Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity

Worthington, John J.; Reimann, Frank; Gribble, Fiona M.

doi:10.1038/mi.2017.73

Cited by 199 publications

(153 citation statements)

References 342 publications

(408 reference statements)

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“…Most importantly, this quick and efficient response is enabled by a subset of anterior EECs that transmit the signal from the lumen to the visceral mesoderm by releasing DH31, a neuropeptide that presents a conserved function with CGRP in mammals ( Fig 7F ). This work reinforces the importance of EECs in the defense mechanisms of the gut, beyond the recent discovery of their involvement in innate immune response [ 38 , 45 , 51 , 52 ] and in addition to their well-known functions in regulating feeding behavior and digestive physiology [ 30 ].…”

Section: Discussionsupporting

confidence: 71%

The DH31/CGRP enteroendocrine peptide triggers intestinal contractions favoring the elimination of opportunistic bacteria

et al. 2018

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The digestive tract is the first organ affected by the ingestion of foodborne bacteria. While commensal bacteria become resident, opportunistic or virulent bacteria are eliminated from the gut by the local innate immune system. Here we characterize a new mechanism of defense, independent of the immune system, in Drosophila melanogaster. We observed strong contractions of longitudinal visceral muscle fibers for the first 2 hours following bacterial ingestion. We showed that these visceral muscle contractions are induced by immune reactive oxygen species (ROS) that accumulate in the lumen and depend on the ROS-sensing TRPA1 receptor. We then demonstrate that both ROS and TRPA1 are required in a subset of anterior enteroendocrine cells for the release of the DH31 neuropeptide which activates its receptor in the neighboring visceral muscles. The resulting contractions of the visceral muscles favors quick expulsion of the bacteria, limiting their presence in the gut. Our results unveil a precocious mechanism of defense against ingested opportunistic bacteria, whether they are Gram-positive like Bacillus thuringiensis or Gram-negative like Erwinia carotovora carotovora. Finally, we found that the human homolog of DH31, CGRP, has a conserved function in Drosophila.

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Section: Discussionsupporting

confidence: 71%

The DH31/CGRP enteroendocrine peptide triggers intestinal contractions favoring the elimination of opportunistic bacteria

et al. 2018

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“…Enteroendocrine cells (EECs) are key sensors of nutrients and microbial metabolites 14,25 that secrete diverse hormones and function as metabolic signal transduction units 26 . EECs have been reported to comprise 8 distinct sub-classes, such that cells expressing Sct, Cck, Gcg or GIP are traditionally termed S, I, L and K cells 14 .…”

Section: Resultsmentioning

confidence: 99%

A single-cell survey of the small intestinal epithelium

Haber

Biton

Rogel

et al. 2017

Nature

1,416

115

1,694

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Intestinal epithelial cells (IECs) absorb nutrients, respond to microbes, provide barrier function and help coordinate immune responses. We profiled 53,193 individual epithelial cells from mouse small intestine and organoids, and characterized novel subtypes and their gene signatures. We showed unexpected diversity of hormone-secreting enteroendocrine cells and constructed their novel taxonomy. We distinguished between two tuft cell subtypes, one of which expresses the epithelial cytokine TSLP and CD45 (Ptprc), the pan-immune marker not previously associated with non-hematopoietic cells. We also characterized how cell-intrinsic states and cell proportions respond to bacterial and helminth infections. Salmonella infection caused an increase in Paneth cells and enterocytes abundance, and broad activation of an antimicrobial program. In contrast, Heligmosomoides polygyrus caused an expansion of goblet and tuft cell populations. Our survey highlights new markers and programs, associates sensory molecules to cell types, and uncovers principles of gut homeostasis and response to pathogens.

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“…The intestinal epithelium, among the most important interfaces between the body and the environment, not only plays a part in nutrient absorption but also acts as a barrier against the vast amount of commensal intestinal microorganisms and pathogenic microbes ( Artis and Grencis, 2008 ; Peterson and Artis, 2014 ). Therefore, the integrity of the epithelial monolayer is critical for the health of the gut, and epithelial dysfunction is a hallmark of intestinal disorders such as IBDs ( Citalan-Madrid et al, 2017 ; Worthington et al, 2017 ). In the TNBS-induced murine colitis model, ethanol is essential for providing access to intestinal epithelial cells, impairing barrier function, and allowing TNBS to penetrate the bowel wall.…”

Section: Discussionmentioning

confidence: 99%

Sodium Butyrate Inhibits Inflammation and Maintains Epithelium Barrier Integrity in a TNBS-induced Inflammatory Bowel Disease Mice Model

et al. 2018

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G Protein Coupled Receptor 109A (GPR109A), which belongs to the G protein coupled receptor family, can be activated by niacin, butyrate, and β-hydroxybutyric acid. Here, we assessed the anti-inflammatory activity of sodium butyrate (SB) on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mice, an experimental model that resembles Crohn's disease, and explored the potential mechanism of SB in inflammatory bowel disease (IBD). In vivo, experimental GPR109a−/− and wild-type (WT) mice were administered SB (5 g/L) in their drinking water for 6 weeks. The mice were then administered TNBS via rectal perfusion to imitate colitis. In vitro, RAW246.7 macrophages, Caco-2 cells, and primary peritoneal macrophages were used to investigate the protective roles of SB on lipopolysaccharide (LPS)-induced inflammatory response and epithelium barrier dysfunction. In vivo, SB significantly ameliorated the inflammatory response and intestinal epithelium barrier dysfunction in TNBS-induced WT mice, but failed to provide a protective effect in TNBS-induced GPR109a−/− mice. In vitro, pre-treatment with SB dramatically inhibited the expression of TNF-α and IL-6 in LPS-induced RAW246.7 macrophages. SB inhibited the LPS-induced phosphorylation of the NF-κB p65 and AKT signaling pathways, but failed to inhibit the phosphorylation of the MAPK signaling pathway. Our data indicated that SB ameliorated the TNBS-induced inflammatory response and intestinal epithelium barrier dysfunction through activating GPR109A and inhibiting the AKT and NF-κB p65 signaling pathways. These findings therefore extend the understanding of GPR109A receptor function and provide a new theoretical basis for treatment of IBD.

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Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity

Cited by 199 publications

References 342 publications

The DH31/CGRP enteroendocrine peptide triggers intestinal contractions favoring the elimination of opportunistic bacteria

The DH31/CGRP enteroendocrine peptide triggers intestinal contractions favoring the elimination of opportunistic bacteria

A single-cell survey of the small intestinal epithelium

Sodium Butyrate Inhibits Inflammation and Maintains Epithelium Barrier Integrity in a TNBS-induced Inflammatory Bowel Disease Mice Model

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