Microbial Control of Intestinal Homeostasis via Enteroendocrine Cell Innate Immune Signaling

Abstract

A community of commensal microbes, known as the intestinal microbiota, resides within the gastrointestinal tract of animals and plays a role in maintenance of host metabolic homeostasis and resistance to pathogen invasion. Enteroendocrine cells, which are relatively rare in the intestinal epithelium, have evolved to sense and respond to these commensal microbes. Specifically, they express G-protein-coupled receptors and functional innate immune signaling pathways that recognize products of microbial metabolism and microbe-associated molecular patterns, respectively. Here we review recent evidence from Drosophila melanogaster that microbial cues recruit antimicrobial, mechanical, and metabolic branches of the enteroendocrine innate immune system and argue that this response may play a role not only in maintaining host metabolic homeostasis but also in intestinal resistance to invasion by bacterial, viral, and parasitic pathogens.

Keywords: Drosophila melanogaster.; colonization resistance; enteroendocrine cell; enteroendocrine peptide; innate immunity; intestinal microbiota; metabolism.

Figure 1:. A comparison of the dipteran and mammalian gastrointestinal tracts.

(A) The commensal microbiota of Drosophila gastrointestinal tract resides principally in the anterior midgut. Digestion of complex carbohydrates is predicted to occur in this compartment. Transit of microbes to the posterior midgut is restricted by the low pH of the middle midgut. Therefore, the posterior midgut is relatively microbe-free except during overwhelming infection. (B) The mammalian intestine has similar compartments. However, their order is shuffled. Ingested microbes first encounter the acidic stomach. This, along with bile secretion and rapid flow through the small intestine, ensures that the burden of microbes in the small intestine is low. The microbial burden increases as the large intestine is reached, and the density of microbes in the large intestine is extremely high. It is in the latter compartment that digestion of many complex carbohydrates occurs.

Figure 2:. Key Figure: A model for the impact of the commensal microbiota on the anterior midgut immune response and the impact of pathogens on the posterior midgut immune response.

(A) Viable microbes that comprise the commensal microbiota of the anterior midgut produce acetate and shed peptidoglycan. These two products are necessary for activation of the IMD pathway within DH31/Tk-expressing enteroendocrine cells. In the anterior midgut, the membrane-associated receptor PGRP-LC is the principal sensor of peptidoglycan. IMD pathway signaling in these cells results in expression of AMPs, Tk, and DH31. The ultimate result is control of the microbiota through antimicrobial action, intestinal contractions, and inhibition of lipid synthesis within enterocytes. (B) In antibiotic-treated, germ-free, or IMD pathway mutant flies, the IMD pathway is not activated, and AMPs, Tk, and DH31 are not made. The absence of Tk expression leads to increased numbers of lipid droplets within enterocytes presumably due to de-repression of lipid synthesis. In addition, decreased levels of DH31 result in decreased intestinal contractions. (C) In the uninfected fly, there is little signaling through the IMD pathway of the posterior midgut, and expression of IMD pathway-regulated genes is repressed by the transcription factor Caudal. Because Tk expression in the posterior midgut is not under control of the IMD pathway, Tk is expressed and homeostatic levels of lipids are synthesized in enterocytes. (D) Pathogens such as V. cholerae gain access to the posterior midgut. In this case, peptidoglycan activates the IMD pathway, and AMP synthesis is increased. Because V. cholerae activates degradation of phospholipids, lipid droplets coalesce, leading to larger lipid droplets in spite of an overall decrease in TAG stores. Abbreviations: ABX, antibiotic; TCT, tracheal cytotoxin; TKR, tachykinin receptor; VM, visceral muscle; EC, enterocyte; EE, enteroendocrine; TAG, triacylglycerol.