Journal of Biomedical Translational Research
Research Institute of Veterinary Medicine, Chungbuk National University
Review Article

Inflammatory bowel disease pathogenesis mediated by Th17 cells: cytokines, microbiota, and therapies

Ji-Hyun Park1, Min Hyeok Lee1, Chan-Su Park1,*
1Department of Manufacturing Pharmacy, College of Pharmacy, Chungbuk National University, Cheongju 28644, Korea
*Corresponding author: Chan-Su Park, Department of Manufacturing Pharmacy, College of Pharmacy, Chungbuk National University, Cheongju 28644, Korea, Tel: +82-43-261-2996, E-mail:

© Research Institute of Veterinary Medicine, Chungbuk National University.

Received: Jun 06, 2024; Revised: Jun 14, 2024; Accepted: Jun 14, 2024


Inflammatory bowel disease (IBD) is a chronic condition characterized by continuous inflammation of the gastrointestinal tract that varies in intensity over time. IBD is caused by several factors including aberrant gut flora, immunological dysregulation, altered environmental conditions, and genetic variations. However, the pathogenesis of IBD remains unclear. Studies have indicated that an imbalance between T helper 17 (Th17) and regulatory T (Treg) cells contributes significantly to the development of IBD. Intestinal Tregs suppress inflammation and are critical for maintaining tissue homeostasis. Th17 cells are known to play an important role in the development and pathogenesis of IBD and provide non-inflammatory support for the integrity of the intestinal barrier against bacterial and fungal infections. Therefore, the Th17/Treg cell balance is crucial in the pathogenesis of IBD and gut integrity. The microenvironment of the intestinal mucosal immunity is regulated by the secretion of cytokines associated with Th17 cells and Tregs. Several studies have indicated that the gut bacteria contribute to the control of the immune milieu and play a key role in the regulation of Th17 cell development. Intestinal bacteria and cytokines control Th17 cell development. Th17 cells secrete cytokines that regulate the immune microenvironment in the gut mucosa. This review provides an overview of Th17 cells and examines the strategies for treating patients with IBD using Th17 cell-targeted drugs.

Keywords: cytokines; inflammatory bowel diseases; microbiota; colitis, ulcerative; Th17 cells


Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the small and large intestines. Ulcerative colitis and Crohn's disease are the two main forms of IBD. Several experimental results have shown that the dysregulation of CD4+ T helper cell (Th cell) function can lead to intestinal mucosal inflammation. Experimental evidence from mouse models has shown that the adoptive transfer of naïve CD4+ T cells without residual activated/memory/Treg cells into immunodeficient recipient mice initiates IBD development [1].

T helper (Th) play important roles in the adaptive immune response by coordinating the expansion and regulation of CD8+ T cells, macrophages, and B cells, and recruiting innate immune cells to the site of inflammation. Upon antigenic stimulation, naïve CD4+ Th cells differentiate into specialized effector subsets, namely T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), T follicular helper (Tfh), and regulatory T (Treg) cells, with distinct patterns of cytokine production and effector functions [2]. Th1 cells are differentiated upon stimulation with interleukin (IL)-12 via signal transducer and activator of transcription 4 (STAT4) signaling and upon interferon (IFN)-γ stimulation via STAT1, which induces expression of transcription factor T-box 21 (T-bet) and of IFN-γ. Th2 cells are induced by IL-4 via STAT6 signaling, which promotes the expression of the transcription factors GATA3, IL-4, IL-5, and IL-13. Classically, Th1- and Th2-mediated immune responses have been linked to IBD pathogenesis [3]. However, numerous studies have shown that an imbalance between Th17 and Treg cells contributes significantly to IBD development [46]. Owing to their significance in the gut mucosal immune response and contribution to autoimmune disorders, Th17 cells have received increasing attention in recent years. In this review, we discuss the role of Th17 cells in IBD pathogenesis and their therapeutic potential.


Th17 cells are exclusively abundant in the small and large intestinal lamina propria (LP), where they contribute to the mutualistic link between the host and microbiota. Th17 cells have protective roles against bacterial and fungal infections that invade at intestinal barrier. However, uncontrolled Th17 cells activity has been linked to several autoimmune diseases. Compared to Th17 cells, Treg cells play a critical role in maintaining immune tolerance and suppressing inflammation to maintain tissue homeostasis. However, when this Th17/Treg balance is disrupted, mice become vulnerable to various infections and autoimmune diseases. Therefore, the Th17/Treg cell balance in the intestine is important to maintain gut integrity against bacterial and fungal infection, while preventing autoimmune disease, such as IBD. Abundant Th17 cells are commonly seen in patients with IBD and mouse models of colitis. These cells primarily contribute to the development of IBD by secreting cytokines, such as IL-17, IL-22, and IL-26. This review focuses on Th17 cell differentiation and the involvement of Th17 cells in IBD development and progression.


IL-17 and IL-22 secreted by Th17 cells induce antimicrobial peptide production to maintain the barrier integrity under homeostatic conditions [7]. IL-17 activates stromal and myeloid cells to produce G-CSF, which induces neutrophil production in the bone marrow and produces chemokines that recruit neutrophils to the gut. IL-22 induces goblet cell hyperplasia and helminth expulsion during intestinal infection. Additionally, intestinal epithelial cells (IECs) express IL-23 receptor (IL-23R) under homeostatic conditions and may respond to IL-23 stimulation by producing protective IL-22, which supports the intestinal barrier function. Moreover, CCL20 a chemokine produced by activated epithelial cells and Th17 cells, increases the recruitment of CCR6-expressing Th17 cells to the site of infection. Consequently, genetic defects in IL-17a and IL-17f in mice increase their susceptibility to opportunistic infections of mucosal bacteria, such as Staphylococcus aureus and Citrobacter rodentium [8]. Therefore, Th17 cells are critical for defense against pathogenic extracellular bacteria and fungi.


Besides the regulation of intestinal flora, Th17 cells may also exhibit pathogenic features, particularly following their stimulation with IL-23, IL-1β, transforming growth factor (TGF)β3, and serum amyloid A antigen (SAA). Pathogenic or non-pathogenic differentiation of Th17 cells is regulated by distinct cytokines (Fig. 1). For example, in vitro polarization of naïve CD4+ T cells by IL-6 and TGFβ1 stimulation generates non-pathogenic Th17 cells that produce IL-17 and IL-10, however, induce a little tissue inflammation, whereas IL-6, TGFβ1, and IL-23, or IL-1β, IL-6, and IL-23 can induce pathogenic Th17 cells that contribute to tissue inflammation [911]. IL-6 along with SAAs or TGFβ3 can also induce pathogenic Th17 cells [12] (Fig. 1).

Fig. 1. Differentiation of Th17 cells. Naïve CD4+ T cells can be differentiated into different Th subsets with distinct cytokine profiles (Th1, Th2, Treg, Th17). This process is regulated by specific cytokines and activation of particular transcription factors, as indicated. IL-12 and IFN-γ can induce the differentiation of Th1 cells, whereas IL-4 alone increases the differentiation of Th2 cells. Naïve CD4+ T cells stimulated with IL-6/TGFβ1 in vitro drive non-pathogenic Th17 cells differentiation, whereas IL-6/TGFβ1/IL-23, IL-6/IL-1ß/IL-23, IL-6/TGFβ3, or IL-6/SAAs drive pathogenic Th17 cells differentiation. Non-pathogenic Th17 cells are characterized by secreting of immune-regulatory molecules, such as IL-17, IL-22, IL-10, and CD5L to promote tissue homeostasis and anti-fungal protection. However, pathogenic Th17 cells express high amount of proinflammatory cytokines, including IFN-γ, GM-CSF, TNF-α, T-bet, and IL-23R. This type of Th17 cells plays a crucial role in the development of tissue inflammation and autoimmune disease. In the absence of inflammatory cytokines, TGFβ alone promotes naïve CD4+ T cells to differentiate into Treg cells for the maintenance of immune tolerance. IFN, interferon; T-bet, transcription factor T-box 21; Th, T helper; IL, interleukin; DC, dendritic cell; TGF, transforming growth factor; Treg, regulatory T; RORγt, the retinoic acid receptor-related orphan receptor γt; GM-CSF, granulocyte-macrophage colony-stimulating factor; TNF, tumor necrosis factor.
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IL-10 producing non-pathogenic Th17 cells promote tissue homeostasis and protection [13], whereas pathogenic Th17 cells secrete proinflammatory cytokines such as IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-α, exacerbating autoimmune disorders [14]. IL-23 drives intestinal Th17 proliferation and enhances the development of pathogenic T cells that secrete proinflammatory cytokines such as IFN-γ [15], while IL-23R signaling negatively regulates the survival of intestinal Treg cells [16, 17]. Although pathogenic and non-pathogenic Th17 cells are dependent on the retinoic acid receptor-related orphan receptor γt (RORγt) for their differentiation, the switch between non-pathogenic and pathogenic Th17 cells remains an unelucidated.

Th17 cells transdifferentiate into Th1 and Treg cells. IL-12 and IL-23 can both induce the conversion from Th17 cells into Th1 cells by altering cytokine secretion from IL-17 to INF-γ in a STAT4- and T-bet-dependent manner, which is required for the pathogenesis of colitis [15]. Notably, IL-23 drives intestinal inflammation, promotes intestinal Th17 cell accumulation, and enhances the emergence of IL-17+IFN- γ+ colitogenic T cells in the gut [15, 17]. Moreover, Th17 cells can promotes colitis-associated intestinal fibrosis, which can result in internal strictures, structural distortion, and loss of function. IL-17A inhibits migratory capacity and promotes the production of the extracellular matrix collagen of myofibroblasts [18]. IL-6 and IL-21 stimulate the expression of amphiregulin expression in Th17 cells [19]. Amphiregulin increases proliferation and collagen expression in intestinal myofibroblast, which leads to more severe intestinal fibrosis [19]. Treg cell therapy has been shown to be beneficial in several IBD models. In the presence of Symbiotic segmental filamentous bacteria (SFB), some intestinal Th17 cells lose IL-17A expression and acquire IL-10 expression [20]. Circulating IL-17 producing FOXP3+ CD4+ T cells are increased, while the suppressive activity of Tregs is significantly reduced in patients with IBD compared with that in healthy control subjects [21]. These results suggested plasticity in the transdifferentiation of Th17 and Treg cells. Thus, Th17 cell plasticity plays an important role in regulating intestinal immune responses in patients with IBD.


Th17 cells were first discovered in 2005 as a Th cell lineage that is independent of Th1- and Th2-related transcription factors (T-bet, STAT1, STAT4, and STAT6) [22]. Th17 cell differentiation can be divided into three stages: induction (driven by TGFβ and IL-6/IL-21), amplification (triggered by IL-21), and stabilization (maintained by IL-23 and IL-1β). Naïve CD4+ T cells can be differentiated into Th17 cells in the presence of TGFβ, which in turn drive SMAD signaling, and IL-6 and IL-21, which activate the transcription factor STAT3 [23]. Phosphorylated STAT3 interacts with the IL-17 promoter and activates the master transcription factors of Th17 cells, RORγt and RORα, which promotes expression of the IL-23R on the surface of Th17 cells [24]. Thus, differentiation and activation of Th17 cells is stringently governed by various cytokines, multiple transcription factors (AP-1, JunB, aryl hydrocarbon receptor [Ahr], IRF4, BATF, c-Maf, PLZ, PPARγt, and EGR-2), and environmental factors such as gut microbes and their metabolites.


IL-6 is a pleiotropic cytokine produced by several cell types, including macrophages, dendritic cells (DCs), monocytes, endothelial cells, and IECs. Although various hematopoietic and non-hematopoietic cells can produce IL-6, Korn et al. reported that SIRPa+ IRF4-expressing DCs, equivalent to murine intestinal CD103+CD11b+ DCs, are crucial for priming pathogenic Th17 cells by transplanting IL-6 into T cells [25]. IL-6 stimulates Th17 cell development by upregulating RORγt through the JAK2-STAT3 signaling pathway [26]. IL-6 signaling is critical for maintaining the Th17/Treg balance, because IL-6 inhibits TGFβ-induced Treg differentiation [11]. Phosphorylated STAT3 can inhibit TGFβ-induced expression of FOXP3, which encodes a transcription factor that binds and antagonizes the function of RORγt, and thereby inhibits the generation of Treg cells. Hyperactivation of STAT3 in naïve CD4+ T cells promotes Th17 cell differentiation, whereas ablation of STAT3 impairs Th17 cell differentiation and skews towards differentiation into FOXP3+ Treg cells [24, 27]. IL-6 triggers the expression of IL-21, which amplifies the autocrine loop and further induces the expression of IL-21 and surface IL-23R on naïve CD4+ T cells [26]. In addition, in IBD, macrophages release IL-6, which facilitates resistance to apoptosis and accumulation of aberrant T-cell in the intestinal mucosa, and promotes the persistence of pathogenic Th17 cells [28].

TGFβ is also a pleiotropic cytokine and can be produced by many types of cells, such as epithelial cells, DCs, T cells, and fibroblasts. TGFβ is abundant in the intestinal cells because its production is upregulated by various factors, such as bacteria, viruses, and cytokines. TGFβ is required for differentiation of Th17 and Treg cell and can induce both RORγt and FOXP3 expression via SMAD signaling. At high concentrations, TGFβ inhibits IL-23R expression and favors FOXP3+ Treg differentiation by antagonizing RORγt, whereas low TGFβ levels combine with IL-6 and IL-21 to enhance the expression of IL-23R and promote Th17 cell differentiation [11]. In Th17 cells, TGFβ promotes IL-22 production via Ahr induction and PI3K signaling [29]. IL-23 is a proinflammatory cytokine with a heterodimeric structure composed of the p19 and p40 subunits. The IL-23 p40 subunit is shared by the IL-12 p40 subunit [30]. IL-23 signals via the IL-12Rβ1 subunit (shared with IL-12-p40) and its unique IL-23Rα subunit.

IL-23R in turn stimulates JAK2 and TYK2 and activates STAT3, promoting transcription of IL-23R and RORC (which encodes RORγt) [31]. IL-12 is a heterodimer cytokine composed of the IL-12 p40 subunit and the IL-12 p35 subunit, and it signals through IL-12Rβ1 and IL-12Rβ2 [30]. The difference in IL-23- and IL-12-dependent signaling is partly due to the preferential activation of STAT3 by IL-23, and STAT4 by IL-12. IL-23 is mainly secreted by DCs, tissue-resident macrophages, and neutrophils upon non-self (microbial products such as lipopolysaccharide and peptidoglycans) and self-signals (prostaglandin E2 and adenosine 5’-triphosphate [ATP]) upon risk or injury [32]. The production of IL-23 can be further increased by CD40–CD40L interactions, which drive a positive feedback loop in DC activation [33]. IL-23 is not a Th17 cell-differentiating factor instead acts on previously differentiated Th17 cells, stabilizing their pathogenic function, in the absence of IL-23R in naïve CD4+ T cells [10, 34]. IL-23 can promote Th17 cell proliferation and secretion of proinflammatory cytokines, such as IFN-γ, GM-CSF, and TNF-α [17, 30, 34]. IL-23 promotes intestinal inflammation and exacerbates IBD progression [35, 36]. Results of a meta-analysis suggest that genetic polymorphisms in IL-23R are significantly associated with susceptibility to IBD [37]. In addition, activation of IL-23R signaling impairs the stability and function of intestinal Tregs, indicating that IL-23 affects the Th17/Treg cell balance in IBD [16].

IL-1β was first described as a lymphocyte-activating factor that stimulates T lymphocytes. IL-1β performs a range of proinflammatory activities. It is primarily produced by activated macrophages, monocytes, T-cells, NK cells, and endothelial cells [38]. IL-1 and IL-23 can be secreted by DCs upon stimulation with microbes, such as the bacterial NOD2-ligand muramyl dipeptide [39]. IL-1 is expressed as an inactive precursor, which must be proteolytically cleaved by the enzyme caspase-1 to become the active IL-1β cytokine. The key mediator of IL-1 cleavage in the intestine is the NOD-like receptor protein 3 (NLRP3) inflammasome, which activates caspase-1. Under intestinal inflammatory conditions, the NLRP3 inflammasome-expressing intestinal macrophages and DCs are activated and further secrete IL-1β [40]. IL-1β increases the intensity and duration of pSTAT3 signaling by inhibiting SOCS3, a feedback inhibitor of JAK2/STAT3 signaling [41]. IL-1β controls transcription factors, including IRF4, RORγt, BATF, and NFKBZ [42]. Thus, IL-1β enhances Th17 cell differentiation and inhibits Treg cell differentiation by suppressing TGFβ-induced FOXP3 expression in naive CD4+ T cells. IL-1β synergizes with IL-6 and IL-23 in the intestinal LP to generate pathogenic Th17 cells that produce IFN-γ, independently of TGFβ1 [9, 43]. IL-1 signaling is essential for driving the development of colitis by promoting the accumulation and survival of Th17 cells in the intestine [44].

IL-21 is a pleiotropic cytokine primarily produced by Th17, NKT, and T follicular helper cells. IL-21R is expressed in various cells, including T cells, NK cells, DCs, and NKT cells. IL-21 secreted by the Th17 cells stabilizes and expands the Th17 lineage in an autocrine manner. IL-21 is produced by Th17 cells, and upregulates IL-17 production and expression of RORγt in a STAT3 dependent manner [45]. IL-21 and TGFβ1 together can also induce Th17 cell differentiation in the absence of IL-6, and IL-21R-deficient T cells fail to promote Th17 cell differentiation [45]. IL-21 promotes IL-23R expression in naïve CD4+ T cells, which increases cellular responsiveness to IL-23 [26]. Several studies have focused on the pro-inflammatory effects of IL-21 signaling in IBD [46, 47], whereas some studies reveal that IL-21 signaling suppresses intestinal inflammation [48]. The precise involvement of IL-21 signaling in IBD warrants further investigation.


DCs are professional antigen-presenting cells that regulate T-cell tolerance and priming. In the intestine, DCs continuously encounter harmless food antigens and commensal microbes that maintain homeostasis. Under steady-state conditions, DCs can induce T-cell tolerance to harmless antigens to avoid undesirable immune responses. In other contexts, T-cell priming by DCs, which induce proinflammatory responses against pathogens and/or infected cells.

The importance of DCs in the pathogenesis of IBD has been demonstrated previously. In animals with dextran sulfate sodium (DSS)-induced colitis, transfer of bone marrow-derived DCs worsens inflammation, whereas depletion of bone marrow-derived DCs reduces inflammation [49]. The administration of an agonistic anti-CD40 antibody to T- and B-cell-deficient mice was adequate to activate DCs and induce IL-23-dependent intestinal inflammation [50]. In CD, LP DCs are activated and produce high levels of IL-12 and IL-6 [51]. Production of proinflammatory cytokines by DCs is correlated with disease and gut microbiota composition [52]. In the mesenteric lymph nodes (MLNs) of patients with CD, DCs produce high levels of IL-23, IL-17, and IFN-γ upon bacterial stimulation, and their CD4+ T cells secrete increased levels of IL-17 and IFN-γ [53].

Intestinal DCs are heterogeneous, however, they can be classified into three major subsets: CD103+CD11b+ DCs, CD103+CD11b DCs, and CD103CD11b+ DCs [54]. These three DC subsets upregulate CCR7 levels and migrate to the MLNs, and instruct naïve CD4+ T cells to respond to intestinal antigens and drive Th17 cell differentiation [55]. In particular, IRF4 transcription factor-expressing intestinal DC subsets (CD103+CD11b+ and CD103CD11b+) promote Th17 cell differentiation in MLNs [56]. Mice lacking IRF4-dependent DCs showed a reduced number of Th17 cells in their MLNs and intestines [57]. These studies show that IRF4 expressing DCs promote Th17 cell development in MLNs, primarily through the secretion of IL-6 [25, 57].

Innate immune signaling is important for regulating Th17/Treg immune balance in the intestinal tract. DC activation by several Toll-like receptor (TLR) ligands, including TLR2, TLR3, and TLR9, induces secretion of IL-6, IL-1β, and IL-23, which can promote differentiation of Th17 cells and gut inflammation [57, 58]. DCs that phagocytose apoptotic cells in the absence of microbial signals secrete TGFβ, which can promote Treg cell development. However, phagocytosis of infected apoptotic cells triggers the combined expression of IL-6 and TGFβ in a T-cell receptor-dependent manner, which alternatively promotes Th17 cell development [59]. These results suggest that DCs influence the development and activity of Th17 cells.


Microbiota influences the development and homeostasis of the immune system and is associated with IBD. Germ-free (GF) mice show markedly reduced numbers of LP Th17 cells [7]. The colonization of GF mice with different complex microbiota or their metabolites can increase the number of Th17 cells in the intestine [7]. GF- and antibiotic-treated mice showed attenuated intestinal inflammation; however, weakened intestinal barrier function in DSS-induced colitis [60]. The introduction of microbiota from humans with IBD into GF mice increased the number of Th17 and Th2 cells and decreased the number of Treg cells, whereas the transfer of microbiota from healthy donors increased the number of Treg cells [4]. Colonization of GF mice with human microbiota in IBD also increases colonic inflammation and exacerbates disease severity in a T-cell transfer-induced colitis model [4]. Recent clinical trials have shown that IBD can be treated using fecal microbiota transplantation (FMT) [61].

Adhesion of microbes to IECs is crucial for Th17 cell development and effector function, thus maintaining the mucosal barrier function. SFB are among the most potent and well-characterized commensals that induce antigen-specific Th17 cell differentiation in the terminal ileum of the small intestine [62]. SFB adhere tightly to the IECs of the ileum. SFB upregulate reactive oxygen species and transfer SFB-associated proteins into IECs via microbial adhesion-triggered endocytosis, thus upregulating IL-1β and IL-23 production from CX3CR1-expressing macrophages [63]. CX3CR1-expressing macrophage-derived IL-23 and IL-1β activate group 3 innate lymphoid cells (ILC3s) to produce IL-22 [64], which stimulates the secretion of SAA 1 and 2 [65]. The co-culture of SFB and epithelial cell lines can also increase SAA expression in vitro [66]. SAAs stimulate DCs to produce IL-6, TGFβ, IL-23, and IL-1β, resulting in Th17 cell development and survival [65]. These steady-state Th17 cells are required for protection against the intestinal pathogenic bacteria [67, 68]. Notably, SAAs are significantly upregulated in patients with IBD [69]. SAAs can directly induce the differentiation and pathogenicity of colitogenic Th17 cells, thereby exacerbating colonic inflammation in IBD [12]. Moreover, 20 bacterial strains isolated from the feces of UC patients showed epithelial cell-adhesive characteristics and induced Th17 cells in the mouse colon [68].

Multiple environmental factors contribute to intestinal Th17 cell activation. For example, ATP derived from symbiotic bacteria stimulates CD70hiCD11clo LP cells to produce TGFβ, IL-6, and IL-23, thus promoting Th17 cell differentiation [70]. A high-salt diet increased the risk of colitis by inducing a pathogenic Th17 response in mice [71]. High-salt conditions stimulate p38/MAPK signaling involving NFAT and SGK1 during cytokine-induced Th17 polarization [71]. A ketogenic diet alters the gut microbiome, contributing to a decrease in intestinal Th17 cells [72] and alleviates DSS-induced colitis by inhibiting colonic ILC3s [73]. Eggerthella lenta, the human gut bacteria produce the Cgr2 enzyme, which induces IL-17a production in intestinal Th17 cells [74]. E. lenta are enriched in patients with IBD and exacerbate colitis in an RORγ-dependent manner in mice [74]. E. lenta-induced colitis can be inhibited by increasing dietary arginine levels, which in turn inhibits the effect of Cgr2 [74].


Given the important role of Th17 cells in intestinal inflammation, neutralizing antibodies, and small molecules targeting Th17 cells and their associated cytokines may have therapeutic effects in controlling IBD (Table 1). Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, is approved by the FDA for the treatment of IBD [75]. In addition, selective IL-23-p19 inhibiting antibodies (risankizumab, brazikumab, guselkumab, and mirikizumab) have shown clinical benefits, including endoscopic remission and mucosal healing and are currently undergoing clinical trials [7679]. IL-17A neutralizing mAbs (Secukinumab and ixekizumab) and IL-17A receptor-neutralizing mAbs (brodalumab) have exhibited opposite effects, with aggravation of IBD leading to premature termination of various trials [8082]. Secukinumab, ixekizumab, and brodalumab are widely used for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, and active ankylosing spondylitis [83]. The mechanisms underlying these paradoxical gastrointestinal effects are not well understood however, might suggest impaired intestinal epithelial barrier integrity, as IL-17A regulates epithelial tight junction proteins such as occludin. Vidofludimus is a novel oral immunomodulator that downregulates IL-17A, IL-17F, and IFN-γ levels by interference with the JAK/STAT3 and NFκB pathways [84]. Vidofludimus improved both acute and chronic DSS-induced colitis in mice [85] and patients with IBD [84]. These results suggest that inhibition of multiple cytokines may be effective in the treatment of IBD.

Table 1. Therapies targeting Th17 cells for IBD
Target Drug Experimental model or clinical trial status Effective Ref
IL-12/23 p40 Ustekinumab Phase III Yes [75]
IL-23p19 Risankizumab Phase III/II Yes [76]
Brazikumab Phase III/II Yes [77]
Guselkumab Phase III/II Yes [78]
Mirikizumab Phase III/II Yes [79]
IL-23 receptor PTG-200 Phase II/I Yes [86]
IL-17A Secukinumab Phase II No [80]
Ixekizumab Phase III No [81]
IL-17 receptor Brodalumab Phase II No [82]
IL-17A/IL-17F/IFN-γ Vidofludimus Phase I/II Yes [84]
IL-6 trans-signaling Olamine (sgp130Fc) Phase II Yes [87]
IL-6 receptor Tocilizumab Phase II Yes [88]
IL-1β Canakinumab Phase I
(very early onset IBD)
Yes [89]
IL-1β receptor Anakinra Phase II Yes [90]
JAK inhibitor Tofacitinib FDA approved Yes [91]
α4β7 Vedolizumab FDA approved Yes [92]
TNF-α Infliximab, Adalimumab, Certolizumab FDA approved Yes [93]

Th17, T helper 17; IBD, inflammatory bowel disease; IL, interleukin; IFN, interferon; JAK, Janus kinase; TNF, tumor necrosis factor; FDA, Food and Drug Administration.

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Gut microbiota and its metabolites play a role in maintaining gut barrier integrity and IBD by regulating Th17/Treg cell development and activity. Thus, the interactions between the gut microbiota and Th17/Treg cells may be promising targets for the treatment of IBD. Studies have shown that FMT, probiotics, and plant extracts are a potential therapeutic solution for IBD by targeting the gut microbiota based on the Th17/Treg cell balance (Table 2).

Table 2. Therapies targeting gut microbiota
Type Drug or method Effect Ref
Th17/Treg ratio Microbiota
Plant extract Rabdosia serra Reduce Lactobacillus ↑ Bacteroidetes ↑ [5]
Stigmasterol Reduce Clostridia, Helicobacter ↑ Streptococcus ↓ [94]
Juglone Reduce Firmicutes ↑ Bacteroidetes ↓ [95]
Parthenolide Reduce Alloprevotella ↑ Bacteroides ↓ [96]
Probiotics Lactobacillus paracasei R3 Reduce - [97]
Lactobacillus rhamnosus GG Reduce - [98]
Lactobacillus acidophilus Reduce - [99]
Carbohydrate Pectic oligosaccharides Reduce Bacteroidetes ↑ Firmicutes ↓ [100]
Isomaltulose Reduce Bacteroidetes ↑ Firmicutes ↓ [101]
Fatty acid Linoleic acid Reduce Bacteroidetes ↑ Firmicutes ↓ [6]
Butyrate Reduce - [102]

Th, T helper; Treg, regulatory T.

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Intestinal Th17 cells and the cytokines they produce, play critical roles in the pathogenesis of IBD. These results are being actively studied for the development of immunotherapies for IBD. In addition, gut microbiota-based therapies are consistently being developed for the prevention and treatment of IBD. However, several questions remain unanswered. More fundamental and translational studies are required to further understand the relationship between gut microbiota and mucosal immunity. Adjusting the gut microbiome, selecting certain bacteria, and performing FMT in conjunction with biological therapies may improve the diagnosis, and aid in prevention, and treatment of IBD.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.


This work was supported by the research grant of the Chungbuk National University in 2022.

Ethics Approval

Not applicable.



Steinbach EC, Gipson GR, Sheikh SZ. Induction of murine intestinal inflammation by adoptive transfer of effector CD4+ CD45RB high T cells into immunodeficient mice. J Vis Exp. 2015; 98e52533


Lee GR. Molecular mechanisms of T helper cell differentiation and functional specialization. Immune Netw. 2023; 23e4


Peluso I, Pallone F, Monteleone G. Interleukin-12 and Th1 immune response in Crohn’s disease: pathogenetic relevance and therapeutic inplication. World J Gastroenterol. 2006; 12:5606-5610


Britton GJ, Contijoch EJ, Mogno I, Vennaro OH, Llewellyn SR, Ng R, Li Z, Mortha A, Merad M, Das A, Gevers D, McGovern DPB, Singh N, Braun J, Jacobs JP, Clemente JC, Grinspan A, Sands BE, Colombel JF, Dubinsky MC, Faith JJ. Microbiotas from humans with inflammatory bowel disease alter the balance of gut Th17 and RORγt(+) regulatory T cells and exacerbate colitis in mice. Immunity. 2019; 50:212-224.E4


Li H, Wang Y, Shao S, Yu H, Wang D, Li C, Yuan Q, Liu W, Cao J, Wang X, Guo H, Wu X, Wang S. Rabdosia serra alleviates dextran sulfate sodium salt-induced colitis in mice through anti-inflammation, regulating Th17/Treg balance, maintaining intestinal barrier integrity, and modulating gut microbiota. J Pharm Anal. 2022; 12:824-838


Jia L, Jiang Y, Wu L, Fu J, Du J, Luo Z, Guo L, Xu J, Liu Y. Porphyromonas gingivalis aggravates colitis via a gut microbiota-linoleic acid metabolism-Th17/Treg cell balance axis. Nat Commun. 2024; 15:1617


Sun CY, Yang N, Zheng ZL, Liu D, Xu QL. T helper 17 (Th17) cell responses to the gut microbiota in human diseases. Biomed Pharmacother. 2023; 161:114483


Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y, Fujikado N, Tanahashi Y, Akitsu A, Kotaki H, Sudo K, Nakae S, Sasakawa C, Iwakura Y. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity. 2009; 30:108-119


Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature. 2010; 467:967-971


McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O’Shea JJ, Cua DJ. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo. Nat Immunol. 2009; 10:314-324


Zhou L, Lopes JE, Chong MMW, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature. 2008; 453:236-240


Lee JY, Hall JA, Kroehling L, Wu L, Najar T, Nguyen HH, Lin WY, Yeung ST, Moura Silva H, Li D, Hine A, Loke P, Hudesman D, Martin JC, Kenigsberg E, Merad M, Khanna KM, Littman DR. Serum amyloid A proteins induce pathogenic Th17 cells and promote inflammatory disease. Cell. 2020; 180:79-91.E16


Wang C, Yosef N, Gaublomme J, Park H, Regev A, Kuchroo VK. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell. 2015; 163:1413-1427


Wu B, Wan Y. Molecular control of pathogenic Th17 cells in autoimmune diseases. Int Immunopharmacol. 2020; 80:106187


Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci USA. 2015; 112:7061-7066


Jacobse J, Brown RE, Li J, Pilat JM, Pham L, Short SP, Peek CT, Rolong A, Kay Washington M, Martinez-Barricarte R, Byndloss MX, Shelton C, Markle JG, Latour YL, Allaman MM, Cassat JE, Wilson KT, Choksi YA, Williams CS, Lau KS, Flynn CR, Casanova JL, Rings EHHM, Samsom JN, Goettel JA. Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells. Cell Rep. 2023; 42:112128


Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ, Powrie F. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity. 2010; 33:279-288


Biancheri P, Pender SLF, Ammoscato F, Giuffrida P, Sampietro G, Ardizzone S, Ghanbari A, Curciarello R, Pasini A, Monteleone G, Corazza GR, MacDonald TT, Di Sabatino A. The role of interleukin 17 in Crohn’s disease-associated intestinal fibrosis. Fibrogenesis Tissue Repair. 2013; 6:13


Zhao X, Yang W, Yu T, Yu Y, Cui X, Zhou Z, Yang H, Yu Y, Bilotta AJ, Yao S, Xu J, Zhou J, Yochum GS, Koltun WA, Portolese A, Zeng D, Xie J, Pinchuk IV, Zhang H, Cong Y. Th17 cell-derived amphiregulin promotes colitis-associated intestinal fibrosis through activation of mTOR and MEK in intestinal myofibroblasts. Gastroenterology. 2023; 164:89-102


Gagliani N, Carolina Amezcua Vesely M, Iseppon A, Brockmann L, Xu H, Palm NW, de Zoete MR, Licona-Limón P, Paiva RS, Ching T, Weaver C, Zi X, Pan X, Fan R, Garmire LX, Cotton MJ, Drier Y, Bernstein B, Geginat J, Stockinger B, Esplugues E, Huber S, Flavell RA. TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature. 2015; 523:221-225


Ueno A, Jijon H, Chan R, Ford K, Hirota C, Kaplan GG, Beck PL, Iacucci M, Fort Gasia M, Barkema HW, Panaccione R, Ghosh S. Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatory T cells in inflammatory bowel disease patients. Inflamm Bowel Dis. 2013; 19:2522-2534


Park H, Li Z, Yang XO, Hee Chang S, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6:1133-1141


Muranski P, Restifo NP. Essentials of Th17 cell commitment and plasticity. Blood. 2013; 121:2402-2414


Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007; 282:9358-9363


Heink S, Yogev N, Garbers C, Herwerth M, Aly L, Gasperi C, Husterer V, Croxford AL, Möller-Hackbarth K, Bartsch HS, Sotlar K, Krebs S, Regen T, Blum H, Hemmer B, Misgeld T, Wunderlich TF, Hidalgo J, Oukka M, Rose-John S, Schmidt-Supprian M, Waisman A, Korn T. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol. 2017; 18:74-85


Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007; 8:967-974


Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, Hipkiss EL, Getnet D, Goldberg MV, Maris CH, Housseau F, Yu H, Pardoll DM, Drake CG. Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol. 2007; 179:4313-4317


Harbour SN, Ditoro DF, Witte SJ, Zindl CL, Gao M, Schoeb TR, Jones GW, Jones SA, Hatton RD, Weaver CT. TH17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity. Sci Immunol. 2020; 5:1-16


Perez LG, Kempski J, McGee HM, Pelzcar P, Agalioti T, Giannou A, Konczalla L, Brockmann L, Wahib R, Xu H, Carolina Amezcua Vesely M, Soukou S, Steglich B, Bedke T, Manthey C, Seiz O, Diercks BP, Gnafakis S, Guse AH, Perez D, Izbicki JR, Gagliani N, Flavell RA, Huber S. TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer. Nat Commun. 2020; 11:1-2


Teng MWL, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM, Cua DJ. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015; 21:719-729


Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O’Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002; 168:5699-5708


Neurath MF. IL-23 in inflammatory bowel diseases and colon cancer. Cytokine Growth Factor Rev. 2019; 45:1-8


McKenzie BS, Kastelein RA, Cua DJ. Understanding the IL-23–IL-17 immune pathway. Trends Immunol. 2006; 27:17-23


Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005; 201:233-240


Feng T, Qin H, Wang L, Benveniste EN, Elson CO, Cong Y. Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production. J Immunol. 2011; 186:6313-6318


Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ. Interleukin-23 drives innate and T cell–mediated intestinal inflammation. J Exp Med. 2006; 203:2473-2483


Liu M, Zhu W, Wang J, Zhang J, Guo X, Wang J, Song J, Dong W. Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: a meta-analysis. Clin Res Hepatol Gastroenterol. 2015; 39:516-525


Zhao R, Zhou H, Su SB. A critical role for interleukin-1β in the progression of autoimmune diseases. Int Immunopharmacol. 2013; 17:658-669


van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, Muller FJ, Hommes DW, Zaat SAJ, Kapsenberg ML, de Jong EC. Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity. 2007; 27:660-669


Mao L, Kitani A, Strober W, Fuss IJ. The role of NLRP3 and IL-1β in the pathogenesis of inflammatory bowel disease. Front Immunol. 2018; 9:2566


Basu R, Whitley SK, Bhaumik S, Zindl CL, Schoeb TR, Benveniste EN, Pear WS, Hatton RD, Weaver CT. IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell–iTreg cell balance. Nat Immunol. 2015; 16:286-295


Ikeda S, Saijo S, Murayama MA, Shimizu K, Akitsu A, Iwakura Y. Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-β–induced Foxp3 expression. J Immunol. 2014; 192:1449-1458


Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009; 30:576-587


Coccia M, Harrison OJ, Schiering C, Asquith MJ, Becher B, Powrie F, Maloy KJ. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells. J Exp Med. 2012; 209:1595-1609


Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature. 2007; 448:484-487


Fina D, Sarra M, Fantini MC, Rizzo A, Caruso R, Caprioli F, Stolfi C, Cardolini I, Dottori M, Boirivant M, Pallone F, MacDonald TT, Monteleone G. Regulation of gut inflammation and Th17 cell response by interleukin-21. Gastroenterology. 2008; 134:1038-1048.E2


Holm TL, Tornehave D, Søndergaard H, Helding Kvist P, Sondergaard BC, Hansen L, Brunsgaard Hermit M, Holgersen K, Vergo S, Stensgaard Frederiksen K, Haase C, Lundsgaard D. Evaluating IL-21 as a potential therapeutic target in Crohn’s disease. Gastroenterol Res Pract. 2018; 2018:5962624


Wang Y, Jiang X, Zhu J, Yue D, Zhang X, Wang X, You Y, Wang B, Xu Y, Lu C, Sun X, Yoshikai Y. IL-21/IL-21R signaling suppresses intestinal inflammation induced by DSS through regulation of Th responses in lamina propria in mice. Sci Rep. 2016; 6:31881


Berndt BE, Zhang M, Chen GH, Huffnagle GB, Kao JY. The role of dendritic cells in the development of acute dextran sulfate sodium colitis. J Immunol. 2007; 179:6255-6262


Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R, Robinson N, Buonocore S, Tlaskalova-Hogenova H, Cua DJ, Powrie F. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006; 25:309-318


Hart AL, Al-Hassi HO, Rigby RJ, Bell SJ, Emmanuel AV, Knight SC, Kamm MA, Stagg AJ. Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology. 2005; 129:50-65


Ng SC, Benjamin JL, McCarthy NE, Hedin RH, Koutsoumpas A, Plamondon S, Price CL, Hart AL, Kamm MA, Forbes A, Knight SC, Lindsay JO, Whelan K, Stagg AJ. Relationship between human intestinal dendritic cells, gut microbiota, and disease activity in Crohn’s disease. Inflamm Bowel Dis. 2011; 17:2027-2037


Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T. Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn’s disease. Gastroenterology. 2009; 137:1736-1745


Cerovic V, Bain CC, Mowat AM, Milling SWF. Intestinal macrophages and dendritic cells: what’s the difference?. Trends Immunol. 2014; 35:270-277


Huang HI, Jewell ML, Youssef N, Huang MN, Hauser ER, Fee BE, Rudemiller NP, Privratsky JR, Zhang JJ, Reyes EY, Wang D, Taylor GA, Gunn MD, Ko DC, Cook DN, Chandramohan V, Crowley SD, Elena Hammer G. Th17 immunity in the colon is controlled by two novel subsets of colon-specific mononuclear phagocytes. Front Immunol. 2021; 12:661290


Liang J, Huang HI, Benzatti FP, Karlsson AB, Zhang JJ, Youssef N, Ma A, Hale LP, Hammer GE. Inflammatory Th1 and Th17 in the intestine are each driven by functionally specialized dendritic cells with distinct requirements for MyD88. Cell Rep. 2016; 17:1330-1343


Persson EK, Uronen-Hansson H, Semmrich M, Rivollier A, Hägerbrand K, Marsal J, Gudjonsson S, Håkansson U, Reizis B, Kotarsky K, Agace WW. IRF4 transcription-factor-dependent CD103+CD11b+ dendritic cells drive mucosal T helper 17 cell differentiation. Immunity. 2013; 38:958-969


Tanaka J, Watanabe N, Kido M, Saga K, Akamatsu T, Nishio A, Chiba T. Human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2-polarizing conditions. Clin Exp Allergy. 2009; 39:89-100


Torchinsky MB, Garaude J, Martin AP, Magarian Blander J. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature. 2009; 458:78-82


Hernández-Chirlaque C, Aranda CJ, Ocón B, Capitán-Cañadas F, Ortega-González M, Jesús Carrero J, Dolores Suárez M, Zarzuelo A, Sánchez de Medina F, Martínez-Augustin O. Germ-free and antibiotic-treated mice are highly susceptible to epithelial injury in DSS colitis. J Crohns Colitis. 2016; 10:1324-1335


Zhang X, Ishikawa D, Ohkusa T, Fukuda S, Nagahara A. Hot topics on fecal microbiota transplantation for the treatment of inflammatory bowel disease. Front Med. 2022; 9:1068567


Yang Y, Torchinsky MB, Gobert M, Xiong H, Xu M, Linehan JL, Alonzo F, Ng C, Chen A, Lin X, Sczesnak A, Liao JJ, Torres VJ, Jenkins MK, Lafaille JJ, Littman DR. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature. 2014; 510:152-156


Ladinsky MS, Araujo LP, Zhang X, Veltri J, Galan-Diez M, Soualhi S, Lee C, Irie K, Pinker EY, Narushima S, Bandyopadhyay S, Nagayama M, Elhenawy W, Coombes BK, Ferraris RP, Honda K, Iliev ID, Gao N, Bjorkman PJ, Ivanov II. Endocytosis of commensal antigens by intestinal epithelial cells regulates mucosal T cell homeostasis. Science. 2019; 363:1-11


Longman RS, Diehl GE, Victorio DA, Huh JR, Galan C, Miraldi ER, Swaminath A, Bonneau R, Scherl EJ, Littman DR. CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med. 2014; 211:1571-1583


Sano T, Huang W, Hall JA, Yang Y, Chen A, Gavzy SJ, Lee JY, Ziel JW, Miraldi ER, Domingos AI, Bonneau R, Littman DR. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell. 2015; 163:381-393


Schnupf P, Gaboriau-Routhiau V, Gros M, Friedman R, Moya-Nilges M, Nigro G, Cerf-Bensussan N, Philippe Sansonetti J. Growth and host interaction of mouse segmented filamentous bacteria in vitro. Nature. 2015; 520:99-103


Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009; 139:485-498


Atarashi K, Tanoue T, Ando M, Kamada N, Nagano Y, Narushima S, Suda W, Imaoka A, Setoyama H, Nagamori T, Ishikawa E, Shima T, Hara T, Kado S, Jinnohara T, Ohno H, Kondo T, Toyooka K, Watanabe E, Yokoyama S, Tokoro S, Mori H, Noguchi Y, Morita H, Ivanov II, Sugiyama T, Nuñez G, Gray Camp J, Hattori M, Umesaki Y, Honda K. Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell. 2015; 163:367-380


Chen R, Chen Q, Zheng J, Zeng Z, Chen M, Li L, Zhang S. Serum amyloid protein A in inflammatory bowel disease: from bench to bedside. Cell Death Discov. 2023; 9:154


Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, Takeda K. ATP drives lamina propria TH17 cell differentiation. Nature. 2008; 455:808-812


Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013; 496:518-522


Ang QY, Alexander M, Newman JC, Tian Y, Cai J, Upadhyay V, Turnbaugh JA, Verdin E, Hall KD, Leibel RL, Ravussin E, Rosenbaum M, Patterson AD, Turnbaugh PJ. Ketogenic diets alter the gut microbiome resulting in decreased intestinal Th17 cells. Cell. 2020; 181:1263-1275.E16


Kong C, Yan X, Liu Y, Huang L, Zhu Y, He J, Gao R, Kalady MF, Goel A, Qin H, Ma Y. Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome. Signal Transduct Target Ther. 2021; 6:154


Alexander M, Yan Ang Q, Nayak RR, Bustion AE, Sandy M, Zhang B, Upadhyay V, Pollard KS, Lynch SV, Turnbaugh PJ. Human gut bacterial metabolism drives Th17 activation and colitis. Cell Host Microbe. 2022; 30:17-30.E9


Panaccione R, Danese S, Sandborn WJ, O’Brien CD, Zhou Y, Zhang H, Adedokun OJ, Tikhonov I, Targan S, Abreu MT, Hisamatsu T, Scherl EJ, Leong RW, Rowbotham DS, Arasaradnam RP, Sands BE, Marano C. Ustekinumab is effective and safe for ulcerative colitis through 2 years of maintenance therapy. Aliment Pharmacol Ther. 2020; 52:1658-1675


Feagan BG, Sandborn WJ, D’Haens G, Panés J, Kaser A, Ferrante M, Louis E, Franchimont D, Dewit O, Seidler U, Kim KJ, Neurath MF, Schreiber S, Scholl P, Pamulapati C, Lalovic B, Visvanathan S, Padula SJ, Herichova I, Soaita A, Hall DB, Böcher WO. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn’s disease: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 2017; 389:1699-1709


Sands BE, Chen J, Feagan BG, Penney M, Rees WA, Danese S, Higgins PDR, Newbold P, Faggioni R, Patra K, Li J, Klekotka P, Morehouse C, Pulkstenis E, Drappa J, van der Merwe R, Gasser RA. Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn’s disease: a phase 2a study. Gastroenterology. 2017; 153:77-86.E6


Sandborn WJ, D’Haens GR, Reinisch W, Panés J, Chan D, Gonzalez S, Weisel K, Germinaro M, Ellen Frustaci M, Yang Z, Adedokun OJ, Han C, Panaccione R, Hisamatsu T, Danese S, Rubin DT, Sands BE, Afzali A, Andrews JM, Feagan BG. Guselkumab for the treatment of Crohn’s disease: induction results from the phase 2 GALAXI-1 study. Gastroenterology. 2022; 162:1650-1664.E8


Sands BE, Peyrin-Biroulet L, Kierkus J, Higgins PDR, Fischer M, Jairath V, Hirai F, D’Haens G, Belin RM, Miller D, Gomez-Valderas E, Naegeli AN, Tuttle JL, Pollack PF, Sandborn WJ. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with Crohn’s disease. Gastroenterology. 2022; 162:495-508


Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PDR, Wehkamp J, Feagan BG, Yao MD, Karczewski M, Karczewski J, Pezous N, Bek S, Bruin G, Mellgard B, Berger C, Londei M, Bertolino AP, Tougas G, Travis SPL. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012; 61:1693-1700


Philipose J, Ahmed M, Idiculla PS, Mulrooney SM, Gumaste VV. Severe de novo ulcerative colitis following Ixekizumab therapy. Case Rep Gastroenterol. 2018; 12:617-621


Targan SR, Brian F, Severine V, Remo P, Gil MY, Carol L, Dalin L, Chris R, Richard N, Nan Z, Yun C, Yi-Hsiang H, Shao-Lee L, Paul K. A randomized, double-blind, placebo-controlled phase 2 study of brodalumab in patients with moderate-to-severe Crohn’s disease. Am J Gastroenterol. 2016; 111:1599-1607


Fauny M, Moulin D, D’Amico F, Netter P, Petitpain N, Arnone D, Jouzeau JY, Loeuille D, Peyrin-Biroulet L. Paradoxical gastrointestinal effects of interleukin-17 blockers. Ann Rheum Dis. 2020; 79:1132-1138


Herrlinger KR, Diculescu M, Fellermann K, Hartmann H, Howaldt S, Nikolov R, Petrov A, Reindl W, Otte JM, Stoynov S, Strauch U, Sturm A, Voiosu R, Ammendola A, Dietrich B, Hentsch B, Stange EF. Efficacy, safety and tolerability of vidofludimus in patients with inflammatory bowel disease: the ENTRANCE study. J Crohns Colitis. 2013; 7:636-643


Fitzpatrick LR, Deml L, Hofmann C, Small JS, Groeppel M, Hamm S, Lemstra S, Leban J, Ammendola A. 4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease. Inflamm Bowel Dis. 2010; 16:1763-1777


Moschen AR, Tilg H, Raine T. IL-12, IL-23 and IL-17 in IBD: immunobiology and therapeutic targeting. Nat Rev Gastroenterol Hepatol. 2019; 16:185-196


Schreiber S, Aden K, Bernardes JP, Conrad C, Tran F, Höper H, Volk V, Mishra N, Ira Blase J, Nikolaus S, Bethge J, Kühbacher T, Röcken C, Chen M, Cottingham I, Petri N, Rasmussen BB, Lokau J, Lenk L, Garbers C, Feuerhake F, Rose-John S, Waetzig GH, Rosenstiel P. Therapeutic interleukin-6 trans-signaling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease. Gastroenterology. 2021; 160:2354-2366.E11


Danese S, Vermeire S, Hellstern P, Panaccione R, Rogler G, Fraser G, Kohn A, Desreumaux P, Leong RW, Comer GM, Cataldi F, Banerjee1 A, Maguire MK, Li1 C, Rath N, Beebe1 J, Schreiber S. Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn’s disease (ANDANTE I and II). Gut. 2019; 68:40-48


Shaul E, Conrad MA, Dawany N, Patel T, Canavan MC, Baccarella A, Weinbrom S, Aleynick D, Sullivan KE, Kelsen JR. Canakinumab for the treatment of autoinflammatory very early onset-inflammatory bowel disease. Front Immunol. 2022; 13:972114


Thomas MG, Bayliss C, Bond S, Dowling F, Galea J, Jairath V, Lamb C, Probert C, Timperley-Preece E, Watson A, Whitehead L, Williams JG, Parkes M, Kaser A, Raine T. Trial summary and protocol for a phase II randomised placebo-controlled double-blinded trial of Interleukin 1 blockade in acute severe colitis: the IASO trial. BMJ Open. 2019; 9e023765


D’Amico F, Parigi TL, Fiorino G, Peyrin-Biroulet L, Danese S. Tofacitinib in the treatment of ulcerative colitis: efficacy and safety from clinical trials to real-world experience. Therap Adv Gastroenterol. 2019; 12:1756284819848631


Crooks B, Barnes T, Limdi JK. Vedolizumab in the treatment of inflammatory bowel disease: evolving paradigms. Drugs Context. 2020; 9:1-15


Papamichael K, Lin S, Moore M, Papaioannou G, Sattler L, Cheifetz AS. Infliximab in inflammatory bowel disease. Ther Adv Chronic Dis. 2019; 10:2040622319838443


Wen S, He L, Zhong Z, Zhao R, Weng S, Mi H, Liu F. Stigmasterol restores the balance of Treg/Th17 cells by activating the butyrate-PPARγ axis in colitis. Front Immunol. 2021; 12:741934


Hua Y, Liu R, Lu M, Guan X, Zhuang S, Tian Y, Zhang Z, Cui L. Juglone regulates gut microbiota and Th17/Treg balance in DSS-induced ulcerative colitis. Int Immunopharmacol. 2021; 97:107683


Liu YJ, Tang B, Wang FC, Tang L, Lei YY, Luo Y, Huang SJ, Yang M, Wu LY, Wang W, Liu S, Yang SM, Zhao XY. Parthenolide ameliorates colon inflammation through regulating Treg/Th17 balance in a gut microbiota-dependent manner. Theranostics. 2020; 10:5225-5241


Huang J, Yang Z, Li Y, Chai X, Liang Y, Lin B, Ye Z, Zhang S, Che Z, Zhang H, Zhang X, Zhang Z, Chen T, Yang W, Zeng J. Lactobacillus paracasei R3 protects against dextran sulfate sodium (DSS)-induced colitis in mice via regulating Th17/Treg cell balance. J Transl Med. 2021; 19:356


Jia L, Wu R, Han N, Fu J, Luo Z, Guo L, Su Y, Du J, Liu Y. Porphyromonas gingivalis and Lactobacillus rhamnosus GG regulate the Th17/Treg balance in colitis via TLR4 and TLR2. Clin Transl Immunol. 2020; 9e1213


Park JS, Choi JW, Jhun J, Kwon JY, Lee BI, Yang CW, Park SH, Cho ML. Lactobacillus acidophilus improves intestinal inflammation in an acute colitis mouse model by regulation of Th17 and Treg cell balance and fibrosis development. J Med Food. 2018; 21:215-224


Wang H, Liu N, Yang Z, Zhao K, Pang H, Shao K, Zhou Z, Li S, He N. Preventive effect of pectic oligosaccharides on acute colitis model mice: modulating epithelial barrier, gut microbiota and Treg/Th17 balance. Food Funct. 2022; 13:9999-10012


Zhou Z, Yu S, Cui L, Shao K, Pang H, Wang Z, He N, Li S. Isomaltulose alleviates acute colitis via modulating gut microbiota and the Treg/Th17 balance in mice. Food Funct. 2022; 13:8572-8584


Chen L, Sun M, Wu W, Yang W, Huang X, Xiao Y, Ma C, Xu L, Yao S, Liu Z, Cong Y. Microbiota metabolite butyrate differentially regulates Th1 and Th17 cells’ differentiation and function in induction of colitis. Inflamm Bowel Dis. 2019; 25:1450-1461