Impaired Autophagy in Intestinal Epithelial Cells Alters Gut Microbiota and Host Immune Responses

Abstract

Establishing and maintaining beneficial interactions between the host and associated gut microbiota are pivotal requirements for host health. Autophagy is an important catabolic recycling pathway that degrades long-lived proteins and some organelles by lysosome to maintain cellular homeostasis. Although impaired autophagy is thought to be closely correlated with Crohn's disease (CD), the functional role of autophagy in the maintenance of gut microbiota is poorly understood. As autophagy-related 5 () is a key gene associated with the extension of the phagophoric membrane in autophagic vesicles, we established a gut-specific knockout mouse model, and we found that the disruption of autophagic flux in the intenstinal epithelium cells dramatically altered the composition of the gut microbiota and reduced alpha diversity. Microbial function prediction indicated that the pathway allocated for infectious diseases was enriched in mice. " Arthromitus" and the family were increased in mice, whereas and the family were reduced. Transcriptome analysis revealed that two key inflammatory bowel disease (IBD)-related transcription factors, RORC and TBX21, of host cells were upregulated in mice, thus elevating the Muc2-related immunological response. The findings suggest that intestinal autophagy plays a vital role in modulating the diversity and composition of gut microbiota. The homeostasis of host-microbiota interactions is of great importance to host health. Previous studies demonstrated that disruption of autophagy was linked to inflammatory bowel disease. However, the interaction mechanism of gut microbiota regulated by autophagy was obscure. In an intestinal epithelium-specific autophagy-related 5 () knockout mouse model, we observed a significant alteration and decreased diversity in the gut microbiota of -deficient mice compared with that of wild-type mice. Although the numbers of some organisms (e.g., and members of the family) associated with the control of inflammation decreased, those of proinflammationory bacteria (e.g., " Arthromitus") and potential pathogens (the family) increased in mice. Differential gene expression analysis revealed that two key genes, and, involved in inflammatory bowel disease were upregulated in mice. Our study suggests that deficiency results in an imbalance of the host-microbe interaction and deterioration of the gut microenvironment.

Mycobacterium tuberculosis, antimicrobials, immunity, and lung–gut microbiota crosstalk: current updates and emerging advances

“…Particularly, the depletion of the gut microbiome induces autophagy. 38 Notably, direct treatment of macrophages with antimicrobials has produced conflicting results, depending on the antibiotic used. Whereas some studies saw no direct effect of antimicrobials on autophagy, others did 4,39 ( Table 1).…”

“…Specifically, autophagy shapes the contents of the microbiome, which, in turn, also modulates immune responses. 38,46 These suggest that other pathologies, such as HIV, which negatively affects the immune system and autophagy, can indirectly affect Mtb through the microbiome. 17,47 Yang et al observed a significant alteration and reduced diversity in the microbiota of atg5 knockout mice such that inflammation-reducing species, such as Akkermansia muciniphila and members of the Lachnospiraceae family, diminished, while proinflammatory (Candidatus athromitus) and pathogenic (Pasteurellaceae) bacteria flourished ( Fig.…”

Interfaces between microbes and membranes of host epithelial cells in hemipteran midguts

“…By entering cytoplasm of mammalian intestinal cells, a native microbe of the intestinal microbiota of mammals activates autophagy. Imbalanced intestinal microbiota are associated with defects in autophagy and excessive activation of immune responses (Yang et al, ). In arthropods and tardigrades, autophagy of microbes commonly occurs in midgut cells as a measure to ensure survival of host cells (Rost‐Roszkowska, Vilimova, et al, ; Rost‐Roszkowska, Poprawa, & Kaczmarek, ).…”

Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

“…Autophagy is particularly well studied in maintaining the function of Paneth cells and protecting against pathogenic bacteria . Recently, disruption of IEC autophagy has also been shown to dramatically alter the composition of the gut microbiota and reduce intestinal microbial alpha‐diversity in mice . Another recent study showed that serotonin production by enterochromaffin cells modulates gut microbial composition, and AMPs secreted by IECs have been broadly reported to influence the composition of intestinal gut microbes .…”

“…[40][41][42][43][44] Recently, disruption of IEC autophagy has also been shown to dramatically alter the composition of the gut microbiota and reduce intestinal microbial alphadiversity in mice. 45 Another recent study showed that serotonin production by enterochromaffin cells modulates gut microbial composition, 46 and AMPs secreted by IECs have been broadly reported to influence the composition of intestinal gut microbes. [47][48][49] The NLRP6-inflammasome is also highly expressed by IECs, and previous studies have shown that NLRP6 helps to maintain eubiosis of the intestinal microbiota.…”