The interplay between intestinal bacteria and host metabolism in health and disease: lessons from Drosophila melanogaster

Abstract

All higher organisms negotiate a truce with their commensal microbes and battle pathogenic microbes on a daily basis. Much attention has been given to the role of the innate immune system in controlling intestinal microbes and to the strategies used by intestinal microbes to overcome the host immune response. However, it is becoming increasingly clear that the metabolisms of intestinal microbes and their hosts are linked and that this interaction is equally important for host health and well-being. For instance, an individual's array of commensal microbes can influence their predisposition to chronic metabolic diseases such as diabetes and obesity. A better understanding of host-microbe metabolic interactions is important in defining the molecular bases of these disorders and could potentially lead to new therapeutic avenues. Key advances in this area have been made using Drosophila melanogaster. Here, we review studies that have explored the impact of both commensal and pathogenic intestinal microbes on Drosophila carbohydrate and lipid metabolism. These studies have helped to elucidate the metabolites produced by intestinal microbes, the intestinal receptors that sense these metabolites, and the signaling pathways through which these metabolites manipulate host metabolism. Furthermore, they suggest that targeting microbial metabolism could represent an effective therapeutic strategy for human metabolic diseases and intestinal infection.

Keywords: Commensal; Drosophila melanogaster; Metabolism; Microbiota; Pathogen.

Fig. 1.

A comparison of the mammalian and Drosophila melanogaster intestines. (A) The contour of the mammalian intestinal epithelium consists of peaks and valleys termed villi (singular: villus) and crypts, respectively. Several cell types with distinct functions are found within the epithelium. Enterocytes, whose surface area is maximized by numerous protrusions known as microvilli, are principally responsible for nutrient absorption. Goblet cells, which are distributed throughout the epithelium, secrete the protective mucus layer composed of polysaccharides and proteins that covers the epithelial surface. Located in crypts, enteroendocrine cells secrete small bioactive peptides in response to signals from nutrients and commensal bacteria in the intestinal lumen. Paneth cells, which are found at the crypt base, secrete antimicrobial peptides and create a stem cell niche. Two stem cell populations are found in the mammalian intestine. Stem cells positioned at the crypt base divide at a constant rate to replenish the epithelium. Division of stem cells located at the +4 position is activated by intestinal insult or infection. The resident commensal microbiota is found within and on top of the mucus layer. (B) The Drosophila intestinal epithelium lacks villi and crypts and consists of only three cell types: enterocytes, enteroendocrine cells and stem cells. The peritrophic membrane (or matrix), a structure analogous to intestinal mucus, covers the epithelial surface. The intestinal lumen is colonized by a much less diverse microbiota.

Fig. 2.

Signaling pathways through which gut microbiota modulate host carbohydrate and lipid metabolism. Consumed nutrients are metabolized by the gut microbiota to produce bioactive metabolites that are sensed by the mammalian and possibly the Drosophila epithelium. Short-chain fatty acids (SCFAs), the product of bacterial carbohydrate fermentation, and other bacterial metabolites are taken up by enterocytes (note that the villi are not shown in this representation) and converted into metabolically active molecules such as acetyl-CoA, or sensed by specific G-protein-coupled receptors (GPCRs) expressed on the surfaces of enterocytes and enteroendocrine cells. This, in turn, triggers release of enteroendocrine peptides into the systemic circulation and activates signaling cascades that modulate host carbohydrate and lipid utilization both in the intestine and systemically. Dietary triacylglycerides (TAGs) are hydrolyzed into monoacylglycerides (MAGs) and free fatty acids (FFAs) before being absorbed by enterocytes. These lipids accumulate within the leaflets of the endoplasmic reticulum (ER) membrane and are then packaged either into lipid droplets for storage or into lipoprotein particles for transport to other tissues.

Fig. 3.

Pathogens and non-pathogens modulate intestinal metabolism differently. The metabolites produced by commensal (non-pathogenic) bacteria play a key role in maintaining gut homeostasis, and bacteriophages trim and tailor the bacterial population. The peritropic membrane comprises chitin and proteins. By secreting proteases and chitinases, bacterial pathogens can digest, and thus weaken, the peritrophic barrier, allowing these bacteria to invade the intestinal epithelium. Alternatively, a non-invasive pathogen might interrupt signaling between commensals and the host intestine by consuming commensal metabolites or producing virulence factors that mute host signaling pathways. If intestinal lipid metabolism is dysregulated, the resulting lipid droplets within enterocytes can provide a platform for replication of viruses that exploit these organelles, thus promoting viral superinfection.