disordered intestinal flora and discordant immune response are associated with the development of ulcerative colitis (UC). Recent work has described the ability of macrophages to undergo repolarization toward a proinflammatory M1 or anti-inflammatory M2 phenotype in response to particular bacterium-derived signals. Fusobacterium nucleatum ( F. nucleatum, Fn ) is a species of intestinal commensal bacteria with potential pathogenicity, but its association with UC and how it may contribute to progression of UC is largely unknown. In this study, we provide new evidence that F. nucleatum accumulated heavily in the intestine of UC patients and was accompanied by the secretion of IFN-γ and the skewing of M1 macrophages. Mechanistically, our data showed that F. nucleatum aggravated dextran sodium sulfate (DSS)-induced colitis in the production of Th1-related cytokines IFN-γ through the AKT2 signaling pathway in vitro and in vivo . To further confirm the disease-relevance of these shifts in macrophage repolarization in response to F. nucleatum , stimulated bone marrow-derived macrophages (BMDMs) were transferred into recipient mice with DSS colitis. This transfer resulted in increased disease activity and inflammatory cytokine production. Taken together, we show clearly that F. nucleatum can promote the progression of UC via proinflammatory M1 macrophage skewing, and targeting F. nucleatum or AKT2 signaling may be a viable means of blocking development of UC.

Gut Dysbiosis Is Related With Activity And Remission Phases Of Ulcerative Colitis And Healthy Condition

“…Consistently, we found a signi cant ability of the genus Bilophila and Fusobacterium to selectively associate with cases of UC activity/remission. This agrees with the literature that describes a functional role for these bacteria in UC [64,65,66,67] and suggests its potential clinical bene t for an early identi cation of clinical-therapeutic phases of UC [68,69].…”

Intestinal Flora and Disease Mutually Shape the Regional Immune System in the Intestinal Tract

“…The key direct effect induced by disorders of the intestinal microbiota is the destruction of immune system homeostasis in the intestinal tract, which leads to various gastrointestinal diseases (11,12). For instance, Liu et al reported that F. nucleatum aggravates progression of ulcerative colitis (77). Specifically, the bacterium induces M1 differentiation of macrophages in the intestinal mucosal lymphoid tissue; simultaneously, the Th1-associated cytokine IFN-γ is produced by the AKT2 signaling pathway, aggravating the disease (77).…”

“…For instance, Liu et al reported that F. nucleatum aggravates progression of ulcerative colitis (77). Specifically, the bacterium induces M1 differentiation of macrophages in the intestinal mucosal lymphoid tissue; simultaneously, the Th1-associated cytokine IFN-γ is produced by the AKT2 signaling pathway, aggravating the disease (77). Moreover, in colitis, the intestinal microbiota and specific microbial components activate downstream MyD88 and PI3K pathways through TLR2, to activate IL-10-producing B cells.…”

Essential Role of Nonessential Amino Acid Glutamine in Atherosclerotic Cardiovascular Disease

“…The differentiation and activation of monocytes or macrophages are the key processes for the development and stability of As (Cochain and Zernecke, 2015). During this illness, monocytes migrate from the bloodstream into the subintima and differentiate into macrophages, which then undergo different polarization states after being stimulated by different signals (Kawano et al, 2019;Liu et al, 2019). The activation states of macrophages are divided into M1 (classical activation) and M2 (alternatively activation) polarizations (Murray et al, 2014).…”