In all metazoans, the intestinal tract is an essential organ to integrate nutritional signaling, hormonal cues and immunometabolic networks. The dysregulation of intestinal epithelium functions can impact organism physiology and, in humans, leads to devastating and complex diseases, such as inflammatory bowel diseases, intestinal cancers, and obesity. Two decades ago, the discovery of an immune response in the intestine of the genetic model system, Drosophila melanogaster, sparked interest in using this model organism to dissect the mechanisms that govern gut (patho) physiology in humans. In 2007, the finding of the intestinal stem cell lineage, followed by the development of tools available for its manipulation in vivo, helped to elucidate the structural organization and functions of the fly intestine and its similarity with mammalian gastrointestinal systems. To date, studies of the Drosophila gut have already helped to shed light on a broad range of biological questions regarding stem cells and their niches, interorgan communication, immunity and immunometabolism, making the Drosophila a promising model organism for human enteric studies. This review summarizes our current knowledge of the structure and functions of the Drosophila melanogaster intestine, asserting its validity as an emerging model system to study gut physiology, regeneration, immune defenses and host-microbiota interactions.

The immune response is essential to protect organisms from infection and an altered self. An organism’s overall metabolic status is now recognized as an important and long-overlooked mediator of immunity and has spurred new explorations of immune-related metabolic abnormalities. Peroxisomes are essential metabolic organelles with a central role in the synthesis and turnover of complex lipids and reactive species. Peroxisomes have recently been identified as pivotal regulators of immune functions and inflammation in the development and during infection, defining a new branch of immunometabolism. This review summarizes the current evidence that has helped to identify peroxisomes as central regulators of immunity and highlights the peroxisomal proteins and metabolites that have acquired relevance in human pathologies for their link to the development of inflammation, neuropathies, aging and cancer. This review then describes how peroxisomes govern immune signaling strategies such as phagocytosis and cytokine production and their relevance in fighting bacterial and viral infections. The mechanisms by which peroxisomes either control the activation of the immune response or trigger cellular metabolic changes that activate and resolve immune responses are also described.

Phagocytosis, signal transduction, and inflammatory responses require changes in lipid metabolism. Peroxisomes have key roles in fatty acid homeostasis and in regulating immune function. We find that Drosophila macrophages lacking peroxisomes have perturbed lipid profiles, which reduce host survival after infection. Using lipidomic, transcriptomic, and genetic screens, we determine that peroxisomes contribute to the cell membrane glycerophospholipid composition necessary to induce Rho1-dependent signals, which drive cytoskeletal remodeling during macrophage activation. Loss of peroxisome function increases membrane phosphatidic acid (PA) and recruits RhoGAPp190 during infection, inhibiting Rho1-mediated responses. Peroxisome-glycerophospholipid-Rho1 signaling also controls cytoskeleton remodeling in mouse immune cells. While high levels of PA in cells without peroxisomes inhibit inflammatory phenotypes, large numbers of peroxisomes and low amounts of cell membrane PA are features of immune cells from patients with inflammatory Kawasaki disease and juvenile idiopathic arthritis. Our findings reveal potential metabolic markers and therapeutic targets for immune diseases and metabolic disorders.

The gastrointestinal tract communicates with the nervous system through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the enteric nervous system, the vagus nerve, the immune system, endocrine signals, the microbiota, and its metabolites. Alteration of communications in the gut-brain axis is emerging as an overlooked cause of neuroinflammation. Neuroinflammation is a common feature of the pathogenic mechanisms involved in various neurodegenerative diseases (NDs) that are incurable and debilitating conditions resulting in progressive degeneration and death of neurons, such as in Alzheimer and Parkinson diseases. NDs are a leading cause of global death and disability, and the incidences are expected to increase in the following decades if prevention strategies and successful treatment remain elusive. To date, the etiology of NDs is unclear due to the complexity of the mechanisms of diseases involving genetic and environmental factors, including diet and microbiota. Emerging evidence suggests that changes in diet, alteration of the microbiota, and deregulation of metabolism in the intestinal epithelium influence the inflammatory status of the neurons linked to disease insurgence and progression. This review will describe the leading players of the so-called diet-microbiota-gut-brain (DMGB) axis in the context of NDs. We will report recent findings from studies in model organisms such as rodents and fruit flies that support the role of diets, commensals, and intestinal epithelial functions as an overlooked primary regulator of brain health. We will finish discussing the pivotal role of metabolisms of cellular organelles such as mitochondria and peroxisomes in maintaining the DMGB axis and how alteration of the latter can be used as early disease makers and novel therapeutic targets.