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

Abstract

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.

Metabolism and growth adaptation to environmental conditions in Drosophila

“…Processed peptides from those prepropeptides marked with an asterisk have been identified in mass-spectrometric assays of the adult midgut [ 198 ]. Evidence for release of enteroendocrine peptides (processed or not) and downstream function has been reported for BursA [ 199 – 201 ], Dh31 [ 202 , 203 ], NPF [ 204 ], and Tk [ 205 ]. Tk, either from neurons terminating near or on the IPCs or from the gut, activates its receptor TkR99D in the IPCs, where it is required for proper regulation of DILP2 and DILP3 expression [ 205 , 206 ].…”

TRPA1 Channel Activation Inhibits Motor Activity in the Mouse Colon

“…The role of mucosal TRPA1 signaling may be to detect and respond to inflammation within the colon, but studies in Drosophila have shown that colonization of the intestine by pathogenic bacteria can activate contractions of the Drosophila gut via a TRPA1 mechanism which may serve a protective response to rid the intestine of harmful bacteria (Benguettat et al, 2018). It would be interesting to see whether this novel pathway is replicated in the mammalian gut and so would also implicate TRPA1 as a sensor for the gastrointestinal microbiome.…”

Physiological and Pathological Regulation of Peripheral Metabolism by Gut-Peptide Hormones in Drosophila

“…ISC/EB Dl, ILP6, egr, Hh, spi, wg, Upd1, and Upd2 (Ohlstein and Spradling, 2007;Karpowicz et al, 2010;Osman et al, 2012;Tian et al, 2015Tian et al, , 2016Doupe et al, 2018) EC Hh, Dpp, Gbb, Krn, PGRP-SA, PGRP-SB1, PGRP-SC1a, PGRP-SC1b, PGRP-SC2, PGRP-SD, PGRP-LB, Upd1, Upd2, and Upd3 (Werner et al, 2000;Bischoff et al, 2006;Jiang et al, , 2011Osman et al, 2012;Guo et al, 2014;Jiang, 2014, 2017;Lee et al, 2015;Iatsenko et al, 2016) EE AstA, AstC, AstB/Mip, CCHa1, CCHa2, sli, Orcokinin B, CCAP, Nplp2, Gbp5, and ITP (Veenstra et al, 2008;Biteau and Jasper, 2014;Veenstra and Ida, 2014;Ren et al, 2015;Chen et al, 2016a;Benguettat et al, 2018;Rommelaere et al, 2019;Hung et al,…”

“…A recent study using the cytoplasmic calcium reporter CaLexA has indicated that dietary amino acids like casein peptone and lysine directly activate intracellular Ca 2+ cascade, an increase in which is associated with peptide release in multiple endocrine cells (Dus et al, 2015;Benguettat et al, 2018;Oh et al, 2019), in Tk + and DH31 + EEs (Park et al, 2016). Consistently, the protein level and release of Tk peptides in EEs are increased in starved flies and other insects to control gut mobility and EC lipogenesis (Winther and Nassel, 2001;Song et al, 2014), while refeeding flies only yeast that contains plenty of amino acids, but not sucrose or coconut oil, blunts the increase in Tk peptide level (Song et al, 2014).…”