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The Drosophila gut: A gatekeeper and coordinator of organism fitness and physiology

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Abstract Multicellular organisms have evolved organs and tissues with highly specialized tasks. For instance, nutrients are assimilated by the gut, sensed, processed, stored, and released by adipose tissues and liver to provide energy consumed by peripheral organ activities. The function of each organ is modified by local clues and systemic signals derived from other organs to ensure a coordinated response accommodating the physiological needs of the organism. The intestine, which represents one of the largest interfaces between the internal and external environment, plays a key role in sensing and relaying environmental inputs such as nutrients and microbial derivatives to other organs to produce systemic responses. In turn, gut physiology and immunity are regulated by multiple signals emanating from other organs including the brain and the adipose tissues. In this review, we highlight physiological processes where the gut serves as a key organ in coupling systemic signals or environmental cues with organism growth, metabolism, immune activity, aging, or behavior. Robust strategies involving intraorgan and interorgan signaling pathways have evolved to preserve gut size in homeostatic conditions and restrict growth during damage‐induced regenerative phases. Here we review some of the mechanisms that maintain gut size homeostasis and point out known examples of homeostasis‐breaking events that promote gut plasticity to accommodate changes in the external or internal environment. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration
(a) Schematic of the Drosophila midgut: EC, enterocyte; EE, enteroendocrine cell; ISC, intestinal stem cell; VM, visceral muscles. Immunostaining of midgut with the EE cells labeled in red using an anti‐prospero antibody, the ISCs labeled in green (GFP is expressed under the control of the progenitorspecific escargot promotor), and the ECs displaying large polyploid nuclei labeled in white using a DAPI staining. (b) Schematic of the crypt and the neighboring villi of the mammalian small intestine. ISCs are surrounded by paneth cells that constitute an important part of the ISC niche. As ISCs are pushed out the crypt, they mature into transient amplifying (TA) progenitor cells, which, as they move up the villi, differentiate into absorptive ECs or secretory enteroendocrine, goblet, tuft, or paneth cells. Following differentiation, paneth cells move downward to the bottom of the crypt
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The microbiome exerts numerous effects on host behavior. The presence of bacteria‐derived PGNs in the body cavity reduces oviposition. Hyperactivation of the IMD pathway in the gut results in the release of the neurotransmitter 5‐HT and abnormal social behaviors. The majority of the signals coupling microbiome‐association with host behavior have not been identified (X)
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The gut and the fat body, two major immune organs, communicate extensively to coordinate immune responses across tissues. In the case of severe oral infections, the gut signals to the fat body to elicit a systemic immune response (black arrows). In response to septic infections, hemocyte‐derived Upd3 serves as an intermediate to coordinate immune responses in the fat body and gut (blue arrows)
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The gut is a major nutrient‐sensing organ that secretes multiple signals to promote glucose and lipid storage or mobilization of energy stores according to nutrient availability (black lines). In turn, the gut receives multiple signals emanating from the fat body, brain and gonads to adjust digestion, metabolism and gut motility (blue lines). AKH, adipokinetic hormone; AKHR, AKH receptor; Daw, dawdle; DH44, diuretic hormone 44; DILPs, Drosophila insulin‐like peptides; Upds, unpaired ligands
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In nutrient‐poor conditions, commensal bacteria‐derived acetate promotes growth and lipid homeostasis by activating IMD signaling in ECs and EE cells. Activation of the IMD pathway in EE cells results in the secretion of TK that plays a key role in regulating lipid homeostasis in gut epithelial cells and systemic insulin signaling thereby promoting growth. In addition, activation of IMD in ECs results in increases levels of host proteases, which facilitates the breakdown of proteins into amino acids thereby increasing the assimilation of amino acids. Increased levels of amino acids trigger the activation of the nutrient sensor, dTOR, in the fat body, which through a neuronal relay stimulates the releases of Dilps to promote growth and development. In axenic flies, reduced IMD signaling in ECs and EE cells results in a failure to mobilize lipid stores, decreased insulin signaling and reduced growth
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(a) In homeostatic conditions, fly intestinal stem cell division is controlled by numerous signals, including growth factors (Krn, Vn, and Spi), Wg (WNT in mammals), Dilp3, Dpp (BMP homologue), and Hh, emanating from neighboring gut epithelial cells, the visceral muscles, and nongastrointestinal sources (black arrows). (b) In mammals, the proliferation of ISCs residing in the crypt is similarly stimulated by WNT ligands, R‐spondin (WNT agonist), Notch ligands, and growth factors secreted from neighboring epithelial paneth cells and the mesenchymal niche (black arrows). In mammals, BMP antagonists are crucial for maintaining stem cells in the crypt by preventing their maturation. In response to injury of the gut epithelium, ISC proliferation is stimulated by the release of cytokines from ECs and EBs, hemocyte‐derived Dpp, and systemic Dilps in flies (a, red arrows) and by the cytokine, interleukin‐22 (IL‐22) derived from a subgroup of innate lymphoid cells (ILC3s) in mammals (b, red arrows). BMP, bone morphogenetic protein; Dilp3, Drosophila insulin‐like peptide 3; DLL 1 and 4, Delta‐like 1 and 2; Dpp, Decapentaplegic; EGF, epidermal growth factor; Hh, Hedgehog; Krn, Keren; TGF‐α, transforming growth factor‐alpha; Upd 2and 3, Unpaired 2 and 3; Vn, Vein; Wg, Wingless
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Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration
Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells
Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches
Nervous System Development > Flies