Context-Dependent Regulation of Type17 Immunity by Microbiota at the Intestinal Barrier

Context-dependent Th17 responses to the microbiota

Two functionally distinct populations of Th17 cells develop differently in response to context-dependent environmental cues: tissue-resident, homeostatic Th17 cells that contribute to gut homeostasis (5, 6), whereas proinflammatory Th17 cells are involved in the development of a variety of inflammatory disorders (37, 38, 39) (Figs. 1 and 2).

Figure 2
Context-dependent regulation of the Th17 plasticity during homeostasis and disease. During homeostasis, SFB colonization in the small intestine promotes homeostatic Th17 cell differentiation, whereas H. hepaticus induces RORγt⁺ Treg, expressing c-MAF, and limiting Th17 cells during homeostasis. The neuropeptide VIP released from enteric neurons following food intake induces IL-22 production in ILC3s, protecting the intestinal epithelial barrier integrity by promoting fucosylation and AMP production in IECs. Bacterial colonization in mice with immune dysfunction such as IL-10/IL-10 receptor loss or Treg dysfunction (MAF-deficient), leads to the development of a pathogenic Th17 phenotype, secreting the pro-inflammatory cytokines, GM-CSF and IFN-γ, which are induced by H. hepaticus through SAAs, IL-23R signaling, as well as IL-1R signaling.

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The microbiota plays a significant role in regulating the differentiation of homeostatic and pathogenic Th17 cells in the gut. Of this microbiota, the most studied segmented filamentous bacteria (SFB) attach to epithelial cells in the terminal ileum and induce naïve Ag-specific CD4⁺ T cells in the draining mesenteric lymph nodes (mLN) to increase transcription factor RORγt expression and differentiate into Th17 cells (6, 26, 27, 32, 40, 41) (Fig. 2 left). These Th17 cells then migrate to the intestinal lamina propria, where they perform homeostatic functions, such as wound healing (42, 43, 44). An SFB-triggered circuit in which ILC3 secretion of IL-22 is critical for local epithelial production of serum amyloid A (SAA)1 and SAA2, which act directly on poised Th17 cells to amplify effector cytokine production (42) (Fig. 2 left). In the SFB-colonized ileum lamina propria, CD11c⁺ cells stimulate SFB-specific Th17 cells via MHCII loaded with bacterial Ags (32, 40). Commensal-induced Th17 cells strengthen the epithelial barrier by increasing the expression of antimicrobial defensins, apical NADPH oxidase, and the transcytosis of secretory IgA, thereby enhancing the host’s protection against pathogens (45) (Figs. 1 and 2).

While SFB induces non-inflammatory and protective Th17 cells, enteric pathogens, such as Citrobacter rodentium (C. rodentium) (39), trigger pathogenic Th17 cell differentiation in inflammatory conditions, indicating that Th17 cell function is context-dependent (Fig. 2 right). Contrary to conventional pathogens that cause disease in healthy hosts, emerging data suggest that microbial species associated with chronic inflammation are typically harmless and widely colonize in healthy persons (46). These types of resident pathogenic microorganisms, such as Helicobacter hepaticus (H. hepaticus) (46, 47, 48, 49), Enterococcus faecalis (50, 51), have been referred to as “pathobionts” (46) because their pathogenic function is “dual-faced” depending on an additional factor such as genetic susceptibility or environmental context of the host. Particularly, H. hepaticus has been causally linked to large-bowel inflammation in immunocompromised mice (e.g. IL-10/IL-10R-knockout), but it induces no overt pathology in wild-type animals (47, 52). At steady state, the majority of H. hepaticus-induced Th cells are RORγt⁺FOXP3⁺ peripheral Treg (pTreg), which are necessary for gut homeostasis maintenance (47) (Fig. 2 left). In contrast, under inflammatory conditions and/or Treg dysfunctions, T cells specific for H. hepaticus differentiate into pathogenic Th17 cells with features including T-BET expression together with RORγt and pro-inflammatory cytokines IFN-γ and IL-17 (47) (Fig. 2 right). Proinflammatory cytokines, IL-1β, IL-23 and SAAs signal into T cells promoting their proliferation and accumulation in the colon and favor the development of the IL-17A⁺IFN-γ⁺ pathogenic Th17 cells while inhibiting FOXP3 expression (38, 48, 53) (Fig. 2 right). Additionally, the transcription factor c-MAF is necessary for pTreg differentiation (54) (Fig. 2). c-MAF affects both the differentiation and function of CD4⁺ T cells in distinct T cell subtypes, including the regulation of IL-10 production in various Th cell populations and repression of IL-22 in Th17 cells, via a TGF-β-dependent mechanism involving direct binding of c-MAF to the IL-22 promoter (55). During colonization with H. hepaticus, the homeostatic state is maintained by RORγt⁺ Treg, which mediate host tolerance to bacteria and inhibit pro-inflammatory Th17 cells in a c-MAF-dependent manner, however pTreg-specific deletion of c-MAF leads to impaired intestinal Treg differentiation and function, including diminished IL-10 production and promotes differentiation of bacteria-specific specific pathogenic Th17 cells and spontaneous colitis (Fig. 2 right) (47).

Despite extensive in vitro and in vivo research (37, 56, 57), however, the local differentiation cues that distinguish homeostatic type17 functions, such as those that maintain intestinal epithelial integrity, from pathogenic type17 functions associated with the pathogenesis of chronic inflammatory diseases are not fully understood. For the development of more effective treatments, a deeper understanding of the upstream regulators that initiate cell type-specific and context-dependent pathogenic Th17 programs will be necessary.

ILC3 cells

ILC3 cells are Ag-independent innate-like type17 cells that express RORγt and contribute to maintaining intestinal homeostasis using a variety of mechanisms (57, 58, 59, 60). Unlike the adaptive lymphocytes, which are activated in lymph nodes following Ag recognition and migrate to the inflammation site, activation of the tissue-resident ILC3s occurs directly in the intestine, mediated by inflammatory cytokines (58, 59, 60, 61). ILC3s are a heterogeneous population that may develop into either the lymphoid tissue inducer (LTi) lineage or ILC3 cells that express the natural cytotoxic receptor (62). By stimulating intestinal epithelial cells (IECs) and regulating Th17 cell function, ILC3 cells play a key role in the control of host-microbiota interactions (63) (Figs. 1 and 2). The relationship between the intestinal microbiota and ILC3 is bidirectional; gut microbes and microbial metabolites regulate IL-22 production in ILC3s, while ILC3-secreted IL-22 acts on the microbiota both directly and indirectly through IEC regulation (61) (Figs. 1 and 2). ILC3-produced IL-22 induces antimicrobial peptide (AMP) production in IECs (61) and play a prominent role in epithelial fucosylation, which is required for the establishment of an environmental niche for commensal bacteria in the small intestine (64) (Figs. 1 and 2). ILC3s interact with non-immune parenchymal cells as well as gut microorganisms to control IL-22 production (65). The neuropeptide vasoactive intestinal peptide (VIP), which is generated by enteric neurons, is triggered by food intake and aids in nutrient absorption and mounts immunological responses by suppressing IL-22 production in ILC3s in a VIP receptor VIPR2-dependent manner, increasing host vulnerability to C. rodentium infection (65) (Fig. 2 left).

MAIT cells

MAIT cells are another unconventional subset of T cell that responds to vitamin B2 derivatives such as ribityl-lumazines (7-hydoxy-6-methyl-8-d-ribityllumazine) and 6-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), which are generated by bacteria delivered through MR1 (66) (Fig. 3-1). MAIT cells identify MHC class Ib protein MR1 Ags through the invariant TCR (Vα19 Jα33 in mice and Vα7.2 Jα33 in humans) (35). The notion that the microbiota is critical for the formation and education of immune cells also pertains to MAIT cells. MAIT cells are absent in animals deficient in microbiota, demonstrating that MAIT cell formation is dependent on commensal bacteria (2). Although the precise activities of these cells in host health and disease remain unclear, barrier-resident MAIT cells are RORγt⁺ and exhibit a type17 effector phenotype in mice (67). In response to local commensal sensing, skin MAIT cells produce IL-17A, which is IL-1 and IL-18 dependent (68) and promotes wound healing (69). MAIT cells provide resistance to various pathogen infections including Escherichia coli, Mycobacterium, Klebsiella, Francisella, and Legionella (70). MAIT cells also detect acute viral infections through IL-18, IL-15, and type I IFN sensing (71).

Figure 3
Antigen-dependent regulation of Type17 immune response. 1) Antigen-driven activation of unconventional T cells. NKT cells and MAIT cells recognize bacterial antigens loaded on the Cd1d molecule and MR1 molecule, respectively, which are expressed by APCs. Also, γδ T cells recognize the microbial antigens presented on APCs via γδ TCR. 2) Antigen presentation by immune populations. Professional antigen presenting cells, such as dendritic cells and macrophages, modulate T cell responses to microbiota through MHCII signaling. ILC3 cells also express MHCII molecules and directly interact with T cells. Antigen presentation by ILC3s is essential for Treg cell differentiation in response to Helicobacter hepaticus colonization in a CCR7^- and αV integrin (ITGAV)-dependent manner. 3) Antigen presentation by IECs. Intestinal epithelial expression of MHCII regulates the crosstalk between epithelial cells and CD4⁺ T cells. The contact between ISCs and Tregs promotes self-renewal of stem cells, whereas ISC-Th17 interactions induce differentiation. 4) MHCII transfer from IECs to MNPs. Epithelial MHCII might induce an immune response against microbes through MHCII molecule transfer from IECs to myeloid cells via exosomes.

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γδ T cells

γδ T cells, which are found between the intestinal epithelial cells as IELs, are the initial line of defense against enteric infections (72). γδ T cells are important early responders in a variety of infectious disease models, releasing cytokines such as IL-17 and IFN-γ (73). Certain commensals may increase the frequency of IL-17⁺IL-1R1⁺ T cells, therefore preventing disease (74). γδ T cells generate IL-17A, which protects mice against Clostridium difficile infection (75). Vγ9Vδ2⁺ and Vγ9Vδ1⁺ T cell subsets in humans recognize lipids and phosphoantigens such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), a microbial precursor of isopentenyl pyrophosphate (76) (Fig. 3-1). Microbiota deficiency has no discernible influence on the formation or number of intestinal IELs (72). However, microbiota depletion results in altered patterns of IEL localization along the crypt-villus axis, with a considerable shift toward the small intestine crypts due to their high mobility (72). Additionally, regenerating islet-derived protein type 3 (REGIII) synthesis is elevated in small intestine IELs in response to bacterial colonization and in colon-resident IELs following colonic injury caused by dextran sulfate sodium (DSS) (77, 78).

iNKT cells

iNKT cells are a distinct type of unconventional T cell that recognize microbial and host-derived glycolipids through the MHC class Ib protein CD1d and express an invariant chain in conjunction with a limited number of TCR chains (34) (Fig. 3-1). When activated, iNKT cells rapidly release cytokines and in mice, subsets equivalent to Th1, Th2, and Th17 cells are identified based on their lineage-specific cytokine production (79); however, these features are less apparent in humans (79). Despite recent studies recognizing reciprocal crosstalk between iNKT cells and the microbiota (80), the processes that lead to the differentiation of iNKT cells, particularly those at barrier sites, remain poorly understood. Germ-free (GF) mice exhibit a greater number of immature, hyporesponsive iNKTs in the lamina propria and epithelium of the small intestine and colon (81). Increased CXCL16 chemokine production in the intestines of GF mice lead to increased iNKT cell accumulation compared to SPF animals (81). Additionally, the impact of altered gut microbiota on iNKT cell-dependent inflammation at mucosal surfaces has been reported in research employing GF mice that show CD1d-dependent severe tissue damage and inflammation in IBD (81).

Microbial Ag presentation by immune populations

APCs are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting Ags for recognition by lymphocytes. Bacterial activation of Th17 cells in the gut is dependent on intestinal dendritic cells (DCs) presenting commensal bacterial Ags, such as from SFB through MHCII (90, 91). During inflammation, the inflammatory DCs, differentiated from Ly6C^hi monocytes, are recruited to the site of inflammation where they present Ag to both CD4⁺ and CD8⁺ T cells (92). Inflammatory DCs promote the development of naive CD4⁺ T cells into Th17 cells via activation of STAT3 by IL6R signaling, which induces expression of the lineage-specific transcription factor RORγt (70, 71, 72) (Fig. 3-2). On the other hand, ILC3s restrict the differentiation of Th17 cells by serving as unconventional APCs by directly triggering cell death of activated commensal bacteria-specific T lymphocytes (63) (Fig. 3-2). Unsurprisingly, deletion of MHCII on ILC3s leads to low-grade systemic inflammation as a consequence of CD4⁺ T cell activation and spontaneous IBD formation due to elevated amounts of IL-17, IFN-γ, and TNF-α producing CD4⁺ T cells in the colon (88, 93). ILC3s are also required for microbiota-specific pTreg induction, carried out by the presentation of MHCII Ags, the chemokine receptor CCR7, and α_v integrin (ITGAV) that regulates TGF-β activation (Fig. 3-2) (94). Additionally, ILC3 expression of MHCII negatively impact the interaction between T follicular helper (T_FH) cells and B cells, resulting in decreased mucosal IgA production in the colon and associated effects on the microbiota (95).

Ag presentation by IECs: MHCII linking IEC to mucosal immunity

MHCII expression on IECs was first described more than two decades ago (98), but its potential role in mucosal immunity has only recently drawn attention. However, the precise function of epithelial MHCII is still unknown. A recent study revealed that ISCs express MHCII and function as non-conventional APCs, and their interactions with Th cells control ISC renewal and differentiation, thereby shaping the gut microenvironment homeostasis (89) (Fig. 3-3). Treg and their major cytokine IL-10 contribute to the maintenance of the small intestinal LGR5⁺ ISC niche, whereas Treg deficiency leads to aberrant epithelial cell differentiation, resulting in a decreased LGR5⁺ ISC pool and an accumulation of developed cells (89) (Fig. 3-3). IEC-specific MHCII-deficient mice exhibit worse disease outcomes following T-cell transfer or chemical (DSS)-induced colitis, as well as greater susceptibility to enteric infection, while effector T-cell activation in mesenteric lymph nodes (mLNs) is unaffected (100). Moreover, mice with an IEC-intrinsic deletion of MHCII are healthy, but have reduced amounts of microbial-bound IgA, regulatory T cells (Tregs), and immunological repertoire selection due to altered interindividual microbiota diversity (101). Microbial adhesion-triggered endocytosis is another mechanism by which commensal bacteria affect the development and function of host T cells. This indicates that IECs acquire antigens from commensal bacteria by direct contact in order to generate T cell responses to the resident microbiota (102). Although this strategy is adequate to initiate a CD4⁺ T cell response and commensal-specific homeostatic Th17 cell development, the mechanisms by which these Ags are processed and delivered to immune cells remain unknown (102). IECs can also secrete exosomes containing MHCII molecules, which intestinal mononuclear phagocytes (MNPs) can obtain and use to mediate adaptive responses to microbial Ags (101) (Fig. 3-4). Furthermore, Graft-versus-host disease model studies demonstrate that CD4⁺ and CD8⁺ T lymphocytes inhibit bone marrow transplantation-induced intestinal injury by targeting ISCs expressing MHCI and MHCII (99). Thus, MHCII on intestinal epithelium, in addition to conventional and unconventional APC immune compartments, is essential for limiting adaptive responses to gut microbial antigens and sustaining intestinal homeostasis.

Secondary bile acids (BAs)

BAs, a byproduct of cholesterol metabolism, are synthesized in the liver, secreted into the duodenum and flows to terminal ileum where most primary bile acids are reabsorbed. The remainder travel to the large intestine, in which they are metabolized by commensal bacteria to form secondary bile acids with modified chemical structures (103). Secondary BAs are well-known for their anti-inflammatory effects on CD4⁺ T cells in the intestine. Inhibiting secondary BA production in bacteria causes a drop in Th17 levels, whereas secondary BA therapy activates RORγt⁺FOXP3⁺ pTreg and reduces gastrointestinal inflammation (104) (Fig. 4). Both isoalloLCA and 3-oxoLCA, which are derivatives of lithocholic acid (LCA), are T cell regulators inhibiting the differentiation of Th17 cells while promoting the differentiation of Treg cells (105) (Fig. 4). 3-OxoLCA inhibits the differentiation of Th17 cells by directly binding to the key transcription factor RORγt, whereas isoalloLCA promotes the differentiation of Treg cells via the production of mitochondrial ROS (mitoROS), resulting in the upregulation of FOXP3 (105) (Fig. 4). The isoalloLCA-mediated enhancement of Treg cell differentiation requires an intronic Foxp3 enhancer, the conserved noncoding sequence3 (105). In addition, the nuclear hormone receptor NR4A1 is required for the isoalloLCA mediated Treg induction (106). Moreover, Bacteroidetes is the intestinal bacterial phylum capable of metabolizing 3-oxoLCA to isoalloLCA, which implies that a specific commensal bacterium can modulate the immune system by changing host metabolites (106).

Figure 4
Regulation of type17 immunity by non-antigenic molecules. Bacterial metabolites shape intestinal immune responses using different mechanisms. Secondary bile acids regulate Th17/Treg balance by enhancing Treg differentiation and reducing Th17 cell differentiation. Among SCFAs, the most well-studied butyrate promotes Treg differentiation. Propionate suppresses IL-17- and IL-22-producing γδ T cells by inhibiting histone deacetylase. The SCFAs, propionate and acetate, are recognized by the colonic ILC3s through G protein-coupled receptor FFAR2 and these metabolites induce IL-22 production and proliferation of ILC3s, respectively. Pentanoate also acts on CD4⁺ T cells through HDAC-inhibition. Although it inhibits IL-17, IL-10 production in Th17 cells is induced by this SCFA. Dietary tryptophan is metabolized by host cells or microbes: a) The kynurenine pathway in IECs and immune cells, b) the serotonin pathway mediated by TPH1 in enterochromaffin cells and c) Direct conversion of tryptophan to smaller molecules, including AHR ligands by gut microbiota. Trytophan metabolites and AHR ligands may provoke distinct type17 cell subsets, including Tregs, Th17 cells, or ILC3s through AHR. Th17 cells transdifferentiate into Tr1 cells producing IL-10. This process is induced by TGF-β1 signaling and depends on AHR activity. IECs act as gatekeepers of AHR ligand supplies to the host by CYP1A1 expression. Dysregulated production of CYP1A1 results in Ahr-deficient state, which leads to loss of AHR-dependent ILC3 and Th17 cells and increased susceptibility to enteric infection. Moreover, AHR upregulates GPR15 expression, which is positively regulated by FOXP3 and negatively regulated by RORγt in an AHR-dependent manner. On the other hand, SAAs produced by host cells in response to microbial stimuli, induce IL-6 and IL-23 production in CD11c⁺ cells, which promote Th17 cell differentiation. SFB stimulates IL-23 secretion from APCs, acting on ILC3 cells to upregulate the IEC-derived SAAs via IL-22 signaling. Vitamin A can also induce SAA-production in IECs. SAAs deliver retinol to intestinal myeloid cells via direct interaction with LRP1. The transfer of retinol promotes vitamin A-dependent adaptive immunity, inducing homing of both T cells and B cells to the intestine.

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Short chain fatty acids (SCFAs)

SCFAs, such as formic acid (C1), acetic acid (C2), propionic acid (C3), butyric acid (C4), and valeric acid (C5), can induce immune responses or suppress inflammation through a variety of mechanisms, including histone deacetylase (HDAC) inhibition, Acetyl-CoA production, metabolic integration, and G-protein-coupled receptor (GPR) signaling (107) (Fig. 4). SCFAs promote T cell responses depending on the cytokine milieu or host circumstances (107). While SCFAs induce immunological tolerance via IL-10 in the steady state, they boost effector T cells during immune system activation against infection (107) (Fig. 4). Butyrate, which has been recognized for the favorable anti-inflammatory properties, produces functional Treg in the colon using a T-cell intrinsic epigenetic mechanism (108). The pentanoate alters the metabolism of CD4⁺ effector T lymphocytes and B cells, and increases IL-10 production, which is independent of Treg (109). Similar to butyrate, which ameliorates colitis by acting on HDAC1 in Th17 cells, pentanoate suppresses IL-17A production by inhibiting HDAC in CD4⁺ T cells (110) (Fig. 4). SCFAs also suppress the intestinal Th17 development upon SFB colonization of GF mice (110). Another SCFA metabolite, propionate, is a key regulator of IL-17 and IL-22 expression in γδ T cells of the lamina propria and represses IL-17-producing γδ T cells through suppression of HDAC in the caecum and colon (111). Moreover, propionate and acetate are essential for ILC3 homeostasis and IL-22 production in the colon, respectively. Both metabolites act through G protein-coupled receptor free fatty acid receptor 2, which mainly regulates CCR6⁺ ILC3s through activation of AKT and STAT3 signaling pathways (112).

Tryptophan (Trp) metabolites and aryl hydrocarbon receptor (AHR) ligands

Trp is an essential amino acid degraded by gut microbes, intestinal epithelial, and immune cells across three main pathways: a) the kynurenine pathway in both IECs and immune cells, b) the serotonin (5-HT) pathway via Trp hydroxylase 1 (TPH1) in IECs called enterochromaffin, and c) direct conversion of Trp by gut microbes into smaller molecules, such as AHR ligands (113). The AHR, a transcription factor activated by small molecules derived from microbes, diet, and metabolism, contributes to immune homeostasis (114). AHR modulates the Treg/Th17 cell balance, and the direction of this AHR-dependent shift is mediated by the type of ligand that activates the AHR (115, 116) (Fig. 4). A potent activator of AHR, 6-formylindolo[3,2-b]carbazole (FICZ), induces Th17 activation and IL-22 production (Fig. 4) (115). Inversely, the deletion of AHR prevents the localization of Th17 cells in the lamina propria and reduces the disease severity in a colitis mouse model (117). Moreover, AHR can mediate the cell plasticity of Th17 cells in the presence of TGF-β1, enhancing the transdifferentiation of Th17 cells to T regulatory type 1 cells (Tr1), which are IL-10 producers with immunosuppressive function independent of FOXP3 (118). Despite low levels of AHR detected in extraintestinal Treg, it is highly expressed in gut tissue-associated Treg (119). Supporting the functional role of AHR in intestinal homeostasis, the expression of FOXP3, the Treg lineage-defining transcription factor, is reduced in the absence of AHR, and an AHR agonist, dioxin, promotes Treg differentiation and depletes Th17 cells (115). Treg cell-specific deletion of the AHR attenuates intestinal Treg (119). AHR mediates expression of an essential intestinal-homing gene, GPR15, an AHR-target gene in Treg and Th17 cells regulated positively by FOXP3 and negatively by RORγt in an AHR-dependent manner (120) (Fig. 4). In cases of AHR deficiency, reduced levels of GPR15 lead to defective intestinal-homing of Treg in the large intestine (120). Impaired AHR signaling attenuates ILC3, Th17 cells and IL-22 levels following AHR ligand-metabolizing enzyme, Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1), dysregulation in IECs, and causes increased disease susceptibility by infection with C. rodentium (121).

Serum amyloid A (SAA)

SAAs comprise a family of acute-phase reactants that are abundantly produced during inflammation and often correlate with the severity of multiple Th17-associated chronic inflammatory disorders (38). In the intestine, colonization with SFB triggers SAA production, which in turn promotes Th17 cell differentiation directly, as well as indirectly by acting on dendritic cells of lamina propria (Figs. 2 and 4) (26). The epithelial expression of SAA1 and SAA2 is regulated by IL-23 and ILC3-derived IL-22 involving an immune circuit triggered by SFB (Figs. 2 and 4) (42). Recent research has shown that SAAs can substitute for TGF-β in the production of Th17 cells, but that they drive a distinct signaling pathway that results in a proinflammatory differentiation program (38, 42) (Fig. 2). As a result, SAAs contribute in vivo to Th17-mediated pathophysiology, as demonstrated in chronic colitis and EAE in both gain- and loss-of-function models (38). In addition, SAAs support the H. hepaticus-driven colitis, inducing pathogenic features exemplified by T-BET expression during Th17 priming and sensitization of the T cells to cytokines essential for Th17-mediated autoimmune pathogenesis, such as IL-23 and IL-1β (38, 42) (Fig. 2). It remains unclear what distinguishes the SAA-dependent properties associated with pathogenic versus homeostatic Th17 cells. It may be due to the milieu of T cell priming (e.g., lymph nodes draining a healthy small intestine versus an inflammatory large intestine), the presence of other cytokines, the concentration of SAAs encountered, or the cell types that make SAAs (122).

Vitamin A can also induce the SAA production in epithelial cells by retinoic acid-dependent activation of the transcription factor retinoic acid receptor β, which binds directly to SAA promoters (123) (Fig. 4). SAAs transfer retinol to intestinal myeloid cells that produce RA through low-density lipoprotein receptor-related protein 1 (LRP1) (Fig. 4) (124). Thus, SAA or myeloid cell-specific LRP1 deficiency causes impairments to vitamin A-mediated immunity, involving both B and T cell trafficking to gut IgA production (124). Although there is evidence suggesting that retinol and SAAs affect the Th17 cell function, it remains unclear whether these molecules influence the Th17 response through the LRP1 pathway.

Inflammatory bowel disease (IBD)

IBD is a chronic inflammatory disorder in the gastrointestinal tract and manifests as either ulcerative colitis (UC) or Crohn’s disease (CD) (125). IBD is characterized by a changed gut microbial composition, accumulated intestine resident type17 immune cells, and elevated type17 cytokine levels in inflammatory lesions of IBD patients and animal models of colitis (126, 127).

Dysregulation of gut microbial composition and metabolites in IBD

Increased Proteobacteria and decreased Firmicutes species are associated with IBD (125) (Table 1). Levels of Faecalibacterium prausnitzii (F. prausnitzii), one of the most abundant commensal bacteria belonging to Firmicutes phylum, are lower in both UC and CD (125, 128) (Table 1). Mouse studies demonstrate that F. prausnitzii play an anti-inflammatory role in colitis through the regulation of Th17/Treg balance by inhibiting IL-6/STAT3/IL-17 pathway and inducing FOXP3 (110). Moreover, several Clostridium strains derived from humans promote FOXP3⁺ Treg via butyrate-production and induction of IL-10, TGF-β1, and inducible T cell costimulatory (ICOS), thereby suppressing mucosal inflammation in colitis mouse models (129). A significant decrease in Roseburia hominis (R. hominis), a member of the Clostridia cluster XIVa, is observed in UC patients, whereas mouse studies reveal R. hominis upregulates genes involved in promoting gut barrier function, innate immunity, and Treg differentiation in a TLR5-dependent manner (130) (Table 1). Together with Firmicutes, Bacteroidetes dominate the intestine in healthy adults (131). Bacteroidetes species are also altered in IBD, with a decreased abundance in CD and increased numbers in UC (132, 133). The Bacteroidetes species, Bacteroides fragilis (B. fragilis) and enterotoxigenic B. fragilis (ETBF), are present in the stool and biopsy specimens of healthy individuals, yet increased levels of toxin genes are observed in UC and CAC patients (134) (Table 1). Although the nontoxigenic B. fragilis promotes the anti-inflammatory function of Treg through secretion of Polysaccharide A in the mouse intestine, colonization of mice with ETBF upregulates activation of STAT3 in the colon and induces Th17 immune responses (125) by producing a metalloprotease toxin termed B. fragilis toxin (135).

Table 1
Altered microbiota during IBD that are associated with type17 immune modulation

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Dysregulation of the metabolite-mediated host-microbiota crosstalk contributes to disease progression in IBD as well. SCFAs and SCFA-producing bacteria are present at reduced levels in IBD. In addition to the regulatory role of SCFAs in T cell differentiation and function, SCFAs act directly on γδ T cells and restrict IL-17 and IL-22 production by these cells (111). Given that human IL-17-producing γδ T cells accumulate in the intestinal mucosa of IBD patients (136), SCFAs, particularly propionate, are proposed to prevent chronic inflammation through their inhibitory effect on γδ T cell activity (111). Impaired BA metabolism and reduced levels of secondary BA-producing bacteria Ruminococcaceae have been identified in IBD (137). Intestinal BAs are essential for the maintenance of the colonic RORγ⁺FOXP3⁺ Treg in a BA-receptor, the vitamin D receptor (VDR)-dependent manner (104). Therefore, human VDR genetic variants may influence host susceptibility to disease through defective control of the intestinal Treg pool (104).

CAC

The chronic inflammation observed in the patients with IBD is a potent risk for colorectal cancer development, particularly CAC (153). CAC progresses rapidly and is associated with high mortality in 10%–15% of patients with IBD (153). The exact mechanisms underlying the progression from IBD to CAC are not clear, however an overproduction of pro-inflammatory cytokines, including IL-6, TNF-α and IL-17, by both immune and non-immune populations is related to cancer development (154). Recently, various studies report that the intestinal microbial composition is altered both in colitis and CAC and may be involved in chronic inflammation and the tumorigenesis. Increased levels of Bacteroidetes and decreased levels of Firmicutes are found in CAC patients compared to healthy individuals across various studies (155, 156). Furthermore, a comparison between CAC patients and sporadic cancer patients reveals that CAC is associated with increases to the Enterobacteriacae family and Sphingomonas genus and reduced levels of Fusobacterium and Ruminococcus genus (157). On the other hand, some specific bacteria mitigate tumorigenesis. B. fragilis can prevent cancer progression by inhibiting the NLRP3-mediated inflammatory signaling pathway through butyrate production (158), whereas fecal microbiota transplant (FMT) can induce anti-cancer immunity by promoting Treg within the tumor microenvironment (159).

Treatment of IBD targeting type17 immunity

Due to increased levels of Th17 and related cytokines in IBD, several therapeutics were developed to target these cells (126, 160, 161) (Table 2). Anti-IL-17A antibodies are effective in the treatment of a variety of inflammatory diseases, including IBD (146). Anti-IL-17R Ab treatment exacerbate CD (162), whereas anti-p40 subunit antibodies (Ustekinumab, Briakinumab) (126, 163) and anti-IL-6 receptor antibodies (Tocilizumab) target cytokines that control Th17 cell differentiation and thus IL-17 secretion have shown efficacy (126) (Table 2). These findings suggest that IL-17 plays a protective role in inflammatory bowel disease by preserving the integrity of the intestinal barrier, which outweighs its potential for tissue destruction. Blockades of the key cytokine of Th17 cells, IL-17, exacerbate the disease outcome in patients with CD, implicating an enrichment of Th17 and increased levels of IL-17 might exhibit beneficial effects, such as promoting enterocyte proliferation, tight-barrier formation, and epithelial barrier integrity in the intestine (44), a cause for study termination. On the other hand, targeting IL-23 is effective in clinical trials treating Crohn’s disease, specifically in patients with anti-TNF therapy resistance, displaying a good response to ustekinumab, an FDA-approved treatment for moderate-to-severe CD and UC (164). The JAK-STAT pathway is a promising target for the treatment of inflammatory diseases including IBD, however contradictory results are observed in patients with CD or UC (164). Clinical trials applying JAK inhibitor tofacitinib show improved disease outcomes in UC patients, a medication approved by the FDA and EMA for the treatment of moderate-to-severe UC in 2018 (164). Furthermore, selective JAK1 inhibitors, such as upadacitinib and filgotinib, show promising results in early clinical trials in CD (164). The clinical application of antibodies directed against IL-17 signaling provides insights into the function of IL-17 in humans.

Table 2
Therapeutic agents for CD and UC targeting type17 immunity

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As an alternative to immunosuppressive and anti-inflammatory therapies, microbiota-based therapies, including probiotics, prebiotics, and FMT may modulate dysregulated immune responses by correcting gut dysbiosis (125). Initial clinical studies of FMT exhibit promising results in improving UC, however subsequent results are varied (125). Compared to FMT, treatment with individual or a combination of specific microbial strains or bacterial metabolites with anti-inflammatory functions might be a safer therapy option. In particular, due the immune regulatory role of Treg, IL-10 producing Treg inducers such as Faecalibacterium prausnitzii (128), Clostridium species (129), and Bacteroides species (143) may be effective as live biotherapeutic products (LBP) to treat IBD, however there is currently no FDA-approved LBP. Clinical trials with a human-derived multibacterial FMT-derived spore-based drug product SER-287 by Seres Therapeutics failed in Phase IIb due to non-efficient therapy responses (165), whereas trials using the orally-administered rationally-defined bacterial consortium candidate VE202 produced Vedanta Biosciences are ongoing (166).