GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3

Zhao, Ye; Chen, Feidi; Wu, Wei; Sun, Mingming; Bilotta, Anthony J.; Yao, Suxia; Xiao, Yi; Huang, Xiangsheng; Eaves-Pyles, Tonyia; Golovko, George; Fofanov, Yuriy; D’Souza, Warren N.; Zhao, Qihong; Liu, Zhanju; Cong, Yingzi

doi:10.1038/mi.2017.118

Cited by 354 publications

(290 citation statements)

References 51 publications

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“…Bacteroides were shown to inhibit Salmonella Typhimurium through the production of the SCFA, propionate 12 . SCFAs also impact epithelial barrier function by affecting production of host molecules including antimicrobial peptides and epithelial mucins 13,14 . Disturbed microbiota and the loss of colonisation resistance are associated with several pathogen infections including Clostridioides difficile 8 , Enterohemorrhagic E. coli 15 , and Campylobacter jejuni 16 .…”

Section: Introductionmentioning

confidence: 99%

Dissecting individual pathogen-commensal interactions within a complex gut microbiota community

Hassall

Unnikrishnan

2020

Preprint

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14Interactions of commensal bacteria within the gut microbiota and with invading pathogens 15 are critical in determining the outcome of an infection. While murine studies have been 16 valuable, we lack in vitro tools to monitor community responses to pathogens at a single-17 species level. We have developed a multi-species community of nine representative gut 18 species cultured together as a mixed biofilm and tracked numbers of individual species over 19 time using a qPCR-based approach. Introduction of the major nosocomial gut pathogen, 20Clostridiodes difficile, to this community resulted in increased adhesion of commensals and 21 inhibition of C. difficile multiplication. Interestingly, we observed an increase in individual 22Bacteroides species accompanying the inhibition of C. difficile. Furthermore, Bacteroides 23 dorei reduced C. difficile growth within biofilms, suggesting a role for Bacteroides spp in 24 prevention of C. difficile colonisation. We report here an in vitro tool with excellent 25 applications for investigating bacterial interactions within a complex community. 26 27 28 Disturbed microbiota and the loss of colonisation resistance are associated with several 49 pathogen infections including Clostridioides difficile 8 , Enterohemorrhagic E. coli 15 , and 50 Campylobacter jejuni 16 . 51 In the case of C. difficile, a leading cause of healthcare-associated diarrhoea worldwide, 52 colonisation occurs only when the microbiota is altered, usually due to treatment with 53 antibiotics such as fluoroquinolones 17 . The increased susceptibility of C. difficile infection (CDI) 54 after antibiotic-induced dysbiosis of the gut microbiota is well documented 18,19 . While most 55 4 studies demonstrating the link between CDI and antibiotic therapy are based on changes in 56 microbial populations by microbiota sequencing, recent studies have reported mechanisms by 57 which the microbiota can prevent C. difficile infections 20 . The microbiota in a healthy state 58 consumes or converts primary bile acid into secondary bile acids, reducing the ability of C. 59 difficile to germinate 21 . Secondary bile acids such as deoxycholic acid (DCA) and lithocholic 60 acid (LCA), are toxic to vegetative C. difficile 22,23 . Additionally, gut bacteria like Clostridium 61 scindens which encode secondary bile acid synthesis enzymes have been associated to 62 resistance to C. difficile infection 24 . The microbiota not only competes for resources but 63 actively inhibits C. difficile through production of bacteriocins such as the thuricin CD, 64 produced by Bacteroides thuringiensis 25 . 65While the microbiota is clearly important in preventing infections, current knowledge is mainly 66 based on microbiota profiles from faeces. The gut microbiota is composed of bacteria within 67 the lumen, which are usually detected in faeces and bacteria associated with the gut mucosa. 68Few studies have profiled the adherent microbiota population of healthy human guts as they 69 require invasive biopsies 26 . While not much is known abou...

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Section: Introductionmentioning

confidence: 99%

Dissecting individual pathogen-commensal interactions within a complex gut microbiota community

Hassall

Unnikrishnan

2020

Preprint

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“…; Zhao et al . ). There is also considerable evidence for direct and indirect effects of SCFAs on the brain (Dalile et al .…”

Section: Diet‐derived Microbial Metabolites In Health and Diseasementioning

confidence: 97%

“…Thus, SCFAs maintain intestinal homeostasis by regulating differentiation of T cells (Arpaia et al 2013;Furusawa et al 2013;Smith et al 2013;Sun et al 2018), promoting B-cell IgA production (Wu et al 2017) and protecting epithelial barrier integrity (Macia et al 2015;Zhao et al 2018). There is also considerable evidence for direct and indirect effects of SCFAs on the brain (Dalile et al 2019).…”

Section: Short-chain Fatty Acidsmentioning

confidence: 99%

Diet‐derived microbial metabolites in health and disease

Roager

Dragsted

2019

Nutrition Bulletin

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The gut microbiota helps us digest food and has been associated with both good health and risk of disease. Although compositions of the gut microbiota are highly divergent, the gut microbiota exhibits a high level of functional redundancy making it difficult to reliably link gut microbiome patterns to health and diet across individuals. Thus, there is a need to move beyond profiling of the gut microbial composition to the assessment of gut microbial metabolic activity in order to expand knowledge on the impact of the gut microbiota on health. Metabolomics has already proven its utility in identifying gut‐derived microbial metabolites, which may be mediators of diet‐induced host–microbial crosstalk important for health. These diet‐derived metabolites include, among many others, the short‐chain fatty acids originating from bacterial degradation of dietary fibres and proteins, secondary bile acids derived from primary bile acids, microbial tryptophan catabolites resulting from proteolysis, imidazole propionate produced from histidine and trimethylamine N‐oxide, a host–microbial co‐metabolite of nutrients such as phosphatidylcholine, choline and L‐carnitine, present in high‐fat foods. These co‐metabolites have been associated with beneficial and detrimental effects in the host. However, the vast majority of metabolites measured by untargeted metabolomics in human blood and excreta remain unknown and may include additional microbial molecules of importance for health. Thus, there is great potential, yet to be explored, for identifying additional diet‐derived microbial products that affect the host. Herein, we review key advances, challenges and limitations in our understanding of diet–microbiome interactions and diet‐derived microbial metabolites in relation to human health and discuss how metabolomics may shed light on inter‐individual differences in dietary responses.

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“…Indeed, a recent study showed that optimal expression of AMPs requires IEC‐sensing of SCFAs via GPR43. Using Gpr43 −/− mice and enteroids, investigators observed that the AMPs RegIII γ and β ‐defensins 1, 3 and 4 were reduced in the absence of GPR43 or downstream mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) activation …”

Section: Microbiota–iec Crosstalkmentioning

confidence: 99%

“…Using Gpr43 À/ À mice and enteroids, investigators observed that the AMPs RegIIIc and b-defensins 1, 3 and 4 were reduced in the absence of GPR43 or downstream mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) activation. 33 Microbes also induce a number of non-barrier functions in IECs, including changes in metabolism and the biosynthesis of signalling molecules. For example, early during Citrobacter rodentium infection, IECs have been shown to exhibit changes in cholesterol and carbon metabolic pathways, suggesting that IEC metabolism is reprogrammed to meet increased cellular energetic demands during tissue repair.…”

Section: Microbial Regulation Of Iec Growth and Functionmentioning

confidence: 99%

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

2019

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Summary The intestinal epithelium forms a barrier between the microbiota and the rest of the body. In addition, beyond acting as a physical barrier, the function of intestinal epithelial cells (IECs) in sensing and responding to microbial signals is increasingly appreciated and likely has numerous implications for the vast network of immune cells within and below the intestinal epithelium. IECs also respond to factors produced by immune cells, and these can regulate IEC barrier function, proliferation and differentiation, as well as influence the composition of the microbiota. The mechanisms involved in IEC–microbe–immune interactions, however, are not fully characterized. In this review, we explore the ability of IECs to direct intestinal homeostasis by orchestrating communication between intestinal microbes and mucosal innate and adaptive immune cells during physiological and inflammatory conditions. We focus primarily on the most recent findings and call attention to the numerous remaining unknowns regarding the complex crosstalk between IECs, the microbiota and intestinal immune cells.

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GPR43 mediates microbiota metabolite SCFA regulation of antimicrobial peptide expression in intestinal epithelial cells via activation of mTOR and STAT3

Cited by 354 publications

References 51 publications

Dissecting individual pathogen-commensal interactions within a complex gut microbiota community

Dissecting individual pathogen-commensal interactions within a complex gut microbiota community

Diet‐derived microbial metabolites in health and disease

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

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