Possible connection between intestinal tuft cells, ILC2s and obesity

Abstract

Intestinal tuft cells (TCs) are defined as chemosensory cells that can “taste” danger and induce immune responses. They play a critical role in gastrointestinal parasite invasion, inflammatory bowel diseases and high-fat diet-induced obesity. Intestinal IL-25, the unique product of TCs, is a key activator of type 2 immunity, especially to promote group 2 innate lymphoid cells (ILC2s) to secret IL-13. Then the IL-13 mainly promotes intestinal stem cell (ISCs) proliferation into TCs and goblet cells. This pathway formulates the circuit in the intestine. This paper focuses on the potential role of the intestinal TC, ILC2 and their circuit in obesity-induced intestinal damage, and discussion on further study and the potential therapeutic target in obesity.

1 Introduction

Obesity is a worldwide pandemic and a major risk for chronic diseases, including diabetes and cardiovascular disease. The prevalence of obesity has been increasing rapidly worldwide due to changes in lifestyle and diet. Obesity is considered as a typical metabolic syndrome characterized by systemic low-grade chronic inflammation (1). The close interactions between obesity and the gut microbiota and immunity (2) have recently been revealed, but the underlying mechanism has not yet been fully elucidated.

TCs line the epithelial mucosa, such as the intestine, airway and taste bud (3, 4). Although they were discovered more than six decades ago, their exact roles in health remain mysterious. Under homeostatic conditions, a small number of TCs serves as the monitor in the intestines, detecting and responding to various stimuli through the use of succinate (5), sweet and bitter taste receptors. While investigating ulcerative colitis (UC), the researchers noticed a reduction in TCs along with inflammation and tissue damage. However, when they treated UC mice with succinate, they observed an improvement of chronic intestinal inflammation, accompanied by an increase in the number of intestinal TCs (6). TCs are characterized by their apical microvilli and orchestrate the mucosal immune response (7), such as parasite immunity (8–10). Notably, intestinal TCs are unique cells that secrete IL-25 (10), the key activator of ILC2s. In response to IL-25, enteric ILC2s produce type 2 cytokines, including IL-4, IL-5, IL-9 and IL-13, which promote the ISCs differentiation into TCs, thus formulating the circuit (10). The TC-ILC2 circuit is regulated by feed-forward signaling including IL-25, IL-4 and IL-13 (11, 12), which has been shown to regulate intestinal remodeling and homeostasis in response to diet (12). Arora (13) indicated that TCs may be involved in modulating whole-body energy metabolism. ILC2s and their cytokines in the small intestine can also contribute to inflammation and insulin resistance (14). Further understanding of the potential connection between intestinal TC, ILC2 and obesity needs to be conducted. Herein, we review the connection mechanism of the intestinal TC, ILC2 and their circuit in obesity-associated inflammation through intestinal metabolic homeostasis.

2 Intestinal TCs in obesity process

2.1 Distribution, morphology, heterogeneity and origin of intestinal TCs

TCs are mostly present in the columnar epithelium of hollow endoderm-derived organs such as the trachea, thymus, stomach, small intestine, and urethra in mammals (15). Both the small and large intestines contain TCs, with the highest number at the proximal small intestine (16). Cholecystokinin, peptide YY- and glucagon-like peptide-1 (GLP-1) positive endocrine cells are found close to TCs (16). More than 60% of TCs in the small intestine are found in contact with nerve fibers, indicating that TCs are modulators of intestine movements (16) (Figure 1A).

Figure 1

The structure of TCs was first described in 1956 by Rhodin and Dalhamn (17). The “tuft” or “brush” comes from its unique type of brush border, and the apical microvilli of TCs extend into the gut lumen (18). The TC is characterized by its long and compact microvilli, which are connected to a broad network of rootlets that consists of actin, villus, filaments, and microtubules that hold the direction from apical to basal relative to neighboring cells (19–22). The cytoskeleton is largely composed of intermediate actin filaments (18, 23). Cytoplasmic spinules are a special part of TCs that extend from one lateral of the TC border into the adjacent cells, reaching their nuclei, which could be the route for the transport of molecular cargo wrapped with IL-25 or acetylcholine to the adjacent cells (18, 23, 24). These lateral interdigitating spinules appear on TCs ranging from just below the apical tight and adherent junctional complex to the nuclear level. With no secretory vesicles extending down the basal lamina, the basal area of TCs develops protrusions that resemble neuropods, indicating paracrine communication via neuropods (11) (Figure 1B).

By utilizing the single-cell sequence approach, Haber and his colleagues defined two subtypes of TCs, tuft-1 and tuft-2, in the intestine (25). Montoro also found the two subtypes in the mouse tracheal epithelium (26). Tuft-1 signature genes are correlated with neuronal development, whereas Tuft-2 cells are enriched for immune-related genes. SH2 Domain Containing 6 (Sh2d6) and G protein-coupled receptor (GPCR) vomeronasal type-2 receptor 26 (Vmn2r26) have been proposed as exclusive markers for tuft-2 cells (27), while tubulin polymerization-promoting protein family member 3 (Tppp3) is primarily expressed in tuft-1 cells (27). Besides, Tuft-2 cells express significantly higher levels of the Th2-promoting cytokine, thymic stromal lymphopoietin (TSLP) (25, 28). Markers including Arachidonate 5-lipoxygenase (Alox5), Cytochrome c oxidase 1 (Cox1), Cytochrome c oxidase 2 (Cox2), Hematopoietic Prostaglandin D Synthase (Hpgds), HOP Homeobox (Hopx), and phosphoserine epidermal growth factor receptor (p-Egfr) (29–31) exist in both subtypes. POU class 2 homeobox 3 (Pou2f3) is a crucial transcription factor for TC development, showing a shared ancestry with TCs in the gastrointestinal tract and lingual taste buds (9). In addition, growth factor-independent 1B (Gfi1b) is identified as TC-specific master regulators (32, 33). Both markers are expressed constitutively in all TCs (7). However, tuft-1 and tuft-2 cells both express IL-25 (25). Table 1.

Since the intestinal epithelium has rapid turnover and vigorous proliferation, and ISCs renew every 4-7 days, it is essential canonical Wnt signals combined with TGFβ/BMP pathways proceed unperturbed to maintain the integrity of the intestinal epithelial barrier (44). ISCs identified as leucine rich repeat-containing G protein coupled receptor-5 (Lgr5) positive cells, which are responsible for both renewal and regeneration processes and are located at the base of crypts (45). TCs are relatively rare in the intestine and account for 0.4% to 2.3% of the total epithelial cells in the murine intestinal epithelium (25). Unlike other epithelial cells, differentiated intestinal TCs still express Lgr5 (29).

The origin of intestinal TCs has been a controversial topic for years. Gerbe (30) first demonstrated that mature TCs are derived from Lgr5⁺ epithelial stem cells and require atonal bHLH transcription factor 1 (Atoh1) to differentiate, identifying them as the secretory lineage. However, some researchers hold a different opinion that doublecortin-like kinase 1 (DCLK1) positive TCs are derived from Lgr5⁺ stem cells and require neural input for survival in the nonsecretory lineage rather than the columnar lineage (43, 46). Herring (47) used p-Creode analysis of single cells in the intestine with computational and experimental methods to indicate that TCs were possibly Atoh1-independent secretory lineage in the small intestine. while in the colon, TCs arise from an Atoh1-driven alternative developmental program.

2.2 Functional pathways of intestinal TCs

Although TCs were discovered as a unique cell type more than sixty years ago, their function was not fully explored. Sensory and secretory functions were the known main functions of TCs, moreover, they are usually correlated.

TCs exhibit significant similarities with sensory cells. They possess characteristic apical microvilli that are positioned toward the luminal interface, like the tongue’s taste buds. This positioning facilitates access to chemosensory nerve endings. A variety of apical and basolateral receptors allow TCs to detect different parasites, bacteria, viruses or their metabolites (8, 48, 49). TCs taste signal receptors, including Type 1 transduces signals (Tas1Rs) for sweet/umami substances and type 2 for bitter substances (Tas2Rs) (50, 51), succinate receptor 1 (SUCNR1) (5, 12), and free fatty acid receptor 3 (FFAR3) (52) are heterotrimeric guanine nucleotide-binding protein G-coupled receptors (GPCRs). The activation of these distinct receptors triggers a shared signal transduction pathway that involves Gnat3, phospholipase Cβ2 (Plcβ2), inositol triphosphate receptor type 2 (Ip3r2), and Trpm5 a monovalent specific, nonselective cation channel for Na⁺, K⁺, and Cs⁺ ions instead of Ca2⁺ ions (53). Pou2f3 is the master regulator for the generation of Trpm5-expressing chemosensory TCs (54). These Trpm5-expressing TCs are responsible for helminth infection in the gut (8). However, TCs make use of Ip3r2 to regulate cytosolic calcium and Trpm5 activity in response to Trichinella spiralis infection in a small intestinal organoid, while Trpm5 enhanced the release and hyperplasia of IL-25 (51). The loss of activating transcription factor 5 (Atf5) enhanced the TC-ILC2 circuit by promoting TC differentiation in response to parasitic infections (55). While it is controversial, Heligmosomoides polygyrus seems to block the effects of IL-4 and IL-13 and inhibit the gene expression of TCs both in vitro and in vivo (56). As for the intestinal antimicrobial immunity, tuft-2 senses bacterial metabolite N-undecanoylglycine, then Vmn2r26 engages activated G-protein-coupled receptor-phospholipase C gamma2 (GPCR-PLCγ2)-Ca⁽²⁺⁾ signaling axis, which produces prostaglandin D2 (PGD2). PGD2 further enhances antibacterial immunity (27). Moreover, Vmn2r26 signaling also promotes the expression of Spi-B transcription factor, which promotes the expansion of Tuft 2 cells (27). Expressed on the intestinal TCs, CD300lf is identified as a murine norovirus (MNV) receptor, promoting MNV infection in vivo (57). Denatonium, as a bitter substance, is reported to increase intracellular calcium levels in colonic TCs (58). SUCNR1 is a typical receptor that reacts to succinate secreted by symbiotics and helminths (5). FFAR3, another TC receptor, is reported to be sensing indolepropionic acid (IPA), restoring IL-25 function, preventing gut leakage and inhibiting systemic inflammation (52). Interestingly, most reports indicate that multiple taste-associated GPCRs initiate intestinal immunity in TCs (Figure 1C).

TCs are important intestinal secretory cells. The majority of intestinal TCs generate a variety of paracrine and endocrine cytokines, including IL-25 (8), ACh (41), eicosanoids, TSLP and β-endorphins (25). TCs release IL-25 upon helminth infection and activate ILC2s to secrete IL-13, while IL-13 promotes the ISCs differentiation into TCs and goblet cells (10). The IL-25-dependent TC circuit requires macrophage migration inhibitory factor (Mif) (59). TCs express choline acetyltransferase for acetylcholine (ACh) synthesis, leading to the activation of Trpm5 during helminth infection (60). TCs also rapidly synthesize leukotrienes and other eicosanoid derivatives to stimulate competent cells (51, 61). Moreover, TCs are responsible for opioid (62), prostanoid and β-endorphin production (30), which are associated with analgesic effects as well as basic intestinal physiology including intestinal motility, secretion and nutrition absorption (Figure 1C).

2.3 Intestinal TCs in obesity

The intestines play a crucial role in the absorption of nutrients and the elimination of waste materials (63). Excess fat uptake in a Westernized diet is associated with an increased incidence of inflammatory bowel disease, obesity and food allergies (64). High-fat diet (HFD) impairs the intestinal immune system, making it hypersensitive to epithelial damage (65). Besides, it induces the imbalance in the gut microenvironment and active epithelial mucosa cells, including TCs (66).

It is controversial that TCs number varies when the mice are fed with HFD. Widmayer reported that 3 weeks of HFD supply increased the gastral surface mucous cells, mucosal mast cells, and TCs (67), and the expansion TCs demonstrated active leukotriene (LT) secretion. Gastric TCs can quickly sense saturated long-chain fatty acids (LCFAs) through the apical receptors GPR120 (67). Then, it is likely that upon detecting saturated LCFAs, TCs may trigger inflammatory reactions that produce cysteinyl (cys) LTs and activate surface mucous cells and mucosal mast cells, thus regulating the function and integrity of the intestinal mucosa (67). This process could potentially play a role in triggering mucosal inflammation. However, Arora reported that HFD-induced obese mice present an overall decrease of TCs in the small intestine due to the inhibition of IL-25 and TSLP mRNA expression (48). Additionally, Chen (52) and Sun (68) independently observed a reduction in TC population in mice subjected to long-time HFD, which coincided with a decrease in tight junction protein levels. However, TCs were both restored to normal levels following a weight loss intervention. It suggested that restoring the number of TCs in individuals affected by a HFD could potentially promote the restoration of intestinal barrier integrity. Aliluev (69) used single-cell sequencing on small intestinal crypt cells in nutrient-induced obese mice and found a decrease both in TCs and tuft progenitors. Mice fasted for 48 hours presented elevated levels of TCs after refeeding (29). However, a short-term HFD diet for 1, 3, or 7 d decreased the amount of TCs (70). Interestingly, the number of TCs exhibits considerable variation when they are subjected to HFD. It is plausible that the duration of HFD exposure, such as the 3-week HFD regimen employed by Widmayer (67) or the 9-week HFD regimen employed by Arora (48), may contribute to this difference.

Li reported that the succinate-SUCNR1 axis attenuates HFD-induced metabolic disturbance via activating type 2 immune responses and repairing intestinal barrier dysfunction (71). In mice infected with MNV, researchers discovered that intestinal TCs were targeted by MNV to activate mucosal immunity. This activation included various components such as B cell subsets, macrophages, and T cells, which collectively protected against type 1 diabetes in the mice (72).

The listed references provide evidence indicating a connection between disorders in taste cells and metabolic diseases, particularly obesity. Nevertheless, additional research especially the knockout of TCs or the key pathway is needed to further explore the role of TCs in these conditions.

3 ILC2s altered immunity in obesity

3.1 Origin, distribution, and function of ILC2s

ILC2s were recently found to be tissue-resident cells that lack recombination activating gene (RAG)-dependent rearrangement of antigen receptors, despite their particular lymphoid morphology compared to that of T and B cells (73). ILC2s were initially found in early infection of helminths (74). They are defined by biomarkers, including CD127 (IL-7Rα), CD161 (Klrg1) and CD294 (CRTH2) (75) (Table 2), which originate from the common lymphoid progenitor (CLP) in the fetal liver or bone marrow and migrate to peripheral tissues to develop into tissue-resident lymphocytes to combat specific types of infections (88, 89). CLPs are induced by Gata3, Id-2 (90, 91) and the transcription factors Gfi1 and Bcl11b to differentiate into ILC2s (92). ILC2s constitutively express high levels of GATA3 and ROR-α (90, 91), which are required for functional maturation and maintenance. The upstream regulator Bcl11b maintains Gfi1 expression in mature ILC2s (92). ILC2s show the immune function of type 2 immunity, which is stimulated by extracellular parasites, food, microbes and allergens (93–95). IL-25, IL-33, and TSLP activate ILC2s and produce type 2 cytokines IL-4, IL-5, IL-9, IL-13 and amphiregulin, which contribute to pathogen defense, metabolic homeostasis, and tissue remodeling (49, 96–100). ILC2s are divided into two types: natural ILC2s (nILC2s) and inflammatory ILC2s (iILC2s). nILC2s respond to IL-33 and produce IL-9 (93), while iILC2s respond to IL-25 (101) and highly express killer cell lectin-like receptor G1 (KLRG1) (101) and promote their production of IL-13 (102).

3.2 Intestinal ILC2s are involved in obesity

HFD induces systemic low-grade chronic inflammation in animal models and humans. ILC2s work as a bridge linking epithelial cells and the immune system to promote immunity and metabolic homeostasis (103). In adipose tissue, ILC2s induce the type 2 cytokines IL-5 or IL-13 and increase eosinophils numbers, and M2 macrophages stimulate inflammation, which promotes immunity and metabolic homeostasis and curbs obesity (104, 105). In the intestine, Sasaki (14) used Il2rg^−/−Rag2^−/− mice, which genetically lack all types of ILCs and are resistant to HFD-induced obesity, to reveal that intestinal ILC2s rather than WAT are more important in the development of obesity. The controversial results between the intestine and adipose tissue indicate that the immune function of ILC2s is likely dependent on the tissue/organ microenvironment. Administration of succinate in HFD-induced obese mice could enhance goblet cell production via activating type 2 immune responses in the small intestine (71). The expression of IL-4, IL-13, and IL-5 decreased in HFD-fed mice and was restored by berberine, indicating that ILC2s inhibit obesity-related intestinal inflammation (68). In obese human and mouse models, representative cytokines of ILC2s decreased and were rescued by IPA (52). In vitamin A deficient mice, dramatic expansion of IL-13 to produce ILC2 and resistance to nematode infection revealed that ILC2 might be the primary sensor of dietary stress, and innate type 2 immunity may represent a powerful adaptation of the immune system to promote host survival in the face of ongoing barrier challenges (89). The detailed effect of intestinal ILC2s on obesity still needs to be further investigated.

4 The TC-ILC2 circuit in obesity

4.1 Obesity intestinal microbial metabolites disorders potentially altered the circuit

Obesity and obesity-associated inflammation are closely correlated with dysbiosis in the intestinal microbiota (106). Short-chain fatty acids (SCFAs), including acetate, propionate and butyrate, are mostly produced by the gut microbiota (107). Mammalian cells produce succinate as an intermediate metabolite in the tricarboxylic acid cycle (TCA), yet microbes excrete succinate as a metabolic byproduct (108). Obese people have higher serum levels of succinate, which is associated with worse metabolic and specific intestinal microbiota (109). In a diet-induced obese model, succinate reduced body weight and promoted mitochondrial protein metabolism in brown adipose tissue (110). McKinley (29) noted that fasting and refeeding, as well as the introduction of microbiota to germ-free mice, caused dynamic changes in the quantity, composition and protein expression in TCs. Succinate is sufficient to promote the ISC to proliferate into TCs and goblet cells. However, at homeostasis, low levels of intestinal succinate cannot activate TCs (111). In response to the changes in TCs, intestinal microbial metabolites caused by HFD-induced obesity may affect the circuit, but further compelling evidence is required to support this claim.

4.2 The TC-ILC2 circuit potential function in obesity

The process of the circuit being affected can be explained as follows. The IL-25 receptor is the heterodimer of IL-17RB and IL-17RA. IL-25R is expressed in various respondent cells, including smooth muscle cells, basophils, eosinophils, and ILC2s throughout skin, brain, airway, and intestinal tissues (112–114). While TCs are the only cellular sources of IL-25 in the intestine (10), IL-25 induces ILC2s to produce type 2 immunity, which promotes the early immune response when infected (83). CysLTs and IL-25 collaborate to alert ILC2s to synthesize IL-4, IL-5 and IL-13 (61). IL-13 promotes Lgr5⁺ epithelial stem cells to differentiate into TCs or goblet cells, possibly by the Notch signaling pathway (115). In addition, IL-13 also promotes TC production and restores immune homeostasis and mucosal barriers (10). In response to dietary, the TC-ILC2 circuit regulates adaptive intestinal remodeling (12). However, this circuit is disrupted and downregulated IL-25 and TSLP marked TCs in obesity (48). Gut-microbiota-derived succinate promotes TC increase and reduces intestinal inflammation (111). Both TCs and IL-25 decreased in obese patients and animal models (52). These decreases could be restored by berberine via the TAS2Rs Gα-gustducin/Gβ1γ13 signaling pathway (68). IL-25 was first identified as a cytokine that induced naive CD4⁺ T cells into CD4⁺ Th2 cells (116). It plays a crucial role in regulating Th2-type immunity by modulating actin related gene 1(Act1) (117) and also promoting the secretion of Th2 cytokines (74) (Figure 2). Studies on TCs, ILC2s and the circuit response to obesity are limited and more TCs models including organoids and knockout mice could be applied to investigate the mechanism of obesity barrier damage.

Figure 2

5 The TC-ILC2 circuit may be a potential intervention target in obesity

Obese mice induced by HFD were administered IL-25 for 21 days, their body weight, serum glucose and intraperitoneal glucose tolerance were remarkably reversed (118). Despite the circuit, Feng reported that IL-25 promotes M2 macrophage polarization and thereby stimulates lipolysis and mitochondrial activity against obesity (119). IPA supplementation prevents the development of HFD-induced obesity (52), and the dosage of IPA is negatively correlated with obesity-induced inflammation (120). IPA holds potential as a reagent for obesity treatment due to its ability to activate TCs and promote IL-25 production. Furthermore, it exhibits interaction with FFAR3, further highlighting its potential as a valuable tool in combating obesity (52). A recent study by Sun (68) discovered that berberine, when sensed by TAS2Rs in TCs, stimulates the synthesis of IL-25. This feedback in TCs may turn out to be a novel mechanism by which berberine ameliorates obesity. Supplementation of drinking water with succinate robustly suppressed weight gain and improved glucose tolerance in HFD mice, resulting in an elevation in global energy expenditure (121). Thus, intervention targets on TCs, ILC2s or the circuit including IL-25, IPA, berberine and succinate, dramatically reduced the obesity status.

6 Conclusion and prospects

TCs use apical microvilli to taste danger signals, particularly metabolites derived from worms, viruses and bacteria. In response, TCs trigger downstream pathways to produce cytokines such as IL-25 to promote ILC2 activity, leading to Lgr5⁺ stem cell differentiation into TCs in a positive feedforward loop. In obese subjects, the TCs, ILC2s and the circuit are disrupted. IL-25, IPA and berberine have been reported to rescue the altered TC-ILC2 circuit in obese subjects, yet the underlying mechanisms remain to be fully elucidated. TC knockout models (27) and organoids (68, 122) could be better tools for further revealing the mechanism of TCs and ILC2s in obesity.

References

• 1

  Munir M Zakaria ZA Nisar H Ahmed Z Korma SA Esatbeyoglu T . Global human obesity and global social index: relationship and clustering. Front Nutr (2023) 10:1150403. doi: 10.3389/fnut.2023.1150403

  • CrossRef
  • Google Scholar

• 2

  Liu BN Liu XT Liang ZH Wang JH . Gut microbiota in obesity. World J Gastroenterol (2021) 27(25):3837–50. doi: 10.3748/wjg.v27.i25.3837

  • CrossRef
  • Google Scholar

• 3

  Montoro DT Haber AL Rood JE Regev A Rajagopal J . A synthesis concerning conservation and divergence of cell types across epithelia. Cold Spring Harb Perspect Biol (2020) 12(11):a035733. doi: 10.1101/cshperspect.a035733

  • CrossRef
  • Google Scholar

• 4

  Höfer D Püschel B Drenckhahn D . Taste receptor-like cells in the rat gut identified by expression of alpha-gustducin. Proc Natl Acad Sci (1996) 93(13):6631–4. doi: 10.1073/pnas.93.13.6631

  • CrossRef
  • Google Scholar

• 5

  Nadjsombati MS McGinty JW Lyons-Cohen MR Jaffe JB DiPeso L Schneider C et al . Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit. Immunity (2018) 49(1):33–41.e7. doi: 10.1016/j.immuni.2018.06.016

  • CrossRef
  • Google Scholar

• 6

  Banerjee A Herring CA Chen B Kim H Simmons AJ Southard-Smith AN et al . Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation. Gastroenterology (2020) 159(6):2101–15.e5. doi: 10.1053/j.gastro.2020.08.029

  • CrossRef
  • Google Scholar

• 7

  Gerbe F Jay P . Intestinal tuft cells: epithelial sentinels linking luminal cues to the immune system. Mucosal Immunol (2016) 9(6):1353–9. doi: 10.1038/mi.2016.68

  • CrossRef
  • Google Scholar

• 8

  Howitt MR Lavoie S Michaud M Blum AM Tran SV Weinstock JV et al . Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science (2016) 351(6279):1329–33. doi: 10.1126/science.aaf1648

  • CrossRef
  • Google Scholar

• 9

  Gerbe F Sidot E Smyth DJ Ohmoto M Matsumoto I Dardalhon V et al . Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature (2016) 529(7585):226–30. doi: 10.1038/nature16527

  • CrossRef
  • Google Scholar

• 10

  von Moltke J Ji M Liang H-E Locksley RM . Tuft-cell-derived il-25 regulates an intestinal ilc2–epithelial response circuit. Nature (2015) 529(7585):221–5. doi: 10.1038/nature16161

  • CrossRef
  • Google Scholar

• 11

  von Moltke J . Intestinal Tuft Cells. In: SaidHM, editor. Physiology of the Gastrointestinal Tract (Sixth Edition). London: Elsevier Inc. (2018). p. 721–33.

  • Google Scholar

• 12

  Schneider C O’Leary CE von Moltke J Liang H-E Ang QY Turnbaugh PJ et al . A metabolite-triggered tuft cell-ilc2 circuit drives small intestinal remodeling. Cell (2018) 174(2):271–84.e14. doi: 10.1016/j.cell.2018.05.014

  • CrossRef
  • Google Scholar

• 13

  Chen L Li L Ma L Zhao Z Luo S Gong B et al . Il-25–induced shifts in macrophage polarization promote development of beige fat and improve metabolic homeostasis in mice. PloS Biol (2021) 19(8):e3001348. doi: 10.1371/journal.pbio.3001348

  • CrossRef
  • Google Scholar

• 14

  Sasaki T Moro K Kubota T Kubota N Kato T Ohno H et al . Innate lymphoid cells in the induction of obesity. Cell Rep (2019) 28(1):202–17.e7. doi: 10.1016/j.celrep.2019.06.016

  • CrossRef
  • Google Scholar

• 15

  Hendel SK Kellermann L Hausmann A Bindslev N Jensen KB Nielsen OH . Tuft cells and their role in intestinal diseases. Front Immunol (2022) 13:822867. doi: 10.3389/fimmu.2022.822867

  • CrossRef
  • Google Scholar

• 16

  Cheng X Voss U Ekblad E . Tuft cells: distribution and connections with nerves and endocrine cells in mouse intestine. Exp Cell Res (2018) 369(1):105–11. doi: 10.1016/j.yexcr.2018.05.011

  • CrossRef
  • Google Scholar

• 17

  Rhodin J Dalhamn T . Electron microscopy of the tracheal ciliated mucosa in rat. Z für Zellforschung und Mikroskopische Anatomie (1956) 44(4):345–412. doi: 10.1007/BF00345847

  • CrossRef
  • Google Scholar

• 18

  Hoover B Baena V Kaelberer MM Getaneh F Chinchilla S Bohórquez DV . The intestinal tuft cell nanostructure in 3d. Sci Rep (2017) 7(1):1652. doi: 10.1038/s41598-017-01520-x

  • CrossRef
  • Google Scholar

• 19

  Höfer D Drenckhahn D . Identification of the taste cell G-protein, A-gustducin, in brush cells of the rat pancreatic duct system. Histochem Cell Biol (1998) 110(3):303–9. doi: 10.1007/s004180050292

  • CrossRef
  • Google Scholar

• 20

  Morroni M Cangiotti AM Cinti S . Brush cells in the human duodenojejunal junction: an ultrastructural study. J Anat (2007) 211(1):125–31. doi: 10.1111/j.1469-7580.2007.00738.x

  • CrossRef
  • Google Scholar

• 21

  Sato A Hisanaga Y Inoue Y Nagato T Toh H . Three-dimensional structure of apical vesicles of tuft cells in the main excretory duct of the rat submandibular gland. Eur J Morphol (2002) 40(4):235–9. doi: 10.1076/ejom.40.4.235.16690

  • CrossRef
  • Google Scholar

• 22

  Trier JS Allan CH Marcial MA Madara JL . Structural features of the apical and tubulovesicular membranes of rodent small intestinal tuft cells. Anatomical Rec (2005) 219(1):69–77. doi: 10.1002/ar.1092190112

  • CrossRef
  • Google Scholar

• 23

  Höfer D Drenckhahn D . Cytoskeletal markers allowing discrimination between brush cells and other epithelial cells of the gut including enteroendocrine cells. Histochem Cell Biol (1996) 105(5):405–12. doi: 10.1007/BF01463662

  • CrossRef
  • Google Scholar

• 24

  Kozono T Tamura-Nakano M Kawamura YI Tonozuka T Nishikawa A . Novel protocol to observe the intestinal tuft cell using transmission electron microscopy. Biol Open (2022) 11(2):bio059007. doi: 10.1242/bio.059007

  • CrossRef
  • Google Scholar

• 25

  Haber AL Biton M Rogel N Herbst RH Shekhar K Smillie C et al . A single-cell survey of the small intestinal epithelium. Nature (2017) 551(7680):333–9. doi: 10.1038/nature24489

  • CrossRef
  • Google Scholar

• 26

  Montoro DT Haber AL Biton M Vinarsky V Lin B Birket SE et al . A revised airway epithelial hierarchy includes cftr-expressing ionocytes. Nature (2018) 560(7718):319–24. doi: 10.1038/s41586-018-0393-7

  • CrossRef
  • Google Scholar

• 27

  Xiong Z Zhu X Geng J Xu Y Wu R Li C et al . Intestinal tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine. Immunity (2022) 55(4):686–700.e7. doi: 10.1016/j.immuni.2022.03.001

  • CrossRef
  • Google Scholar

• 28

  Biton M Levin A Slyper M Alkalay I Horwitz E Mor H et al . Epithelial micrornas regulate gut mucosal immunity via epithelium–T cell crosstalk. Nat Immunol (2011) 12(3):239–46. doi: 10.1038/ni.1994

  • CrossRef
  • Google Scholar

• 29

  McKinley ET Sui Y Al-Kofahi Y Millis BA Tyska MJ Roland JT et al . Optimized multiplex immunofluorescence single-cell analysis reveals tuft cell heterogeneity. JCI Insight (2017) 2(11):e93487. doi: 10.1172/jci.insight.93487

  • CrossRef
  • Google Scholar

• 30

  Gerbe F van Es JH Makrini L Brulin B Mellitzer G Robine S et al . Distinct atoh1 and neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J Cell Biol (2011) 192(5):767–80. doi: 10.1083/jcb.201010127

  • CrossRef
  • Google Scholar

• 31

  O’Leary CE Schneider C Locksley RM . Tuft cells—Systemically dispersed sensory epithelia integrating immune and neural circuitry. Annu Rev Immunol (2019) 37(1):47–72. doi: 10.1146/annurev-immunol-042718-041505

  • CrossRef
  • Google Scholar

• 32

  Huang Y-H Klingbeil O He X-Y Wu XS Arun G Lu B et al . Pou2f3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev (2018) 32(13-14):915–28. doi: 10.1101/gad.314815.118

  • CrossRef
  • Google Scholar

• 33

  O’Leary CE Ma Z Culpepper T Novak SW DelGiorno KE . New insights into tuft cell formation: implications for structure–function relationships. Curr Opin Cell Biol (2022) 76:102082. doi: 10.1016/j.ceb.2022.102082

  • CrossRef
  • Google Scholar

• 34

  Bomidi C Robertson M Coarfa C Estes MK Blutt SE . Single-cell sequencing of rotavirus-infected intestinal epithelium reveals cell-type specific epithelial repair and tuft cell infection. Proc Natl Acad Sci (2021) 118(45):e2112814118. doi: 10.1073/pnas.2112814118

  • CrossRef
  • Google Scholar

• 35

  Fehervari Z . Intestinal tuft cell function. Nat Immunol (2016) 17(4):355–. doi: 10.1038/ni.3426

  • CrossRef
  • Google Scholar

• 36

  Hoffman MT Kemp SB Salas-Escabillas DJ Zhang Y Steele NG The S et al . The gustatory sensory G-protein gnat3 suppresses pancreatic cancer progression in mice. Cell Mol Gastroenterol Hepatol (2021) 11(2):349–69. doi: 10.1016/j.jcmgh.2020.08.011

  • CrossRef
  • Google Scholar

• 37

  Pan J Zhang L Shao X Huang J . Acetylcholine from tuft cells: the updated insights beyond its immune and chemosensory functions. Front Cell Dev Biol (2020) 8:606. doi: 10.3389/fcell.2020.00606

  • CrossRef
  • Google Scholar

• 38

  Yi J Bergstrom K Fu J Shan X McDaniel JM McGee S et al . Dclk1 in tuft cells promotes inflammation-driven epithelial restitution and mitigates chronic colitis. Cell Death Differentiation (2018) 26(9):1656–69. doi: 10.1038/s41418-018-0237-x

  • CrossRef
  • Google Scholar

• 39

  Kjærgaard S Jensen TSR Feddersen UR Bindslev N Grunddal KV Poulsen SS et al . Decreased number of colonic tuft cells in quiescent ulcerative colitis patients. Eur J Gastroenterol Hepatol (2020) 33(6):817–24. doi: 10.1097/meg.0000000000001959

  • CrossRef
  • Google Scholar

• 40

  Steele SP Melchor SJ Petri WA . Tuft cells: new players in colitis. Trends Mol Med (2016) 22(11):921–4. doi: 10.1016/j.molmed.2016.09.005

  • CrossRef
  • Google Scholar

• 41

  Schütz B Ruppert A-L Strobel O Lazarus M Urade Y Büchler MW et al . Distribution pattern and molecular signature of cholinergic tuft cells in human gastro-intestinal and pancreatic-biliary tract. Sci Rep (2019) 9(1):17466. doi: 10.1038/s41598-019-53997-3

  • CrossRef
  • Google Scholar

• 42

  Banerjee A McKinley ET von Moltke J Coffey RJ Lau KS . Interpreting heterogeneity in intestinal tuft cell structure and function. J Clin Invest (2018) 128(5):1711–9. doi: 10.1172/jci120330

  • CrossRef
  • Google Scholar

• 43

  Bjerknes M Khandanpour C Möröy T Fujiyama T Hoshino M Klisch TJ et al . Origin of the brush cell lineage in the mouse intestinal epithelium. Dev Biol (2012) 362(2):194–218. doi: 10.1016/j.ydbio.2011.12.009

  • CrossRef
  • Google Scholar

• 44

  Reynolds A Wharton N Parris A Mitchell E Sobolewski A Kam C et al . Canonical wnt signals combined with suppressed tgfβ/bmp pathways promote renewal of the native human colonic epithelium. Gut (2014) 63(4):610–21. doi: 10.1136/gutjnl-2012-304067

  • CrossRef
  • Google Scholar

• 45

  Liu Y Chen Y-G . Intestinal epithelial plasticity and regeneration via cell dedifferentiation. Cell Regeneration (2020) 9(1):14. doi: 10.1186/s13619-020-00053-5

  • CrossRef
  • Google Scholar

• 46

  Westphalen CB Asfaha S Hayakawa Y Takemoto Y Lukin DJ Nuber AH et al . Long-lived intestinal tuft cells serve as colon cancer–initiating cells. J Clin Invest (2014) 124(3):1283–95. doi: 10.1172/jci73434

  • CrossRef
  • Google Scholar

• 47

  Herring CA Banerjee A McKinley ET Simmons AJ Ping J Roland JT et al . Unsupervised trajectory analysis of single-cell rna-seq and imaging data reveals alternative tuft cell origins in the gut. Cell Syst (2018) 6(1):37–51.e9. doi: 10.1016/j.cels.2017.10.012

  • CrossRef
  • Google Scholar

• 48

  Arora P Andersen D Moll JM Danneskiold-Samsøe NB Xu L Zhou B et al . Small intestinal tuft cell activity associates with energy metabolism in diet-induced obesity. Front Immunol (2021) 12:629391. doi: 10.3389/fimmu.2021.629391

  • CrossRef
  • Google Scholar

• 49

  Roach SN Fiege JK Shepherd FK Wiggen TD Hunter RC Langlois RA et al . Respiratory influenza virus infection causes dynamic tuft cell and innate lymphoid cell changes in the small intestine. J Virol (2022) 96(9):e0035222. doi: 10.1128/jvi.00352-22

  • CrossRef
  • Google Scholar

• 50

  Howitt MR Cao YG Gologorsky MB Li JA Haber AL Biton M et al . The taste receptor tas1r3 regulates small intestinal tuft cell homeostasis. ImmunoHorizons (2020) 4(1):23–32. doi: 10.4049/immunohorizons.1900099

  • CrossRef
  • Google Scholar

• 51

  Luo X-C Chen Z-H Xue J-B Zhao D-X Lu C Li Y-H et al . Infection by the parasitic helminthtrichinella spiralisactivates a tas2r-mediated signaling pathway in intestinal tuft cells. Proc Natl Acad Sci (2019) 116(12):5564–9. doi: 10.1073/pnas.1812901116

  • CrossRef
  • Google Scholar

• 52

  Chen L Yang Y Sun S Xie Y Pan C Li M et al . Indolepropionic acid reduces obesity-induced metabolic dysfunction through colonic barrier restoration mediated via tuft cell-derived il-25. FEBS J (2022) 289(19):5985–6004. doi: 10.1111/febs.16470

  • CrossRef
  • Google Scholar

• 53

  Gaetani S Larsson MH Håkansson P Jansen FP Magnell K Brodin P . Ablation of trpm5 in mice results in reduced body weight gain and improved glucose tolerance and protects from excessive consumption of sweet palatable food when fed high caloric diets. PloS One (2015) 10(9):e0138373. doi: 10.1371/journal.pone.0138373

  • CrossRef
  • Google Scholar

• 54

  Ishimaru Y Yamashita J Ohmoto M Yamaguchi T Matsumoto I Hirota J . Skn-1a/pou2f3 functions as a master regulator to generate trpm5-expressing chemosensory cells in mice. PloS One (2017) 12(12):e0189340. doi: 10.1371/journal.pone.0189340

  • CrossRef
  • Google Scholar

• 55

  Nakano H Hata A Ishimura U Kosugi R Miyamoto E Nakamura K et al . Activating transcription factor 5 (Atf5) controls intestinal tuft and goblet cell expansion upon succinate-induced type 2 immune responses in mice. Cell Tissue Res (2023) 393(2):343–55. doi: 10.1007/s00441-023-03781-7

  • CrossRef
  • Google Scholar

• 56

  Drurey C Lindholm HT Coakley G Poveda MC Löser S Doolan R et al . Intestinal epithelial tuft cell induction is negated by a murine helminth and its secreted products. J Exp Med (2022) 219(1):e20211140. doi: 10.1084/jem.20211140

  • CrossRef
  • Google Scholar

• 57

  Wilen CB Lee S Hsieh LL Orchard RC Desai C Hykes BL et al . Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science (2018) 360(6385):204–8. doi: 10.1126/science.aar3799

  • CrossRef
  • Google Scholar

• 58

  Schütz B JI Bader S Ringer C von Engelhardt J Chubanov V Gudermann T et al . Chemical coding and chemosensory properties of cholinergic brush cells in the mouse gastrointestinal and biliary tract. Front Physiol (2015) 6:87. doi: 10.3389/fphys.2015.00087

  • CrossRef
  • Google Scholar

• 59

  Varyani F Löser S Filbey KJ Harcus Y Drurey C Poveda MC et al . The il-25-dependent tuft cell circuit driven by intestinal helminths requires macrophage migration inhibitory factor (Mif). Mucosal Immunol (2022) 15(6):1243–56. doi: 10.1038/s41385-022-00496-w

  • CrossRef
  • Google Scholar

• 60

  Billipp TE Fung C Webeck LM Sargent DB Gologorsky MB McDaniel MM et al . Tuft cell-derived acetylcholine regulates epithelial fluid secretion. bioRxiv (2023) 2023-03. doi: 10.1101/2023.03.17.533208

  • CrossRef
  • Google Scholar

• 61

  McGinty JW Ting H-A Billipp TE Nadjsombati MS Khan DM Barrett NA et al . Tuft-cell-derived leukotrienes drive rapid anti-helminth immunity in the small intestine but are dispensable for anti-protist immunity. Immunity (2020) 52(3):528–41.e7. doi: 10.1016/j.immuni.2020.02.005

  • CrossRef
  • Google Scholar

• 62

  Kokrashvili Z Rodriguez D Yevshayeva V Zhou H Margolskee RF Mosinger B . Release of endogenous opioids from duodenal enteroendocrine cells requires trpm5. Gastroenterology (2009) 137(2):598–606.e2. doi: 10.1053/j.gastro.2009.02.070

  • CrossRef
  • Google Scholar

• 63

  Weiss GA Hennet T . Mechanisms and consequences of intestinal dysbiosis. Cell Mol Life Sci (2017) 74(16):2959–77. doi: 10.1007/s00018-017-2509-x

  • CrossRef
  • Google Scholar

• 64

  Chiba M Morita N Nakamura A Tsuji K Harashima E . Increased incidence of inflammatory bowel disease in association with dietary transition (Westernization) in Japan. JMA J (2021) 4(4):347–57. doi: 10.31662/jmaj.2021-0038

  • CrossRef
  • Google Scholar

• 65

  Tanaka S Nemoto Y Takei Y Morikawa R Oshima S Nagaishi T et al . High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage. Biochem Biophys Res Commun (2020) 522(4):971–7. doi: 10.1016/j.bbrc.2019.11.158

  • CrossRef
  • Google Scholar

• 66

  Okumura R Takeda K . Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Exp Mol Med (2017) 49(5):e338–e. doi: 10.1038/emm.2017.20

  • CrossRef
  • Google Scholar

• 67

  Widmayer P Pregitzer P Breer H . Short-term high fat feeding induces inflammatory responses of tuft cells and mucosal barrier cells in the murine stomach. Histol Histopathol (2023) 38(3):273–86. doi: 10.14670/hh-18-503

  • CrossRef
  • Google Scholar

• 68

  Sun S Yang Y Xiong R Ni Y Ma X Hou M et al . Oral berberine ameliorates high-fat diet-induced obesity by activating tas2rs in tuft and endocrine cells in the gut. Life Sci (2022) 311:121141. doi: 10.1016/j.lfs.2022.121141

  • CrossRef
  • Google Scholar

• 69

  Aliluev A Tritschler S Sterr M Oppenländer L Hinterdobler J Greisle T et al . Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice. Nat Metab (2021) 3(9):1202–16. doi: 10.1038/s42255-021-00458-9

  • CrossRef
  • Google Scholar

• 70

  Enriquez JR McCauley HA Zhang KX Sanchez JG Kalin GT Lang RA et al . A dietary change to a high-fat diet initiates a rapid adaptation of the intestine. Cell Rep (2022) 41(7):111641. doi: 10.1016/j.celrep.2022.111641

  • CrossRef
  • Google Scholar

• 71

  Li X Huang G Zhang Y Ren Y Zhang R Zhu W et al . Succinate signaling attenuates high-fat diet-induced metabolic disturbance and intestinal barrier dysfunction. Pharmacol Res (2023) 194:106865. doi: 10.1016/j.phrs.2023.106865

  • CrossRef
  • Google Scholar

• 72

  Pearson JA Tai N Ekanayake-Alper DK Peng J Hu Y Hager K et al . Norovirus changes susceptibility to type 1 diabetes by altering intestinal microbiota and immune cell functions. Front Immunol (2019) 10:2654. doi: 10.3389/fimmu.2019.02654

  • CrossRef
  • Google Scholar

• 73

  Vivier E Artis D Colonna M Diefenbach A Di Santo JP Eberl G et al . Innate lymphoid cells: 10 years on. Cell (2018) 174(5):1054–66. doi: 10.1016/j.cell.2018.07.017

  • CrossRef
  • Google Scholar

• 74

  Fallon PG Ballantyne SJ Mangan NE Barlow JL Dasvarma A Hewett DR et al . Identification of an interleukin (Il)-25–dependent cell population that provides il-4, il-5, and il-13 at the onset of helminth expulsion. J Exp Med (2006) 203(4):1105–16. doi: 10.1084/jem.20051615

  • CrossRef
  • Google Scholar

• 75

  Mjösberg JM Trifari S Crellin NK Peters CP van Drunen CM Piet B et al . Human il-25- and il-33-responsive type 2 innate lymphoid cells are defined by expression of crth2 and cd161. Nat Immunol (2011) 12(11):1055–62. doi: 10.1038/ni.2104

  • CrossRef
  • Google Scholar

• 76

  Ghaedi M Shen ZY Orangi M Martinez-Gonzalez I Wei L Lu X et al . Single-cell analysis of rorα Tracer mouse lung reveals ilc progenitors and effector ilc2 subsets. J Exp Med (2020) 217(3):e20182293. doi: 10.1084/jem.20182293

  • CrossRef
  • Google Scholar

• 77

  Gonzalez-Polo V Pucci-Molineris M Cervera V Gambaro S Yantorno SE Descalzi V et al . Group 2 innate lymphoid cells exhibit progressively higher levels of activation during worsening of liver fibrosis. Ann Hepatol (2019) 18(2):366–72. doi: 10.1016/j.aohep.2018.12.001

  • CrossRef
  • Google Scholar

• 78

  Rajput C Cui T Han M Lei J Hinde JL Wu Q et al . Rorα-dependent type 2 innate lymphoid cells are required and sufficient for mucous metaplasia in immature mice. Am J Physiology-Lung Cell Mol Physiol (2017) 312(6):L983–L93. doi: 10.1152/ajplung.00368.2016

  • CrossRef
  • Google Scholar

• 79

  Kyoizumi S Kubo Y Kajimura J Yoshida K Hayashi T Nakachi K et al . Fate decision between group 3 innate lymphoid and conventional nk cell lineages by notch signaling in human circulating hematopoietic progenitors. J Immunol (2017) 199(8):2777–93. doi: 10.4049/jimmunol.1601711

  • CrossRef
  • Google Scholar

• 80

  Kadel S Ainsua-Enrich E Hatipoglu I Turner S Singh S Khan S et al . A major population of functional klrg1– ilc2s in female lungs contributes to a sex bias in ilc2 numbers. ImmunoHorizons (2018) 2(2):74–86. doi: 10.4049/immunohorizons.1800008

  • CrossRef
  • Google Scholar

• 81

  Oyesola OO Duque C Huang LC Larson EM Früh SP Webb LM et al . The prostaglandin D2 receptor crth2 promotes il-33–induced ilc2 accumulation in the lung. J Immunol (2020) 204(4):1001–11. doi: 10.4049/jimmunol.1900745

  • CrossRef
  • Google Scholar

• 82

  Kanaoka Y Boyce JA . Cysteinyl leukotrienes and their receptors; emerging concepts. Allergy Asthma Immunol Res (2014) 6(4):288–95. doi: 10.4168/aair.2014.6.4.288

  • CrossRef
  • Google Scholar

• 83

  Fritz JH Angkasekwinai P Sodthawon W Jeerawattanawart S Hansakon A Pattanapanyasat K et al . Ilc2s activated by il-25 promote antigen-specific th2 and th9 functions that contribute to the control of trichinella spiralis infection. PloS One (2017) 12(9):e0184684. doi: 10.1371/journal.pone.0184684

  • CrossRef
  • Google Scholar

• 84

  Hoyler T Klose Christoph SN Souabni A Turqueti-Neves A Pfeifer D Rawlins Emma L et al . The transcription factor gata-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity (2012) 37(4):634–48. doi: 10.1016/j.immuni.2012.06.020

  • CrossRef
  • Google Scholar

• 85

  Paclik D Stehle C Lahmann A Hutloff A Romagnani C . Icos regulates the pool of group 2 innate lymphoid cells under homeostatic and inflammatory conditions in mice. Eur J Immunol (2015) 45(10):2766–72. doi: 10.1002/eji.201545635

  • CrossRef
  • Google Scholar

• 86

  Cardoso V Chesné J Ribeiro H García-Cassani B Carvalho T Bouchery T et al . Neuronal regulation of type 2 innate lymphoid cells via neuromedin U. Nature (2017) 549(7671):277–81. doi: 10.1038/nature23469

  • CrossRef
  • Google Scholar

• 87

  Topczewska PM Rompe ZA Jakob MO Stamm A Leclère PS Preußer A et al . Ilc2 require cell-intrinsic st2 signals to promote type 2 immune responses. Front Immunol (2023) 14:1130933. doi: 10.3389/fimmu.2023.1130933

  • CrossRef
  • Google Scholar

• 88

  Nagasawa M Spits H Ros XR . Innate lymphoid cells (Ilcs): cytokine hubs regulating immunity and tissue homeostasis. Cold Spring Harbor Perspect Biol (2018) 10(12):a030304. doi: 10.1101/cshperspect.a030304

  • CrossRef
  • Google Scholar

• 89

  Spencer SP Wilhelm C Yang Q Hall JA Bouladoux N Boyd A et al . Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science (2014) 343(6169):432–7. doi: 10.1126/science.1247606

  • CrossRef
  • Google Scholar

• 90

  Serafini N Klein Wolterink RGJ Satoh-Takayama N Xu W Vosshenrich CAJ Hendriks RW et al . Gata3 drives development of rorγt+ Group 3 innate lymphoid cells. J Exp Med (2014) 211(2):199–208. doi: 10.1084/jem.20131038

  • CrossRef
  • Google Scholar

• 91

  Yagi R Zhong C Northrup Daniel L Yu F Bouladoux N Spencer S et al . The transcription factor gata3 is critical for the development of all il-7rα-expressing innate lymphoid cells. Immunity (2014) 40(3):378–88. doi: 10.1016/j.immuni.2014.01.012

  • CrossRef
  • Google Scholar

• 92

  Walker JA Oliphant CJ Englezakis A Yu Y Clare S Rodewald H-R et al . Bcl11b is essential for group 2 innate lymphoid cell development. J Exp Med (2015) 212(6):875–82. doi: 10.1084/jem.20142224

  • CrossRef
  • Google Scholar

• 93

  Turner J-E Morrison PJ Wilhelm C Wilson M Ahlfors H Renauld J-C et al . Il-9–mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J Exp Med (2013) 210(13):2951–65. doi: 10.1084/jem.20130071

  • CrossRef
  • Google Scholar

• 94

  Lee M Ko H-J Hong S-W Park J Ham S Kim M et al . Dietary antigens suppress the proliferation of type 2 innate lymphoid cells by restraining homeostatic il-25 production. Sci Rep (2022) 12(1):7443. doi: 10.1038/s41598-022-11466-4

  • CrossRef
  • Google Scholar

• 95

  Gury-BenAri M Thaiss CA Serafini N Winter DR Giladi A Lara-Astiaso D et al . The spectrum and regulatory landscape of intestinal innate lymphoid cells are shaped by the microbiome. Cell (2016) 166(5):1231–46.e13. doi: 10.1016/j.cell.2016.07.043

  • CrossRef
  • Google Scholar

• 96

  Neill DR Wong SH Bellosi A Flynn RJ Daly M Langford TKA et al . Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature (2010) 464(7293):1367–70. doi: 10.1038/nature08900

  • CrossRef
  • Google Scholar

• 97

  Monticelli LA Osborne LC Noti M Tran SV Zaiss DMW Artis D . Il-33 promotes an innate immune pathway of intestinal tissue protection dependent on amphiregulin–egfr interactions. Proc Natl Acad Sci (2015) 112(34):10762–7. doi: 10.1073/pnas.1509070112

  • CrossRef
  • Google Scholar

• 98

  Monticelli LA Sonnenberg GF Abt MC Alenghat T Ziegler CG Doering TA et al . Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat Immunol (2011) 12(11):1045–54. doi: 10.1031/ni.2131

  • CrossRef
  • Google Scholar

• 99

  Lai D-M Shu Q Fan J . The origin and role of innate lymphoid cells in the lung. Military Med Res (2016) 3(1):25. doi: 10.1186/s40779-016-0093-2

  • CrossRef
  • Google Scholar

• 100

  Sonnenberg GF Artis D . Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med (2015) 21(7):698–708. doi: 10.1038/nm.3892

  • CrossRef
  • Google Scholar

• 101

  Huang Y Guo L Qiu J Chen X Hu-Li J Siebenlist U et al . Il-25-responsive, lineage-negative klrg1hi cells are multipotential ‘Inflammatory’ Type 2 innate lymphoid cells. Nat Immunol (2014) 16(2):161–9. doi: 10.1038/ni.3078

  • CrossRef
  • Google Scholar

• 102

  Leyva-Castillo JM Galand C Mashiko S Bissonnette R McGurk A Ziegler SF et al . Ilc2 activation by keratinocyte-derived il-25 drives il-13 production at sites of allergic skin inflammation. J Allergy Clin Immunol (2020) 145(6):1606–14.e4. doi: 10.1016/j.jaci.2020.02.026

  • CrossRef
  • Google Scholar

• 103

  Zhen Y Shu W Hou X Wang Y . Innate immune system orchestrates metabolic homeostasis and dysfunction in visceral adipose tissue during obesity. Front Immunol (2021) 12:702835. doi: 10.3389/fimmu.2021.702835

  • CrossRef
  • Google Scholar

• 104

  Molofsky AB Nussbaum JC Liang H-E Van Dyken SJ Cheng LE Mohapatra A et al . Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med (2013) 210(3):535–49. doi: 10.1084/jem.20121964

  • CrossRef
  • Google Scholar

• 105

  Brestoff JR Kim BS Saenz SA Stine RR Monticelli LA Sonnenberg GF et al . Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature (2014) 519(7542):242–6. doi: 10.1038/nature14115

  • CrossRef
  • Google Scholar

• 106

  Cheng Z Zhang L Yang L Chu H . The critical role of gut microbiota in obesity. Front Endocrinol (2022) 13:1025706. doi: 10.3389/fendo.2022.1025706

  • CrossRef
  • Google Scholar

• 107

  Kim CH . Control of lymphocyte functions by gut microbiota-derived short-chain fatty acids. Cell Mol Immunol (2021) 18(5):1161–71. doi: 10.1038/s41423-020-00625-0

  • CrossRef
  • Google Scholar

• 108

  Fernández-Veledo S Vendrell J . Gut microbiota-derived succinate: friend or foe in human metabolic diseases? Rev Endocrine Metab Disord (2019) 20(4):439–47. doi: 10.1007/s11154-019-09513-z

  • CrossRef
  • Google Scholar

• 109

  Serena C Ceperuelo-Mallafré V Keiran N Queipo-Ortuño MI Bernal R Gomez-Huelgas R et al . Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota. ISME J (2018) 12(7):1642–57. doi: 10.1038/s41396-018-0068-2

  • CrossRef
  • Google Scholar

• 110

  Gaspar RS Delafiori J Zuccoli G Carregari VC Prado TP Morari J et al . Exogenous succinate impacts mouse brown adipose tissue mitochondrial proteome and potentiates body mass reduction induced by liraglutide. Am J Physiology-Endocrinol Metab (2023) 324(3):E226–E40. doi: 10.1152/ajpendo.00231.2022

  • CrossRef
  • Google Scholar

• 111

  Lei W Ren W Ohmoto M Urban JF Matsumoto I Margolskee RF et al . Activation of intestinal tuft cell-expressed sucnr1 triggers type 2 immunity in the mouse small intestine. Proc Natl Acad Sci (2018) 115(21):5552–7. doi: 10.1073/pnas.1720758115

  • CrossRef
  • Google Scholar

• 112

  Arumugam P Carroll KL Berceli SA Barnhill S Wrenshall LE . Expression of a functional il-2 receptor in vascular smooth muscle cells. J Immunol (2019) 202(3):694–703. doi: 10.4049/jimmunol.1701151

  • CrossRef
  • Google Scholar

• 113

  Tang W Smith SG Beaudin S Dua B Howie K Gauvreau G et al . Il-25 and il-25 receptor expression on eosinophils from subjects with allergic asthma. Int Arch Allergy Immunol (2014) 163(1):5–10. doi: 10.1159/000355331

  • CrossRef
  • Google Scholar

• 114

  Bellocchia M Boita M Solidoro P Coni F Bardessono M Mercante L et al . Il-25 receptor expression on basophil membrane is related to phenotype and severity of asthma. Eur Respir Soc (2015) 46:PA1093. doi: 10.1183/13993003.congress-2015.PA1093

  • CrossRef
  • Google Scholar

• 115

  Basak O Beumer J Wiebrands K Seno H van Oudenaarden A Clevers H . Induced quiescence of lgr5+ Stem cells in intestinal organoids enables differentiation of hormone-producing enteroendocrine cells. Cell Stem Cell (2017) 20(2):177–90.e4. doi: 10.1016/j.stem.2016.11.001

  • CrossRef
  • Google Scholar

• 116

  Fort MM Cheung J Yen D Li J Zurawski SM Lo S et al . Il-25 induces il-4, il-5, and il-13 and th2-associated pathologies in vivo. Immunity (2001) 15(6):985–95. doi: 10.1016/s1074-7613(01)00243-6

  • CrossRef
  • Google Scholar

• 117

  Claudio E Sønder SU Saret S Carvalho G Ramalingam TR Wynn TA et al . The adaptor protein ciks/act1 is essential for il-25-mediated allergic airway inflammation. J Immunol (2009) 182(3):1617–30. doi: 10.4049/jimmunol.182.3.1617

  • CrossRef
  • Google Scholar

• 118

  Smith AD Fan A Qin B Desai N Zhao A Shea-Donohue T . Il-25 treatment improves metabolic syndrome in high-fat diet and genetic models of obesity. Diabetes Metab Syndrome Obesity: Targets Ther (2021) 14:4875–87. doi: 10.2147/dmso.S335761

  • CrossRef
  • Google Scholar

• 119

  Feng J Li L Ou Z Li Q Gong B Zhao Z et al . Il-25 stimulates M2 macrophage polarization and thereby promotes mitochondrial respiratory capacity and lipolysis in adipose tissues against obesity. Cell Mol Immunol (2017) 15(5):493–505. doi: 10.1038/cmi.2016.71

  • CrossRef
  • Google Scholar

• 120

  Tuomainen M Lindström J Lehtonen M Auriola S Pihlajamäki J Peltonen M et al . Associations of serum indolepropionic acid, a gut microbiota metabolite, with type 2 diabetes and low-grade inflammation in high-risk individuals. Nutr Diabetes (2018) 8(1):35. doi: 10.1038/s41387-018-0046-9

  • CrossRef
  • Google Scholar

• 121

  Mills EL Pierce KA Jedrychowski MP Garrity R Winther S Vidoni S et al . Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature (2018) 560(7716):102–6. doi: 10.1038/s41586-018-0353-2

  • CrossRef
  • Google Scholar

• 122

  Inaba A Arinaga A Tanaka K Endo T Hayatsu N Okazaki Y et al . Interleukin-4 promotes tuft cell differentiation and acetylcholine production in intestinal organoids of non-human primate. Int J Mol Sci (2021) 22(15):7921. doi: 10.3390/ijms22157921

  • CrossRef
  • Google Scholar