How Gut Microbes Nurture Intestinal Stem Cells: A Drosophila Perspective

Abstract

Host-microbiota interactions are key modulators of host physiology and behavior. Accumulating evidence suggests that the complex interplay between microbiota, diet and the intestine controls host health. Great emphasis has been given on how gut microbes have evolved to harvest energy from the diet to control energy balance, host metabolism and fitness. In addition, many metabolites essential for intestinal homeostasis are mainly derived from gut microbiota and can alleviate nutritional imbalances. However, due to the high complexity of the system, the molecular mechanisms that control host-microbiota mutualism, as well as whether and how microbiota affects host intestinal stem cells (ISCs) remain elusive. Drosophila encompasses a low complexity intestinal microbiome and has recently emerged as a system that might uncover evolutionarily conserved mechanisms of microbiota-derived nutrient ISC regulation. Here, we review recent studies using the Drosophila model that directly link microbiota-derived metabolites and ISC function. This research field provides exciting perspectives for putative future treatments of ISC-related diseases based on monitoring and manipulating intestinal microbiota.

Keywords: amino acids; cholesterol; fatty acids; intestinal stem cells; microbiota; midgut; nutrients; sugars; vitamins.

Figure 1

Schematic representation of the transition from healthy microbiota to dysbiosis and its role in human health. Healthy microbiota has a central role in intestinal function, immune response, host physiology and overall fitness. The predominant species of the human intestinal microbiota include Acetobacter pomorum, A. tropicalis, Lactobacillus brevis, L. fructivorans and L. plantarum. Reduced abundance of these species and concomitant gradual increase of opportunistic pathogens leads to dysbiosis, a condition that predisposes to disease.

Figure 2

Homeostasis of the Drosophila intestinal epithelium is mediated by ISCs that respond to microbiota and damaging agents. Commensal and pathogenic bacteria are sensed by the intestinal epithelium and induce innate immune effectors including ROS and AMPs. Two ROS-producing enzymes, the NADPH oxidases, Duox and Nox, are activated in response to pathogens and commensals, respectively. Duox produces ROS in response to pathogen-derived uracil, whereas Nox produces ROS in response to commensal-derived lactate. The innate immunity Imd pathway controls ROS-resistant microbes. Recognition of the bacterially-derived peptidoglycan (PGN) by the transmembrane receptor PGRP-LC and by the intracellular receptor PGRP-LE leads to Imd activation and subsequent secretion of AMPs. Other PGRPs (PGRP-LB and PGRP-SC) are enzymatic and negatively regulate Imd. Intestinal homeostasis is mediated by ISC mitosis and subsequent differentiation. ISC activity is tightly regulated by evolutionarily conserved growth control signaling mechanisms, including the Hippo, IIS and TOR pathways. ISC proliferation is also regulated by secreted IL-6-like cytokines (Upd1, Upd2, Upd3) that trigger the Jak/STAT pathway. EC damage caused by pathogens, drugs and ROS induces the JNK pathway and elevates Upd3 in ECs, which, in turn, triggers Jak/STAT activation in the VM and the release of EGFs (Vein, Keren and Spitz) by the ISC niche. EGFs activate their receptor EGFR in the ISCs and promote ISC proliferation and tissue regeneration. The Wg morphogen is also induced in EBs and promotes ISC proliferation via cMyc in the infected midguts. EEs sense nutrients and serve as a link between the diet-stimulated Dilp3 expression in the VM, which controls ISC proliferation. (ROS: reactive oxygen species; AMPs: antimicrobial peptides; Duox: Dual oxidase; PGN: peptidoglycan; PGRP: peptidoglycan recognition proteins; InR: Insulin receptor; IIS: insulin/IGF-1 signaling; TOR: target of rapamycin; Upd1,2,3: Unpaired1,2,3; JNK: Jun kinase; EGF: epidermal growth factor; EGFR: epidermal growth factor receptor; Wg: Wingless; Dilp3: Drosophila Insulin-like peptide 3; VM: visceral muscle; ISC: intestinal stem cell; EB: enteroblast; EC: enterocyte; EE: enteroendocrine cell).

Figure 3

Bacterially-derived micronutrients control Drosophila ISC activity. A. pomorum-derived isoleucine promotes L. plantarum growth, which produces lactate. Lactate is essential for A. pomorum growth and induces immune responses in the epithelium to maintain basal ISC numbers. Excess sugar promotes dysbiosis and elevated ROS, which downregulate the Jak/STAT pathway and promote ISC differentiation. The microbiota-derived SCFAs are important regulators of ISC homeostasis. EEs recognize the SCFA acetate and respond by secreting Tk. Tk controls lipid metabolism in ECs to maintain ISC proliferation. Other microbiota-derived metabolites, including the PQQ-ADH, bacteriocins and lactate are important regulators of ISC proliferation. A. pomorum PQQ-ADH regulates metabolism, ISC activity and epithelial regeneration via JNK-induced Jak/STAT pathway activation, whereas bacteriocins control pathogenic midgut infection causing EC loss. Lost ECs are replenished via ISC proliferation and differentiation. Moreover, excess lactate produced by L. plantarum triggers ROS via Nox, which increases the number of ISCs. Microbiota-produced biotin is absorbed by the ISCs via the Smvt transporter and regulates ISC proliferation in parallel to the Upd1-Jak/STAT pathway. (SCFAs: short chain fatty acids; Tk: Tachykinin; PQQ-ADH: pyrroloquinoline quinone-dependent alcohol dehydrogenase; ISC: intestinal stem cell; EB: enteroblast; EC: enterocyte; EE: enteroendocrine cell).