Abstract
SummaryInflammatory macrophages play a critical role in gut and extra-gut inflammatory disorders, which may be promoted through the dysbiosis of gut microbiota. However, it is poorly understood how gut microbiota affect inflammatory macrophages. Here, we found that increased Escherichia coli (E. coli) in inflamed colon may induce inflammatory macrophages in gut and extra-gut tissues. These E. coli are different from other commensal and pathogenic E. coli in genomic components and also in ability to induce inflammatory responses. Dominant E. coli from colitic tissues induce gut inflammatory macrophages through a regulating network consisted of IL-18, IFN-γ, IL-12, and IL-22 in gut tissues. These E. coli also directly activate macrophages. Cytosolic inflammasome components PCKδ, NLRC4, caspase8, and caspase1/11 are involved in E. coli-mediated activation in both gut epithelial cells and macrophages. These disclose a novel mechanism for how dysbiosis of gut microbiota in colitis cause inflammatory macrophages related to multiple diseases.
Highlights
The dysbiosis of gut microbiota may promote gut and extra-gut autoimmune and inflammatory disorders such as inflammatory bowel disease (IBD), obesity, atherosclerosis, carcinogenesis, etc (Blander et al, 2017)
Type III secretion system (T3SS) of E. coli O160:H7 was different from pathogenic E. coli O157.H7 such that T3SS of E. coli O160:H7 contained hxlB, irp1, HMWP1, pqqL, hokA, fhaB, fdoG, fdfH, ttuB, bax, PTS-Dga, EIID, dgaD, glmS, GFPT, ABC-2, and CPSE.A, which were not detected in E. coli O157:H7 (Table S1C)
Because inner rod protein of type three secretion systems (TTSS) and functional flagellin (FliC) of gram-negative bacteria-mediated production of mature IL-18 mainly is through NLRC4/caspase1 signal pathway (Miao et al, 2010), we investigated the effects of NLRC4 and caspase1 on E.coli O160:H7-mediated mature IL-18
Summary
The dysbiosis (aberrant gut microbiota composition and function) of gut microbiota may promote gut and extra-gut autoimmune and inflammatory disorders such as inflammatory bowel disease (IBD), obesity, atherosclerosis, carcinogenesis, etc (Blander et al, 2017). The gut lamina propria (LP) macrophages display an anergic phenotype and are essential for intestinal homeostasis (De Schepper et al, 2018); but under inflammatory settings such as DSS-mediated colitis, the conditioning of murine Ly6C+ blood monocytes is impaired, and they give rise to inflammatory macrophages (Zigmond et al, 2012). These inflammatory macrophages produce large amounts of mediators such as TNFa, IL6, IL-1b, reactive oxygen intermediaries, and nitric oxide to cause diseases (MacDonald et al, 2011). What danger signal(s) of gut microbiota induce inflammatory macrophages remains poorly understood
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