Article ID: 2022-0015-IR
Inflammatory bowel diseases (IBD) are currently recognized to involve chronic intestinal inflammation in genetically susceptible individuals. Patients with IBD mainly develop gastrointestinal inflammation, but it is sometimes accompanied by extraintestinal manifestations such as arthritis, erythema nodosum, episcleritis, pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis. These clinical aspects imply the importance of interorgan networks in IBD. In the gastrointestinal tract, immune cells are influenced by multiple local environmental factors including microbiota, dietary environment, and intercellular networks, which further alter molecular networks in immune cells. Therefore, deciphering networks at interorgan, intercellular, and intracellular levels should help to obtain a comprehensive understanding of IBD. This review focuses on the intestinal immune system, which governs the physiological and pathological functions of the digestive system in harmony with the other organs.
René Descartes outlined the rules for understanding the natural world in Discours de la méthode and formed the foundation of natural sciences in the 17th century. Since then, a major part of the scientific method has been a process of problem recognition and the decomposition of problems from complex systems into individual elements that might be necessary for their adequate solution. Although this process remains fundamental to the natural sciences, recent advances in omics technologies allow us to appreciate complexity and dynamism in the natural sciences without radical decomposition. Approaches combining complex systems analysis and the reductionist approach have gradually unveiled the pathogenesis of some diseases, including inflammatory bowel diseases (IBD), involving complex networks at interorgan, intercellular, and intracellular molecular levels (Fig. 1). These multi-layered networks have been shown to dynamically influence the severity and symptoms of IBD. Indeed, IBD are intractable chronic inflammatory diseases of the gastrointestinal tract, which also cause complications in various organs beyond the gastrointestinal tract, including arthritis, cholangitis (e.g., primary sclerosing cholangitis), dermatitis (e.g., erythema nodosum and pyoderma gangrenosum), and psychiatric disorders (e.g., depression). In this review, we provide an overview of intestinal immunity and pathological conditions in the digestive system.
Complex networks at interorgan, intercellular, and intracellular molecular levels shape the pathophysiology of IBD.
The intestinal microenvironment affects distant organs including the liver and brain. At the lamina propria of the intestine, immune cells are exposed to the local microenvironment and exhibit epigenetic modification. MAMP, microbe-associated molecular pattern; LDTF, lineage-determining transcription factor; SDTF, signal-dependent transcription factor; ENS, enteric nervous system.
Various mechanisms in the intestinal tract induce immune tolerance to suppress excessive immune responses. M cells in the intestinal epithelium actively take up antigens in Peyer’s patches (PP) and isolated lymphoid follicles (ILF) and supply them to antigen-presenting cells (APCs). Intracellularly degraded antigens in APCs are presented to the class II major histocompatibility complex (MHC II), which activates and differentiates antigen-specific T and B cells, leading to clearance of pathogenic microorganisms and the establishment of immune tolerance against commensal bacteria. Chronic inflammation is assumed to occur in patients with IBD as a result of a breakdown in this immune regulatory mechanism.1
T helper cells, which play a central role in the intestinal immune system, are known to differentiate from naïve T cells into Th1, Th2, Th17, and suppressive T cells (Treg), among others.2 In the intestinal mucosa and lymph nodes of patients with active Crohn’s disease (CD), elevated levels of IL-12, which is important for Th1 differentiation, and T-bet, a lineage-determining transcription factor (LDTF) for Th1, have been observed.3 Furthermore, an increase in immunoglobulin G1-containing cells and the presence of autoantibodies have been reported in the mucosa of patients with ulcerative colitis (UC), suggesting the involvement of Th2 cells.4,5,6 Therefore, the Th1/Th2 paradigm hypothesis, which postulates that Th1-type cytokines in CD and Th2-type cytokines in UC are responsible for the abnormal immune response, was previously proposed and well accepted until the discovery of Th17 cells.7,8 Several IBD susceptibility genes associated with Th17, such as IL23R, IL12B, JAK2, TYK2, and STAT3, have been identified from genome-wide association studies,9 and an increase in IL-17 expression in the mucosal layer in IBD patients compared with the level in healthy controls was reported,10,11,12 supporting the association between Th17 and IBD. In addition, microorganisms including intestinal bacteria play an important role in the differentiation of Th17 cells. Segmented filamentous bacteria (SFB), spore-forming Gram-positive bacteria that are abundant at the end of the mouse ileum, are known to promote the production of serum amyloid A (SAA) from the epithelium and to have Th17 cell-inducing properties.13 An increase in adherent-invasive Escherichia coli (AIEC) in the intestinal epithelium has also been reported in patients with IBD, while epithelium-adherent pathogens such as Citrobacter rodentium and Candida albicans also promote Th17 cells.14 Although Th17 cells have been extensively studied since their identification,13,15 their roles in IBD remain unclear because of the dichotomous features of intestinal Th17 cells.16 Previous studies that investigated the roles of Th17 cells during colitis took advantage of a transfer colitis model, where naïve CD4+ T cells were transferred to immunodeficient mice, such as Rag1−/− or Rag2−/− mice, leading to the development of severe colitis.17 Notably, donor naïve CD4+ T cells lacking RORγt, the LDTF of Th17 cells, failed to lead to the development of colitis,18 whereas donor naïve CD4+ T cells lacking IL-17A or IL-17R exacerbated the colitis.19 In addition, the neutralization of IL-17 in a mouse DSS-induced acute colitis model20 or human CD was shown to aggravate intestinal inflammation.21 These results raise questions about the colitogenic potential of IL-17A or Th17 effector cytokines. The conflicting findings about whether Th17 has a pathological or protective role in colitis or other immune-mediated diseases subsequently led to the establishment of the concept of ‘pathogenic’ and ‘non-pathogenic’ Th17 cells. Specifically, Th17 cells have been proposed as a heterogeneous cell population with a mixture of ‘non-pathogenic’ Th17 cells, the IL-10-producing suppressive fraction induced in the presence of TGF-β, and ‘pathogenic’ Th17 cells, the T-bet-expressing, inflammation-producing fraction similar to Th1 cells, induced by IL-23 and other factors in the absence of TGF-β.22,23 The presence of two contrasting sets of Th17 cells was also reported in vivo by comparing Th cells obtained from experimental autoimmune encephalomyelitis (EAE) and a small intestinal inflammation model treated with anti-CD3 antibodies24 and by characterizing Th cells in the central nervous system during EAE.25 IL-23 secreted by APCs is an important cytokine for Th17 cell differentiation. It has also been reported that IL-23 stimulation causes Th17 cells to dedifferentiate into more pathogenic Th1 cells.26 We recently found that the miR-221/222 cluster is a novel regulator of gut Th17 cells via the targeting of Il23r mRNA.27 Although it remains difficult to clearly characterize pathogenic and non-pathogenic Th17 cells in the intestine, even by the recently developed single-cell transcriptomic analysis,28 the roles of IL-23 in balancing pathogenic and non-pathogenic Th17 cells during colitis26 and EAE29,30 have gradually been elucidated.
IBD are thought to be caused by a complex combination of genetic and environmental factors and aberrant immune activation in the gastrointestinal tract (Fig. 2). Therefore, therapies that inhibit effector cytokines in the terminal phase of inflammation are currently in clinical use for IBD and improve the clinical outcome regarding inflammation and quality of life31,32,33,34 in cases in which 5-aminosalicylate (5-ASA) is ineffective.
Pathophysiology of inflammatory bowel disease.
Antigen-presenting cells (APCs) and macrophages are activated and produce pro-inflammatory cytokines, including tumor necrosis factor (TNF), IL-6, IL-12, and IL-23. Activated APCs present processed antigens to naïve helper T cells (Tn) and promote the differentiation of Tn to effector T cells, helper T1 (Th1), Th2, and Th17 cells, and regulatory T (Treg) cells. Th1 and its innate counterpart innate lymphoid cells 1 (ILC1s) and natural killer (NK) cells release Th1 cytokines [interferon (IFN)-γ and TNF]; Th2 and ILC2 Th2 cytokines (IL-4, IL-5, and IL-13); Th17 and ILC3 Th17 cytokines (IL-17 and IL-22). Inflammation in lamina propria is involved in the migration and trafficking of lymphoid cells from blood vessels and lymph nodes where integrin and sphingosine-1-phosphase receptors (S1PR) are important. GSALT, gut-selective anti-lymphocyte trafficking.
Currently available biological therapies for IBD were designed to target three cytokines: tumor necrosis factor (TNF), IL-12/23, or IL-23 alone. These biologics are used for both induction and maintenance for remission. Three TNF inhibitors are approved in Japan for treating IBD, namely, infliximab, adalimumab, and golimumab; in addition to these, certolizumab pegol is approved by the United States Food and Drug Administration (FDA). TNF inhibitors are assumed to exert their effects through three pathways of action: (i) neutralizing soluble TNF, (ii) dissociating receptor-bound TNF, and (iii) disrupting TNF-producing cells by binding to membrane-bound TNF.35 These mechanisms of action are also supported by the negative results obtained in a controlled trial of etanercept, a recombinant TNF receptor–IgG Fc fusion protein, in patients with CD36 because etanercept does not exert apoptotic effects, unlike infliximab.37 Meanwhile, recent clinical studies have shown that the use of etanercept increased the incidence of IBD development compared with methotrexate in juvenile rheumatoid arthritis patients.38 Although more experimental research is needed to reveal the causal relationship between etanercept use and IBD, one possible mechanism is that the binding of TNF-α to etanercept prolongs the blood half-life of cytokines, which may in turn promote an inflammatory response in the intestinal mucosa.37
IL-12 (p40 and p35 dimers) and IL-23 (p40 and p19 dimers) share the same p40 and downstream JAK–STAT pathway. Ustekinumab binds to the p40 subunit common to IL-12 and IL-23 and blocks the engagement with its receptor, IL-12Rβ1, while IL-23p19 is targeted by risankizumab, mirikizumab, brazikumab, and guselkumab.39 IL-23 has gradually been recognized as a ‘cytokine hub’ in IBD and autoimmune diseases.40 As discussed above, IL-23 exerts pro-inflammatory effects on Th17 cells and Th1 cells, as well as activating γδT cells and group 3 innate lymphoid cells (ILC3) to produce IL-17A, mainly in psoriatic arthritis and axial spondyloarthritis. However, the IL-23–IL-23R axis has been reported to enable ILC3 to produce IL-22.41,42 IL-22 is an IL-10 cytokine family member and contributes to barrier protection41,43,44,45,46 by supporting epithelial stem cell maintenance,47 epithelial regeneration,46 Paneth cell formation,48 and anti-microbial peptide production.49 Therefore, IL-22 supplementation was reported to have a beneficial effect in a graft-vs-host disease model47 and a DSS-induced colitis model50 and IL-22–Fc fusion protein is currently undergoing testing for the treatment of IBD. These findings raise the possibility that IL-22 and IL-23–IL-23R signaling play complex roles during intestinal inflammation. Indeed, genetic deletion or neutralization of IL-22 was found to ameliorate colitis in some experimental models of colitis induced by anti-CD40 treatment51 or dinitrobenzene sulfonic acid sensitization.52 Moreover, IL-22 has recently been shown to recruit neutrophils and promote inflammatory pathways in patients with UC53 and is associated with resistance to ustekinumab treatment. In addition, short-term treatment with IL-23 induced IL-22 and long-term treatment induced IFN-γ, suggesting that acute stimuli such as infectious colitis and chronic stimuli such as IBD have contrasting effects on intestinal ILC3. Further clinical and experimental exploration is required to clarify the complex roles of IL-23–IL-23R and IL-22 regarding the pathophysiology of IBD. In addition to blockers of cytokine–receptor engagement, integrin inhibitors or gut-selective anti-lymphocyte trafficking agents are another class of molecular targeted drugs. Examples of these that are currently used for the treatment of IBD include vedolizumab, an inhibitor of integrin α4β754,55and carotegrast methyl,56 an inhibitor of integrin α4, which are important for lymphocyte migration into the intestinal tract.
JAK–STAT pathwayExcessive and imbalanced production of inflammatory cytokines is known to be a major cause of the onset, maintenance, and exacerbation of IBD, and biologics such as anti-TNF-α antibodies, which directly suppress inflammatory cytokines, have been shown to exhibit significant therapeutic effects against IBD.57,58,59,60 In addition, antibodies and small-molecule inhibitors targeting IL-12 and IL-23 and their intracellular signaling are being clinically applied in IBD and other autoimmune diseases. The signaling of IL-12 and IL-23, unlike TNF, is mediated by the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) families.
The JAK family is responsible for the signaling of type I and type II cytokine receptors. It is a family of intracytoplasmic tyrosine kinases, consisting of JAK1, JAK2, JAK3, and TYK2,61 which is essential for cytokine signaling with type I and type II cytokine receptors.62,63,64,65 The activation of JAK is negatively regulated by the suppressor of cytokine signaling (SOCS) proteins.66,67 JAK3 expression is largely confined to hematopoietic cells, whereas JAK1, JAK2, and Tyk2 are widely expressed in vivo. In mice, JAK1 deficiency causes embryonic lethality because of abnormal neuronal cell differentiation,68 whereas JAK2 deficiency causes embryonic lethality because of abnormal hematopoietic cell differentiation.69 Mutations and deletion of TYK2 also cause mild immunodeficiency or hyper-IgE syndrome,70 whereas mutations and deletion of JAK3 cause severe combined immunodeficiency from the defective differentiation and proliferation of immune system cells as well as deficiency of the common-gamma chain (encoded by the IL2RG gene) in both humans and mice.65,71,72,73,74
JAKs also cause the recruitment and phosphorylation of their downstream transcription factor, STAT, to cytokine receptors, where STAT forms a dimer after activation and is translocated to the nucleus61,75 (Fig. 3). There are seven types of STAT (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6), which activate JAKs and STATs specific to each cytokine receptor. The combinations of activated JAKs are diverse, as shown in Fig. 3, with JAK1 mainly mediating cytokines such as the IL-6 family using the gp130 chain and TYK2 mainly mediating IL-12 and IL-23 signaling, sharing the IL-12β chain with type I interferon receptors. JAK2 is also responsible for signaling of the granulocyte-macrophage colony-stimulating factor family members such as erythropoietin, IL-3, and IL-5. JAK3, meanwhile, plays important roles in the signaling of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, which are recognized as common gamma-chain cytokines.76 Common gamma-chain cytokines generally activate the JAK–STAT pathway, particularly JAK3 and STAT5, to different extents and are critical for the survival and activation of lymphocytes. STAT5B deficiency was shown to result in reduced numbers and impaired function of Treg cells in patients77 and similar findings were observed in mice lacking Stat5b alone or lacking both Stat5a and Stat5b.78,79 In addition, Stat5b deficiency also reduced the number of ILCs in the intestine compared with the number in wild-type or Stat5a-deficient littermates.80 These phenotypes are presumably attributable to the impairment of IL-2 signaling in Treg cells and IL-7 and/or IL-15 signaling in ILCs. Despite the critical roles of JAK3 and STAT5 in the intestinal mucosal immune system, polymorphisms in JAK2, TYK2, STAT1, STAT3, and STAT4, but not JAK3 and STAT5, have been reported to be associated with susceptibility to IBD.81,82
Overview of JAK–STAT signaling.
Type I and type II cytokines bind to their corresponding receptors and exert a wide variety of functions in hematopoiesis and immune responses. Type I and type II cytokine receptors physically associate with JAKs to recruit and phosphorylate STATs to regulate an array of target genes. The combination of different JAKs and STATs illustrates the biological functions of each cytokine and receptor. IFN, interferon; IL, interleukin; LIF, leukemia inhibitory factor; OSM, oncostatin M; EPO, erythropoietin; TPO, thrombopoietin; G-CSF, granulocyte colony-stimulating factor; GH, growth hormone.
Against the above background, the development of immunosuppressive agents that specifically suppress JAK3 has been anticipated.83,84,85 Tofacitinib, like many other JAK inhibitors, is an inhibitor that acts on the ATP-binding site of JAK, but it was initially developed as an isoform-specific JAK3 inhibitor to minimize cytotoxicity and was later found to be a pan-JAK inhibitor that also inhibits JAK1 and JAK2. Tofacitinib is used to treat autoimmune diseases such as rheumatoid arthritis as well as UC because it suppresses a wide range of immune and inflammatory responses by inhibiting multiple JAKs and cytokines simultaneously. Comprehensive analysis of the human kinome has indicated that tofacitinib shows high specificity for the JAK family, with little off-target effects observed for other kinases at equivalent concentrations.86 In addition, global transcriptomic and epigenomic analyses have revealed that the JAK–STAT pathway contributes to organizing the enhancer landscape in immune cells, ILCs,87,88,89,90,91 T cells,92,93,94,95 and stromal cells,96,97,98 as also summarized elsewhere.99 Given that the dynamics of enhancer structures upon stimulation have been intensively studied, the JAK inhibitors might be able to ‘correct’ inflammation-associated enhancer formation.94,100
Several infections, including those caused by varicella and herpes zoster viruses, have been reported as the main side effects of tofacitinib.101 In addition, increased cholesterol production has been reported, similar to side effects reported with anti-IL-6 antibodies (tocilizumab). It has been reported that tofacitinib increases the esterification of cholesterol with high-density lipoprotein (HDL), which is decreased in patients with inflammatory rheumatoid arthritis compared with that in healthy controls. Some consider this to be part of the therapeutic effect rather than a side effect, so further reports on this issue are expected.102 In addition to inflammatory cytokines, tofacitinib also suppresses molecules involved in hematopoiesis such as erythropoietin receptors and IL-11, which has been reported to cause side effects such as anaemia.101 Currently, three JAK inhibitors are approved by the FDA for the treatment of moderate to severe UC82,103: tofacitinib (JAK3 or pan-JAK),104 filgotinib (JAK1),105 and upadacitinib (JAK1).106
Currently unmet medical needsAlthough molecular targeted therapies have become game-changers in IBD treatment, no cure for IBD is currently available, and inadequate efficacy and side effects such as infection remain a major problem in the treatment of IBD. To further investigate potential targets for treating IBD, various molecules that contribute to the differentiation, induction, and activation of immune cells have been identified and many molecular targeted therapies against them have been applied clinically. Owing to high sample availability, most findings in human immunology have been obtained from immune cells in the peripheral blood and lymph nodes, and much remains unknown about the uniqueness of intestinal mucosal immunity. Because the intestinal tract is constantly exposed to foreign substances such as food and pathogens, mucosal immunity has a mechanism of maintaining intestinal homeostasis by forming a complex network of immune cells with the local environment of the intestinal tract, including intestinal bacteria and metabolites. Pursuing this local immune network in the intestinal local environment will enable us to elucidate the key chronic inflammatory mechanism of the intestinal tract. In other words, elucidation of the tissue adaptation mechanisms of immune cells in the intestinal tract is essential for the development of effective therapies corresponding to the mechanisms in the pathogenesis of IBD in each patient. This approach could be applied in the future to personalized medicine with the multiple or sequential administration of different types of immunomodulatory agents but would require definitive biomarkers and clinically available predictive formulae to allow selection of the most suitable agent (Fig. 4).
Current and future IBD treatment strategy.
Therapies could be more personalized by using biomarkers and predictive formulae to select the most suitable agent for each patient.
The gastrointestinal tract is connected to distant organs via humoral and neuronal pathways.107,108,109,110,111,112,113,114 The intestinal tract is an important organ for the digestion and absorption of food, and the absorbed nutrients are transported to the liver via the portal venous system and lymphatic system. The liver, which receives influx from the portal venous system, synthesizes and stores nutrients and detoxifies toxic substances. In addition to the metabolism of these nutrients, the gastrointestinal tract has also been recognized as an immune organ. Intestinal epithelial cells border the intestinal lumen and act as a primary line of defense to prevent the entry of microorganisms and toxic substances into the intestinal mucosal tissue and then from the portal vein to the liver and further into the body. With the disruption of the intestinal barrier following inflammation of the intestinal tract, the immune system of the intestinal tract and liver is activated by a diverse range of microorganisms, including bacteria, viruses and fungi, as well as antigens of microbial origin.115 For example, primary sclerosing cholangitis (PSC) is a progressive chronic inflammatory disease causing fibrotic stenosis of the bile ducts inside and outside the liver, and is often associated with UC, suggesting that chronic inflammation of the hepatobiliary system associated with altered intestinal epithelial barrier function may be involved in its pathogenesis.116 Indeed, it has become clear that local environmental factors in the intestinal tract, including intestinal bacteria, are related not only to intestinal immunity but also to the function and inflammatory control of other organs via the blood, lymphatic vessels, and even the autonomic nervous system. This hypothesis is supported by data showing the presence of gut dysbiosis in inflammasome-deficient mice and alteration of liver immunity in a mouse model of dextran sodium sulfate (DSS)-induced colitis, as well as exacerbation of the nonalcoholic steatohepatitis (NASH) model and the concanavalin A (Con A)-induced acute liver injury model.117,118 Interestingly, exacerbation of liver steatosis is transmissible. Specifically, not only Asc−/− and Il18−/− mice themselves, but also WT mice co-housed with them, exhibited significant exacerbation of NASH.118 It has also been suggested that increased intestinal permeability, referred to as ‘leaky gut’, may contribute to the development of liver diseases, including NASH.115 More recently, liver cirrhosis has been shown to induce increased intestinal permeability or epithelial damage and further disrupt the gut vascular barrier in mouse models of liver cirrhosis induced by a high-fat diet, bile-duct ligation, or carbon tetrachloride.119,120 These reports suggest that the invasion of bacteria into the gut wall triggers certain types of liver disease. Indeed, Klebsiella pneumoniae was detected in the feces of patients with PSC and was shown to disrupt the epithelial barrier, induce Th17 cells, and aggravate a hepatobiliary system injury model.121,122 Meanwhile, a tandem model of DSS enteritis and Con A hepatitis showed that colitis preceding hepatitis induced IL-10-producing CD11b+ macrophages and relieved liver damage. A semi-sterile environment with the administration of an antibiotic cocktail abolished the improvement of Con A hepatitis, suggesting that the gut microbiota is important for the formation of immune tolerance.123 As described above, the ‘gut–liver axis’ via the portal blood plays an important role not only in the absorption and metabolism of nutrients, but also in the maintenance of immunity and in the pathogenesis of chronic inflammation in the liver.
Intestinal immunity and organ connectionsOur understanding of metabolic and immunological homeostasis in the gastrointestinal organs has progressed via studies of hormones and other humoral factors, but in recent years, the importance of the interaction between immune cells and nerve cells has also gradually been recognized. As a result, the regulatory mechanisms in the autonomic nervous system were scrutinized, but little is known about the importance of the neural circuits linking the brain to gastrointestinal organs such as the gastrointestinal tract and liver. The autonomic nervous system, which includes the sympathetic and parasympathetic nervous systems, regulates organ function and systemic metabolism, and it is generally thought that the sympathetic nervous system controls glucose and lipid catabolism, whereas the parasympathetic nervous system, including the vagus nerve, contributes to absorption and promotes glycogen storage in the liver.107,108,109,110,111,112,113,114,124,125,126 Therefore, a focus has also been placed on the link between gut immunity and the nervous system (gut–brain axis). Furthermore, it has been suggested that there is a ‘liver–brain–gut neural arc’, in which intestinal information conveyed to the liver via the gut–liver axis is transmitted from the liver to the brain via the autonomic nervous system. Feedback signals can then travel from the central nervous system to the intestinal tract, which may result in changes in gut immunity and intestinal bacteria. In particular, FOXP3+ peripheral regulatory T cells (pTreg cells), which play an important role in immune tolerance in peripheral organs, are most abundant in mucosal tissues, especially in the intrinsic mucosal layer of the colon,127 and suppress excessive inflammatory responses in the gut. Our group has shown that the liver–brain–gut neural arc maintains colonic pTreg cells and is useful for maintaining gut homeostasis.128 In a recent retrospective cohort study, it was shown that patients with recently diagnosed depression had an increased risk of CD and UC, against which protection might be conferred by antidepressant treatment.129,130 Furthermore, a Swedish cohort study reported an increased cumulative incidence of IBD in patients who underwent vagotomy compared with that in a non-operated group.131 These results suggest that the innervations of the enteric nervous system exert effects not only on gastrointestinal motility and glandular secretion, but also on the regulation of immune cells.124,132,133,134,135 ILC are among the most extensively studied cell types in the context of neuroimmune interaction. Group 2 ILC (ILC2) selectively express neuromedin U (NMU) receptor 1 (NMUR1),136 encoded by Nmur1, and show enhanced proliferation and cytokine production upon NMU stimulation by enteric neurons.137,138 Meanwhile, calcitonin gene-related peptide (CGRP, encoded by Calca) released by cholinergic neurons and adrenaline released by sympathetic neurons suppress ILC2 proliferation and ILC2-mediated inflammation through the CGRP receptor and the beta-2 adrenergic receptor (β2AR), respectively.134,139,140,141,142 β2AR is also expressed by intestinal muscularis macrophages and contributes to protection against enteric pathogens.143,144 It has also been reported that regulatory T cells are maintained in the colon by a neural network between the gut, brain, and liver, as mentioned above.145 Consistent with this, gut Treg cells were found to be decreased in Vip- and Calca-deficient mice.146 Given that the vagal input is important in the maintenance of gut homeostasis, based on clinical studies,129,131 restoration of vagal input is a potential future therapeutic strategy. In a mouse model of DSS colitis, the mice showed worsening of enteritis after vagotomy, while the symptoms were improved by vagus nerve stimulation.147 In addition, vagus nerve stimulation has been shown to have therapeutic effects on CD patients, although this pilot clinical trial only included a relatively small number of patients.148 Further characterization of the local environment of the intestinal tract and immune cells should elucidate the pathophysiological mechanism behind the co-occurrence of autonomic disorders and IBD or other autoimmune diseases.
With the advancement of omics analysis, the function, heterogeneity, and mutual interplay of immune, neural, and stromal cells in the gastrointestinal tract have become clearer. It is expected that omics analysis will promote elucidation of the pathology of IBD and other immune-related diseases, identify genes and cells that can be targeted for treatment, and facilitate the development of new therapeutic agents. In addition, these new technologies enable rigorous analysis of the organ-to-organ and population-to-population interactome and enhance the ability to study novel therapies for inflammatory diseases, infectious diseases, and cancers.
As recipient of the Keio Medical Science Rising Star Award, YM thanks the award committee for their nomination. YM also expresses his deep gratitude to Professor Takanori Kanai for his guidance and inspiration in the lead-up to receipt of the award. This study was funded by the Japan Society for the Promotion of Science (JSPS) KAKENHI [(B) 20H03666 to YM and (A) 20H00536 to TK]; JSPS Grant-in-Aid for Transformative Research Areas [(B) 21H05123 to YM]; Advanced Research and Development Programs for Medical Innovation (AMED-CREST: 21gm1510002h0001 to TK and 22gm1210001h0001 to YM; Practical Research Project for Rare/Intractable Disease: 21ek0109556h0001 to YM); and Keio University Medical Fund. The authors thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
The authors declare no conflicts of interest.
