Peroxisome proliferator-activated receptors in inflammatory bowel disease: linking immunometabolism, lipid signaling, and therapeutic potential
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Abstract
Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis, is a chronic condition marked by immune dysregulation, genetic predisposition, and metabolic disturbances. Emerging evidence highlights the role of lipid metabolism and peroxisome proliferator-activated receptor (PPAR) signaling in modulating immune responses in IBD. PPAR-γ and PPAR-α regulate macrophage polarization, T-cell differentiation, and epithelial barrier integrity, influencing disease severity and progression. Alterations in PPAR activity contribute to metabolic stress and inflammation, linking IBD pathophysiology to immunometabolism. Studies suggest that targeting PPARs may mitigate inflammation through modulation of cytokine production, immune cell function, and gut microbiota interactions. In this review, we focus specifically on CD and explore how PPAR signaling intersects with mesenteric adipose tissue dysfunction and microbial dysbiosis, 2 hallmark features of CD. PPAR agonists, already used in metabolic-inflammatory diseases such as metabolic-associated liver disease, have demonstrated antiinflammatory effects in experimental colitis models. Translating these findings into clinical applications could offer novel treatment strategies for CD. Future research should focus on clinical trials, genetic studies, and microbiota-targeted approaches to elucidate PPAR-driven mechanisms in CD pathogenesis. Understanding the interplay between PPARs, lipid metabolism, and immune responses may lead to innovative therapeutic strategies, improving disease management and patient outcomes.
INTRODUCTION
Inflammatory bowel disease (IBD), manifests as chronic inflammation across various sections of the gastrointestinal tract. Disease activity is influenced by multiple factors, including genetic predisposition, environmental triggers, alterations in gut microbiota, and immune dysregulation [1]. Recent insights into immunometabolism have revealed that metabolic processes within immune cells play a critical role in disease pathogenesis, linking metabolic dysregulation to immune responses in chronic inflammation [2]. Dysregulation in lipid metabolism, mediated by pathways such as peroxisome proliferator-activated receptor (PPAR) signaling, plays a critical role in immune cell function and inflammatory responses in IBD and other metabolic-inflammatory conditions. Lipid metabolism influences key processes such as macrophage polarization, T-cell differentiation, and epithelial barrier integrity, which are central to Crohn’s disease (CD) pathophysiology [3]. For example, in metabolic-associated liver disease, dysregulated lipid metabolism contributes to inflammation and immune dysregulation through ectopic fat deposition, lipotoxicity, and the accumulation of toxic lipid species like ceramides and diacylglycerols [4].
PPARs, a family of nuclear receptor transcription factors, regulate lipid metabolism, energy homeostasis, and immune responses. PPARs exist in 3 isoforms: PPARα, PPARβ/δ, and PPARγ, each encoded by distinct genes and exhibiting tissue-specific expression (Table 1) [5-10]. PPARs function by forming heterodimers with the retinoid X receptor and binding to PPAR response elements in the promoter regions of target genes. Upon ligand binding, PPARs recruit co-activators or corepressors to regulate gene transcription. In immune cells, PPAR activation can suppress pro-inflammatory pathways such as nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) while promoting lipid-catabolic and oxidative metabolic programs [11]. Given these functions, PPARs serve as molecular bridges between metabolic cues (like fatty acids or eicosanoid ligands) and immune cell behavior [7,8,11-14]. In this review, we examine the role of PPAR signaling in the pathogenesis and regulation of IBD, with a particular focus on CD. We explore how PPAR isoforms—especially PPARγ—modulate immune cell phenotypes, maintain epithelial barrier integrity, and influence the inflammatory environment within the gut.
IMMUNOMETABOLIC DYSREGULATION IN CD
CD is fundamentally an immune-mediated disorder, but its pathogenesis cannot be fully explained without considering metabolic context. Immunometabolism refers to how cellular metabolism governs immune cell function and fate. In CD lesions, immune cells exist in a nutrient- and oxygen-deprived milieu, forcing metabolic adaptations that can intensify inflammation. For example, classically activated M1 macrophages (abundant in active CD) rely on aerobic glycolysis and broken tricarboxylic acid cycle activity to sustain rapid cytokine production, whereas anti-inflammatory M2 macrophages use oxidative metabolism and fatty-acid β-oxidation [11]. In CD, the persistent presence of microbial antigens and cytokines (e.g., interferon γ [IFN-γ], tumor necrosis factor α [TNF-α]) drives macrophages toward the pro-inflammatory M1 state, accompanied by metabolic reprogramming that favors glycolytic energy production and lipid droplet accumulation. Similarly, effector T cells in the inflamed gut favor glycolysis, while regulatory T cells and memory T cells depend more on lipid oxidation and mitochondrial respiration. These metabolic programs are tightly linked to the cells’ inflammatory outputs–an emerging paradigm is that tweaking cellular metabolism can modulate immune responses in IBD.
The intestinal microenvironment in CD further reflects this immunometabolic imbalance. Mucosal tissues from CD patients often show an altered lipid profile and energy metabolism signature. Mesenteric adipose tissue hypertrophies into “creeping fat” around areas of transmural inflammation, indicating a redistribution of lipid storage and metabolism to the intestinal vicinity. This creeping fat is not inert; it secretes adipokines like leptin and adiponectin, and pro-inflammatory mediators, which can influence immune cell polarization and fibrosis in the gut. Notably, creeping fat adipocytes exhibit changes in their metabolic gene expression. Single-cell transcriptomic studies have identified a subpopulation of stromal cells within creeping fat that highly expresses lipoprotein lipase and shows elevated transcriptional activity of PPARγ and related lipid metabolic pathways [15,16]. This suggests that PPARγ-driven lipid metabolism in creeping fat may be a response to–or contributor to–intestinal inflammation, potentially by supplying energy-rich lipids or antimicrobial molecules to the inflamed gut wall (e.g., through upregulation of lipid-handling and antibacterial genes). Thus, metabolic reprogramming is intertwined with immune regulation in CD at both the cellular and tissue level.
PPARs are central to immunometabolic regulation, making them well-positioned to influence CD processes. As lipid sensors, PPARs respond to fatty acids, eicosanoids, and other metabolites that accumulate in inflamed or hypoxic tissues. Activation of PPARα or PPARγ can recalibrate the metabolism of macrophages and T cells: for instance, PPAR activation promotes β-oxidation of fatty acids and dampens glycolytic flux, which can push macrophages toward a more restorative M2 phenotype and encourage T cells towards regulatory or less inflammatory states [17]. In parallel, PPAR signaling directly suppresses pro-inflammatory gene transcription (via transrepression of NF-κB, AP-1, and other pathways) and induces genes involved in cellular stress defense (such as antioxidant enzymes and anti-apoptotic factors). These effects exemplify how manipulating metabolism can have downstream immune consequences. Indeed, loss-of-function models have shown that without PPARs enforcing metabolic checks, inflammation is amplified: mice lacking PPARα develop a heightened Th1/Th17 response to commensal microbiota and suffer more severe colitis [18,19].
Moreover, immunometabolic perturbations in CD extend to the epithelial barrier, where energy metabolism influences barrier integrity and mucus production. Butyrate–a short-chain fatty acid (SCFA) produced by gut microbiota–is a prime example of an immunometabolic mediator: it serves as the primary fuel for colonic epithelial cells and also exerts anti-inflammatory effects. Butyrate has been shown to enhance intestinal barrier function by acting on epithelial cell metabolism and by activating PPARγ. In colonic epithelial models, butyrate upregulates PPARγ and stimulates PPAR-responsive genes, thereby tightening junctional complexes and reducing permeability. In active CD, where butyrate-producing microbes are often depleted, reduced PPARγ activity in epithelial cells may contribute to barrier defects and increased translocation of luminal antigens [20]. This example illustrates how microbial metabolites, PPAR signaling, and immune activation form a triad critical to gut homeostasis. In summary, CD can be viewed as a state of pathologic immunometabolism, and PPARs represent nodal points in the network of metabolic and inflammatory pathways. We next examine each PPAR isoform’s specific roles in the context of CD.
PPARγ: MODULATING INFLAMMATION, BARRIER FUNCTION, AND FIBROSIS
PPARγ is the most extensively studied PPAR isoform in IBD and is highly expressed in colonic epithelial cells, adipocytes, and immune cells of the gut mucosa [21]. It functions as a master regulator of adipogenesis and has potent anti-inflammatory properties in immune cells. PPARγ’s role in CD is multifaceted, affecting immune cell polarization, cytokine responses, intestinal barrier maintenance, and fibrotic remodeling.
1. Regulation of Mucosal Immunity
PPARγ serves as an important brake on inflammatory myeloid cells. In macrophages, ligand-activated PPARγ trans-represses inflammatory gene expression–it can interfere with NF-κB and signal transducer and activator of transcription 1 (STAT1) signaling and promote an alternative activation state (M2) characterized by secretion of interleukin (IL)-10 and transforming growth factor β (TGF-β) rather than TNF-α and IL-12 [22,23]. In vivo evidence comes from murine IBD models: mice engineered to lack PPARγ in myeloid cells develop markedly exacerbated colitis with high levels of IFN-γ, enhanced expression of Toll-like receptor (TLR) co-stimulatory molecules, and an accumulation of inflammatory Ly6Chi monocytes [24,25].. Similarly, T cell-specific PPARγ knockout leads to accelerated colitis, with increased Th1/Th17 cytokines (IL-6, IL-1β) and loss of regulatory T cells [26,27]. These findings demonstrate that PPARγ in both innate and adaptive immune compartments restrains pathogenic inflammation in the gut. Mechanistically, PPARγ activation in T cells has been linked to suppression of SOCS3 and NF-κB–dependent apoptotic pathways, as well as preservation of FoxP3+ regulatory T cells [11,26]. Thus, PPARγ acts as an immunoregulatory factor, helping to maintain tolerance to commensals and preventing overactive immune responses in the intestine.
2. Maintenance of Epithelial Integrity
PPARγ is expressed by intestinal epithelial cells (especially in the colon), where it contributes to barrier function and anti-inflammatory signaling. PPARγ activation promotes differentiation of goblet cells and enhances the expression of tight junction proteins, partly via upregulating genes that support mucosal repair and by transcriptional suppression of inflammatory cascades within epithelial cells. In mice with epithelial-specific PPARγ deletion, the colonic epithelium is more susceptible to injury: experimental colitis causes more severe erosions and ulceration in these mice, accompanied by greater leukocyte infiltration [28]. Interestingly, the impact of epithelial PPARγ loss on clinical colitis indices was strain-dependent in studies (significant in C57BL/6 background), but in all cases there was evidence that epithelial PPARγ helps limit inflammatory damage [28,29]. One way PPARγ might protect the epithelium is through influencing immune-epithelial cross-talk–for example, PPARγ in epithelial cells can affect the cytokine milieu (such as IL-10 levels in local lymph nodes) that in turn shapes T cell responses. In summary, PPARγ helps maintain the integrity of the gut lining, making it harder for bacteria and antigens to provoke inflammation.
3. Anti-Fibrotic Effects
CD often leads to transmural fibrosis and stricture formation due to chronic wound-healing responses. PPARγ has emerged as a negative regulator of fibrogenesis in the gut. This stems from PPARγ’s ability to antagonize TGF-β/Smad signaling, the central pathway driving collagen deposition and myofibroblast activation. Indeed, PPARγ agonists inhibit the differentiation of intestinal fibroblasts into collagen-secreting myofibroblasts in vitro [22,30,31]. In other organs, PPARγ ligands have been shown to upregulate anti-fibrotic genes (e.g., matrix metalloproteinases) and downregulate collagen I, and similar mechanisms likely apply in intestinal fibrosis [32]. In a murine model of chronic TNF-driven ileitis, PPARγ activation was found to reduce fibrotic stricture severity by suppressing profibrotic gene expression (such as α-smooth muscle actin and collagen) [33,34]. Clinically, while anti-fibrotic therapy in CD remains an unmet need, these insights position PPARγ as a promising target for preventing or treating strictures. It is notable that standard IBD drugs 5-aminosalicylic acid (5-ASA) compounds activate PPARγ–this is thought to contribute to their anti-inflammatory effect, though 5-ASA alone does not reverse established fibrosis [35,36]. A specially designed 5-ASA derivative (GED-0507, a partial PPARγ agonist) showed anti-fibrotic potential in preclinical studies, but a clinical trial in CD strictures was halted due to recruitment issues [11,33].
4. Evidence in IBD Patients
Translational studies provide hints that PPARγ activity is perturbed in IBD. In ulcerative colitis (UC), PPARγ expression is markedly diminished in inflamed colonic mucosa–one landmark study showed PPARγ mRNA and protein levels in UC patient biopsies were drastically lower than in healthy controls (and even lower than in CD biopsies) [5,37]. This finding aligns with clinical observations that PPARγ agonists (like rosiglitazone) have moderate efficacy in UC. In CD, the reduction of PPARγ appears more nuanced. Several studies have reported that colonic PPARγ mRNA is significantly downregulated in both active CD and UC [38-40]. Another cohort study found that PPARγ levels in non-inflamed areas of CD patients were relatively preserved, and that PPARγ expression did not correlate with CD severity or location, in contrast to UC where it tracked disease activity [39]. These data suggest that while PPARγ is involved in CD pathogenesis, its impairment is less uniform than in UC. Genetic studies echo this pattern: the common functional variant PPARG Pro12Ala (rs1801282), which reduces PPARγ activity, is linked with susceptibility to UC but less associated to CD [41,42]. The lack of a strong genetic association in CD implies that PPARγ dysfunction in CD is likely context-driven (e.g., due to inflammation or microbial products) rather than primary [11]. Importantly, even if not a primary risk gene, PPARγ remains a critical node that can be therapeutically leveraged to modulate downstream inflammation.
5. Summary
In summary, PPARγ in the gut orchestrates a wide array of protective functions: it tempers innate and adaptive immune activation, bolsters the epithelial barrier, and counteracts fibrosis. Insufficient PPARγ activity–whether through genetic predisposition, inhibitory post-translational modifications, or overwhelming inflammatory signals–can remove these brakes, exacerbating the chronic inflammation of CD. The therapeutic implications of this are discussed later; notably, PPARγ agonists are being explored as a means to reinforce these endogenous anti-inflammatory pathways in IBD.
PPARα: INTEGRATING LIPID METABOLISM WITH MUCOSAL IMMUNITY
PPARα is classically known for its role in hepatic lipid oxidation and fasting metabolism, but it is also expressed in the gastrointestinal tract and immune cells where it has significant immunomodulatory effects. In the small intestine, PPARα is present at high levels in the duodenum/jejunum and in various hematopoietic cells including monocytes, macrophages, and dendritic cells [43]. PPARα activation drives transcription of genes for fatty acid β-oxidation (e.g., acyl-CoA oxidase, CPT1) and simultaneously exerts anti-inflammatory actions [44]. In CD, where an imbalance of pro- and anti-inflammatory lipid mediators is evident, PPARα plays a pivotal regulatory role.
1. Host Defense and Tolerance to Microbiota
Elegant studies have shown that PPARα is indispensable for maintaining immune homeostasis in the gut in the face of the microbiota. PPARα-knockout mice exhibit an exaggerated inflammatory reaction to commensal bacteria, resulting in spontaneous or more severe induced colitis [45-47]. This dysregulated response is partly due to PPARα’s role in constraining Th1/Th17 polarization–PPARα-/- mice have an expansion of Th1 and Th17 cells in the colon, along with higher levels of pro-inflammatory cytokines, which can be ameliorated by antibiotic depletion of the microbiota. One critical cytokine influenced by PPARα is IL-22, produced by innate lymphoid cells (ILC3) and Th22 cells. IL-22 is essential for epithelial barrier integrity and antimicrobial peptide production. In PPARα deficiency, IL-22 levels are reduced, compromising epithelial defense [17]. Thus, PPARα helps calibrate the mucosal immune system’s interaction with gut bacteria–it promotes tolerance and balanced immune responses, preventing the overactivation that characterizes IBD.
2. Inflammatory Pathway Modulation
At the molecular level, PPARα activation directly antagonizes key inflammatory signaling pathways. PPARα can physically interact with transcription factors like NF-κB p65 and AP-1 (c-Jun), acting as a transcriptional sink that blunts their ability to induce pro-inflammatory genes [48,49]. For instance, PPARα agonists suppress IL-6 and TNF-α production in activated monocytes and adipocytes by these transrepression mechanisms [50]. PPARα also facilitates the catabolism of inflammatory lipid mediators [6]. In PPARα-null mice, this catabolic pathway is absent and LTB4-driven neutrophilic inflammation is unchecked–indeed, PPARα-/- mice cannot efficiently resolve inflammation mediated by LTB4 and related mediators [51]. Furthermore, PPARα suppresses Th1 differentiation by downregulating T-bet (the master transcription factor for Th1) via inhibition of p38 mitogen-activated protein kinase (MAPK) phosphorylation [52]. Through such mechanisms, PPARα activation broadly attenuates both innate and adaptive inflammatory circuits that are active in CD.
3. Effects on Epithelial Cells and Barrier
While PPARα is less abundant in colonic epithelial cells than PPARγ, it is present in small intestinal epithelium and may contribute to barrier function indirectly. PPARα activation in macrophages and ILC3 leads to higher IL-22, which, as noted, strengthens the epithelial layer by inducing antimicrobial peptides and mucins [53]. Additionally, some metabolites that activate PPARα have been shown to improve epithelial integrity. Palmitoylethanolamide (PEA), a naturally occurring fatty acid ethanolamide and PPARα agonist, is elevated in inflamed intestinal tissues, perhaps as an endogenous protective response [54]. Supplementation with PEA in mice reduced experimental colitis severity and improved gut permeability [55]. Notably, PEA’s anti-inflammatory benefit was lost if PPARα was pharmacologically or genetically blocked, confirming that PPARα mediates a significant part of PEA’s effect [56,57].
4. CD and PPARα in Humans
Similar to PPARγ, PPARα-related pathways are perturbed in IBD patients. Integrative-omics analyses have identified that genes under PPARα regulation are downregulated in IBD mucosa compared to healthy mucosa [3]. This likely reflects the inflammatory milieu down-modulating metabolic genes. Clinically, indirect evidence points to PPARα’s importance: for example, therapy with statins (HMG-CoA reductase inhibitors that also upregulate PPARα expression in liver and macrophages) has been associated with reduced risk of developing CD in epidemiological studies [52,58]. Moreover, in patients with established IBD, those on statins have shown decreased progression to surgery, hinting at a beneficial modulation of disease course [59]. While confounding factors exist, these observations align with the idea that PPARα activation exerts anti-inflammatory and possibly anti-fibrotic effects in CD.
5. Preclinical Therapeutic Studies
PPARα agonists (fibrate drugs) have been tested in animal IBD models with promising, though sometimes conflicting, results. In IL-10 knockout mice (a spontaneous colitis model marked by Th1/Th17 excess), the PPARα agonist fenofibrate significantly reduced colonic inflammation, lowering IFN-γ and IL-17 levels and ameliorating histopathology [60]. This suggests activating PPARα can rein in pathogenic T cell responses. Conversely, a study in acute dextran sulfate sodium (DSS) colitis reported that fenofibrate worsened inflammation and epithelial injury via PPARα-dependent changes in lipid metabolism (e.g., altered ceramide/sphingolipid levels leading to epithelial cell necrosis) [61]. The discrepancy likely owes to differences between chronic versus acute models and highlights that PPARα’s effects might vary with context (timing, cellular target, and presence of certain lipids). Nonetheless, the overall evidence supports an anti-inflammatory role for PPARα, and interest has translated to clinical trials: fibrates are currently being repurposed in early-phase trials for UC (as adjunct therapy), and similar approaches may extend to CD if safety and efficacy signals are positive [62]. Importantly, DSS results are a proxy for IBD but not specific to CD pathology. Further studies using CD models demonstrating transmural inflammation (e.g., IL-10–/–, SAMP1/YitFc, TNFΔARE mice) are warranted to confirm potential translation of PPAR-based interventions to CD.
6. Summary
In conclusion, PPARα serves as an important immunometabolic checkpoint in the gut. It connects the sensing of nutritional and microbial-derived lipids to appropriate immune responses– promoting lipid catabolism and dampening excessive inflammation. In CD, enhancing PPARα activity represents a logical strategy to restore metabolic-immune balance, by clearing pro-inflammatory lipid mediators, bolstering epithelial defenses, and limiting pathogenic T cell responses. Any future therapy targeting PPARα will need to carefully navigate its complex biology (to avoid unwanted metabolic side effects), but the potential to “reset” mucosal immunity via metabolic modulation is a compelling avenue in IBD research.
PPARβ/δ: EMERGING INSIGHTS INTO INTESTINAL HOMEOSTASIS
PPARβ/δ, also referred to as PPARδ, remains the least explored of the PPAR isoforms in the context of CD, yet emerging research highlights its significant influence on intestinal homeostasis and potential relevance to CD pathology. PPARδ is expressed broadly, including in colonic epithelial cells, immune cells, and even Paneth cells of the small intestine [45]. It is a potent regulator of processes like fatty acid metabolism and cellular differentiation. While much attention has focused on its roles in metabolic disorders and cancer, its contributions to gut physiology are now coming into focus. Below, we explore PPARδ’s multifaceted roles in intestinal immunity, epithelial function, and T cell metabolism, alongside considerations for its therapeutic potential in CD.
1. Macrophage Polarization
PPARδ plays a nuanced role in regulating macrophage behavior, distinct from the predominantly anti-inflammatory effects of PPARα and PPARγ. Its impact on macrophage polarization depends on the cellular context and ligand activation. When activated by agonists, PPARδ can suppress pro-inflammatory cytokine release by disrupting its interaction with the transcriptional repressor B-cell lymphoma 6 (BCL-6). In its unliganded state, PPARδ associates with BCL-6 to inhibit anti-inflammatory gene expression, but ligand binding releases this suppression, allowing PPARδ to curb inflammatory pathways [63]. Additionally, CD137 signaling also induces M2 polarization through the STAT6/PPARδ pathway [64].
2. Paneth Cell Function and Microbiota Composition
One of the most intriguing roles of PPARδ is in Paneth cells, the specialized epithelial cells at the base of small intestinal crypts that secrete defensins and shape the microbiome. CD (particularly ileal CD) is associated with Paneth cell dysfunction and reduced antimicrobial peptide secretion, leading to dysbiosis. One study showed that PPARδ is a key regulator of Paneth cell differentiation via interactions with the Hedgehog signaling pathway [65]. Mice lacking PPARδ had significantly fewer Paneth cells and diminished expression of defensins. Consequently, these PPARδ-deficient mice harbored an altered gut microbiota [65,66]. Given that ileal CD is characterized by defective Paneth cells and an expansion of adherent invasive bacteria, PPARδ loss could be a contributing factor to this phenotype. Conversely, ensuring adequate PPARδ activity might preserve Paneth cell numbers and their microbial control function, thereby preventing dysbiotic triggers of inflammation.
3. Metabolic Reprogramming of T Cells
PPARδ has been implicated in the metabolism of T lymphocytes as well. Memory CD8+ T cells, for example, rely on fatty acid oxidation for their long-term persistence. PPARδ is reported to promote the switch from glycolysis to oxidative metabolism during the formation of memory T cells. It can suppress anaerobic glycolysis in activated T cells, thereby favoring a metabolic state that is less inflammatory and more conducive to longevity and immune regulation [67,68]. In CD, where a chronic inflammatory environment may skew T cells towards continuous effector activity (and thus glycolytic metabolism), PPARδ activation might push some of these cells toward a memory or regulatory phenotype by altering their metabolic programming. Additionally, PPARδ in mesenchymal stem/stromal cells has been linked to the regulation of Th17 responses via metabolic effect [69] though this is an emerging area of study.
4. Therapeutic and Cautionary Notes
Unlike PPARα and PPARγ, no PPARδ-targeted therapy is currently in use for IBD. In fact, full agonists of PPARδ (like GW 501516) have raised concerns after causing tumors in rodent studies, halting their clinical development for metabolic diseases. PPARδ’s pro-proliferative effects in certain contexts (e.g., promoting angiogenesis and cell survival in colorectal cancer models) warrant caution [70]. CD patients already carry an elevated risk of colorectal cancer due to chronic inflammation, so any intervention that broadly activates PPARδ would need careful evaluation for cancer risk. On the other hand, selective modulation of PPARδ in immune or Paneth cells might be beneficial. For instance, strategies to boost PPARδ in the intestinal epithelium (without systemic exposure) could enhance barrier defense against bacteria without significant oncogenic risk. An interesting development in another field is the drug seladelpar, a PPARδ agonist tested in primary biliary cholangitis, which appeared safe and effective in phase III trials (no cancers observed over a limited period) [71]. This suggests that with proper targeting and dosing, PPARδ agonism might be harnessed therapeutically. Any such approach in CD would require ensuring that benefits (e.g., restoring Paneth cell function, reducing inflammation) outweigh potential long-term risks.
5. Summary
In summary, PPARβ/δ occupies a unique niche in intestinal homeostasis: it influences macrophage activation, supports Paneth cell-dependent microbial balance, and adjusts T cell metabolism. Its role in CD is less well defined than PPARα/γ, but emerging evidence indicates that a deficiency in PPARδ activity could contribute to microbial dysbiosis and perhaps sustained inflammation in CD patients. More research is needed to clarify whether PPARδ could be a safe therapeutic target or biomarker in IBD. For the remainder of this review, our focus will return to the more immediately translational aspects of PPARα and PPARγ in CD, particularly how we can leverage these pathways for treatment.
CROSSTALK WITH MICROBIOTA, ADIPOSE TISSUE, AND VIRUSES IN PPAR SIGNALING
The activity of PPAR pathways in CD is not only determined by host genetics and cells-intrinsic factors, but also by external and microenvironmental influences. Gut microbes, mesenteric adipose tissue, and viral infections can all modulate PPAR signaling, thereby influencing disease outcomes.
1. Gut Microbiota and PPARs
The intestinal microbiota provides ligands and signals that modulate PPAR activity. Beneficial commensal bacteria produce SCFA like acetate, propionate, and butyrate, which, as discussed, can activate PPARγ in colonocytes and macrophages. By upregulating PPARγ, these microbial metabolites help maintain an anti-inflammatory tone and reinforce the mucosal barrier [72]. When dysbiosis occurs in CD (often a decrease in SCFA-producing Clostridia and an increase in proinflammatory pathobionts), the supply of these PPAR-activating metabolites dwindles. This may lead to reduced PPAR signaling and thereby less restraint on inflammation. On the flip side, certain microbial components drive inflammation that inhibits PPAR function. For example, bacterial lipopolysaccharide through TLR4 activation triggers pathways (MAPK, NF-κB) that can phosphorylate or otherwise impair PPARγ’s transcriptional activity [73]. In IBD patients, increased TLR4 signaling in active disease correlates with decreased PPARγ expression in the colon [74]. There is also evidence of a direct microbiota-PPAR interface: PPARα-deficient mice have an expansion of bacteria that incited colitis, whereas activating PPARα leads to tolerance of microbiota and prevention of dysbiosis-driven inflammation [75,76]. Intriguingly, some bacteria might actively exploit PPAR pathways; one report showed that Enterobacteriaceae (a family often overgrown in CD dysbiosis) can flourish if PPARγ signaling in epithelial cells is suppressed, whereas robust epithelial PPARγ activation can inhibit the bloom of these pro-inflammatory bacteria [75]. In summary, a healthy microbiome likely promotes PPAR activity (through metabolites and low-level tonic signals), and in turn PPARs help maintain a balanced microbiome–a positive feedback loop that, when broken, contributes to IBD.
2. Mesenteric Adipose Tissue (“Creeping Fat”)
CD uniquely features hypertrophy of mesenteric fat wrapping around the inflamed intestine. This creeping fat is not merely a side effect but actively participates in immune regulation. Adipocytes and stromal cells in creeping fat secrete a host of cytokines and adipokines: for instance, leptin (pro-inflammatory, promoting Th1 responses and fibrogenesis) is elevated in CD fat, whereas adiponectin (usually anti-inflammatory) may be dysregulated [77,78]. PPARγ is the master regulator of adipocyte differentiation and function; thus, it is highly relevant in creeping fat biology. In fact, single-cell RNA-seq has identified cell subsets in CD mesenteric fat with upregulated PPARγ signaling, particularly in a subset of preadipocyte/stromal cells that co-express genes for lipid metabolism and antimicrobial defense.16 This suggests creeping fat might mount a PPARγ-driven response to help contain bacterial spread from the intestine (acting as an immunometabolic “firewall”). PPARγ activation in adipose tissue tends to induce adiponectin and suppress leptin, skewing towards anti-inflammatory adipokine profiles. Consistently, thiazolidinedione PPARγ agonists increase adiponectin levels systemically and could potentially do so in mesenteric fat, thereby mitigating local inflammation. Moreover, creeping fat produces PEA and other PPARα ligands in situ [79,80], which may diffuse into the intestine and dampen inflammation. However, if PPAR signaling in creeping fat is insufficient or becomes aberrant, the fat may become a chronic source of inflammation and fibrosis. Leptin from PPARγ-deficient adipocytes, for example, can drive macrophages toward collagen-producing, TNF-secreting phenotypes that exacerbate strictures [81]. Therefore, maintaining normal PPAR function in mesenteric fat is likely important for its proposed “shielding” role in CD. This interplay is complex: creeping fat can be viewed as both a marker of severe CD and an effort by the body to localize disease; PPARs within that fat determine whether it is friend or foe to the intestine.
3. Viral Interactions
Viral infections have been proposed as environmental triggers or exacerbating factors for IBD. Certain viruses can modulate host PPAR pathways, thereby influencing inflammation. For example, influenza virus has been shown to deliberately downregulate PPARγ in alveolar macrophages, causing an exaggerated inflammatory response (a “cytokine storm”) [82]. In that context, treating infected mice with a PPARγ agonist blunted harmful inflammation without impairing viral clearance. While the lung is a different organ, similar principles may apply in the gut: a viral gastroenteritis could transiently suppress PPARγ or PPARα in intestinal immune cells, lowering the threshold for a CD flare. Notably, type I interferons produced during viral infection can inhibit PPARα’s lipid metabolic genes (since interferon signaling shifts cell metabolism toward an antiviral state), which might curtail PPARα’s anti-inflammatory effects during and after the infection. There is also evidence that some viral proteins interact with PPARs; for instance, human immunodeficiency virus type 1 (HIV-1) gp120 was found to influence PPARγ activity in microglia, promoting inflammation [83]. In the gastrointestinal realm, norovirus is temporally linked to triggering flares in CD patients, especially those with genetic autophagy defects. It is conceivable that noroviral infection of intestinal immune cells could interfere with PPARγ, compounding inflammation. On a more positive note, PPAR agonists have shown antiviral benefits in some studies: PPARγ activation can promote barrier integrity during viral infection of the gut. A striking example comes from simian immunodeficiency virus-infected macaques (a model of HIV gut pathology)– administration of a cannabinoid Tetrahydrocannabinol (THC), which engages PPARγ, was found to improve intestinal epithelial integrity and reduce microbial translocation in the infected monkeys [84]. This suggests that enhancing PPARγ during chronic viral infection protects the gut lining and limits immune activation. In summary, viruses can tip the balance of PPAR signaling to favor inflammation, and in such cases PPAR activation could serve as an adjunctive strategy to maintain remission in CD patients prone to viral reactivations.
4. Summary
In essence, PPAR pathways in CD are dynamically influenced by the microbial and viral milieu and by the metabolic signals from adjacent tissues like fat. Understanding these interactions is crucial because they may explain fluctuations in disease activity and responses to therapy. For instance, a patient’s diet (affecting microbiota and metabolites) or intercurrent viral infections might change PPAR activity and thus the effectiveness of a PPAR-targeted treatment. It also opens the door to combination interventions–for example, using prebiotics or probiotics to boost PPAR agonist availability (such as butyrate producers) alongside pharmacologic PPAR activators. The complexity of these networks underscores that successful modulation of PPARs in CD may require a holistic approach, addressing not only the receptor and its ligands but also the environment that feeds into this signaling system.
THERAPEUTIC IMPLICATIONS: PPAR-TARGETED INTERVENTIONS IN CD
Given their significant roles in regulating inflammation and metabolism, PPARs have attracted considerable interest as therapeutic targets in IBD. Both synthetic ligands (drugs developed for other indications) and natural compounds that activate PPARα or PPARγ are being repurposed or optimized for IBD treatment. Synthetic agents like thiazolidinediones (pioglitazone, rosiglitazone, troglitazone) activate PPARγ to reduce pro-inflammatory cytokines and NF-κB signaling, with promising preclinical and early clinical data. PPARα agonists (e.g., fibrates) and dual agonists enhance fatty acid oxidation and suppress inflammation but require careful use due to metabolic risks. Although PPARδ agonists are not yet used clinically due to safety concerns, indirect activation via exercise or partial modulators may offer future potential. Natural compounds—such as omega-3 fatty acids, curcumin, resveratrol, and fiber-derived butyrate—modulate PPAR activity and show anti-inflammatory and gut barrier-enhancing effects in models of colitis. Table 2 reviews the current state of PPAR-directed therapies and their mechanisms of action in the context of preclinical models of IBD such as DSS-induced colitis [33,85-101]. It is important to note that DSS colitis is largely confined to the colon and causes superficial mucosal inflammation, whereas CD often features transmural inflammation, patchy (“skip”) lesions, and frequent ileal involvement, which DSS does not replicate. Notably, DSS-induced inflammation is driven by epithelial injury and innate immune activation, with minimal adaptive (T-cell) priming, and granulomas or fistulas typical of CD pathology do not occur in DSS models. These differences mean that findings from DSS models may not fully translate to CD. For example, PPAR-targeted therapies that show efficacy in DSS colitis might behave differently in a CD-like immune milieu. Indeed, the same PPAR agonist can yield opposite outcomes in different models: fenofibrate (a PPARα agonist) improved chronic Th1-driven colitis in IL-10 knockout mice (a CD-like model) but actually exacerbated acute DSS colitis via altered lipid metabolism and necrosis pathways [60,61]. This underscores while DSS studies provide valuable insights, their relevance to CD must be viewed with caution, given the stark pathophysiological differences.
The Current State of PPAR-Directed Therapies and Their Mechanisms of Action in the Context of Crohn’s Disease
1. Mechanistic Considerations and Personalized Therapy
The therapeutic exploitation of PPARs in CD raises the question of patient selection and personalization. Not all patients may equally benefit from PPAR modulation. Potential factors to consider:
• PPAR expression and activation status: Some patients, especially those with long-standing inflammation, might have profoundly low PPARγ expression in their intestinal tissue (as seen in subsets of IBD patients) [39]. These individuals could be ideal candidates for PPARγ augmentation therapy, since their baseline anti-inflammatory checks are blunted. On the other hand, patients whose disease is primarily driven by pathways unrelated to PPAR (e.g., IL-23/Th17 axis overwhelming everything) might not respond as well to PPAR agonists. Molecular profiling of a biopsy – looking at PPARα/γ target gene expression–could serve as a biomarker of an ongoing PPAR activity. Low PPAR target gene signature might predict a more robust response to a PPAR agonist (because there is more “room” to activate those pathways).
• Genetic polymorphisms: PPARγ Pro12Ala polymorphism and possibly other variants could influence individual responses [41]. While Pro12Ala is not common in CD, if present it results in a less active PPARγ. Paradoxically, one might think patients with this variant would respond even better to PPARγ agonists (as pharmacologic activation might compensate for genetic hypofunction). Conversely, those with inherently hyperactive PPAR variants might not need additional activation. Beyond PPAR genes themselves, polymorphisms in PPAR co-regulators (like PGC1α, or corepressor genes) or upstream signals (like fatty acid binding proteins that deliver ligands to PPAR) could also modulate efficacy. As pharmacogenomic research in IBD advances, we may identify a panel of gene markers that predict who will benefit from PPAR-targeted therapy.
• Disease location and behavior: It is conceivable that colonic-predominant CD might respond differently to PPARγ agonists than small-bowel CD. PPARγ is more highly expressed in the colon, and agents like 5-ASA (a PPARγ activator) work in UC (a colonic disease) but not reliably in small-bowel CD. For small intestine disease, PPARα (abundant in ileal enterocytes and liver) might be more relevant–for example, patients with fistulizing ileal CD might benefit from PPARα-driven improvements in barrier function and bacterial clearance. Likewise, a fibrostenosing phenotype might particularly merit PPARγ therapy for its anti-fibrotic effects, whereas an inflammatory phenotype might benefit from both PPARα and PPARγ activation to quell inflammation.
• Microbiome composition: The baseline microbiota might also guide therapy. A patient whose microbiome is rich in butyrate producers (indicating good natural PPARγ ligand availability) might not need as much PPARγ agonist drug, whereas someone with a dysbiotic, SCFA-depleted microbiome might be a candidate for intensive PPARγ activation (and possibly simultaneous microbiota restoration). There is an intriguing possibility of using microbiome metabolites as surrogate markers for PPAR engagement: e.g., measuring fecal SCFA or lipid mediator levels could reflect how robustly PPAR pathways are being stimulated in the gut.
Looking ahead, a personalized medicine approach for CD could involve stratifying patients by such biomarkers and tailoring a regimen that includes PPAR modulators. For instance, a young adult patient with moderate colonic CD, low PPARγ expression on biopsy, and creeping fat seen on magnetic resonance imaging (suggesting active adipose involvement) might receive a PPARγ agonist plus dietary supplementation (like curcumin and omega-3), on top of standard immune-suppressive therapy, aiming for both inflammation control and fibrosis prevention. On the other hand, an older patient with primarily ileal disease and a history of cardiovascular disease risk (where thiazolidinediones are relatively contraindicated) might be directed more towards a PPARα-focused intervention (like a trial of fenofibrate, given its dual benefit on lipids and inflammation) if appropriate.
2. Translating PPAR Agonist Benefits from Cholestatic Liver Diseases to CD
The successful application of PPAR agonists in cholestatic liver diseases provides a compelling rationale for exploring their use in CD. The anti-inflammatory and anti-fibrotic properties of PPARα and PPARγ agonists observed in cholestatic liver diseases could similarly attenuate intestinal inflammation and fibrosis in CD [102,103].
Moreover, the interplay between mesenteric adipose tissue and intestinal inflammation in CD parallels the role of adipose tissue in primary biliary cholangitis and primary sclerosing cholangitis, where PPAR agonists regulate adipokine secretion and inflammatory responses [103]. Additionally, the safety and tolerability of PPAR agonists as shown in studies on cholestatic liver diseases support its potential trial in CD [104,105]. However, despite the promising short-term biochemical responses observed with newer selective PPAR agonists like elafibranor and seladelpar, long-term efficacy and safety profiles remain areas requiring further investigation [106].
Most PPAR agonists share lipid-binding moieties that facilitate receptor dimerization and anti-NF-κB activity. Future studies should prioritize: (1) comparative trials of PPARα vs PPARγ agonists in CD; (2) pharmacogenomic profiling of PPAR variants; and (3) microbiota-targeted approaches to modulate endogenous PPAR ligands.
FUTURE PERSPECTIVES
Research over the past decade has solidified that PPARα and PPARγ are integral regulators of the immunometabolic disturbances in CD. They function at the intersection of metabolic and inflammatory signaling–a nexus highly relevant to a disease characterized by chronic immune activation amid environmental and dietary challenges. PPARs help govern the balance between pro- and anti-inflammatory immune cells, maintain the integrity of the gut barrier, influence the microbial ecosystem, and even modulate fibrogenesis (Fig. 1). In CD, these receptors often appear underactive or overwhelmed, evidenced by reduced expression in active disease and the exaggerated inflammation seen in PPAR-deficient models [11]. Harnessing PPAR pathways thus represents a compelling strategy to restore homeostasis.
Schematic representation of the proposed anti-inflammatory and barrier-enhancing effects of peroxisome proliferator-activated receptor (PPAR)γ agonism in the gut. Upon activation, PPARγ forms a heterodimer with retinoid X receptor (RXR), binding to peroxisome proliferator response elements and initiating transcriptional programs that (1) upregulate tight junction proteins ZO-1 and occludin, enhancing epithelial barrier integrity; (2) increase adiponectin and suppress nuclear factor kappa B (NF-κB) signaling, leading to reduced pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in mesenteric adipose tissue (MAT); and (3) promote M2 macrophage polarization and regulatory T cell (Treg) differentiation, thereby modulating immunometabolism. Most of the evidence supporting these mechanisms is derived from preclinical models and should be interpreted with caution in the context of human inflammatory bowel disease.
Therapeutically, there is now a clearer path forward for PPAR-targeted approaches in IBD. Clinical trials of PPARγ agonists, while still few, demonstrate proof-of-concept that enhancing PPAR signaling can translate into clinical improvement (as shown in UC and suggested in pilot CD studies). The ongoing development of gut-specific PPAR modulators (like MBF-118) and the exploration of dual agonists or combination treatments provide optimism that efficacy can be achieved without undue side effects. Likewise, repurposing safe existing medications (e.g., fibrates, which have decades of clinical use in metabolic diseases) for adjunct IBD therapy is an attractive low-cost avenue. Even if PPAR agonists by themselves are not sufficient to induce remission in severe CD, they could be combined with immune biologics to address aspects those biologics do not–for example, using a PPARγ agonist alongside an anti-TNF agent might synergistically reduce inflammation and at the same time promote mucosal healing and reduce fibrosis, ultimately improving long-term outcomes.
Moreover, the interplay between gut microbiota and PPARs opens new therapeutic concepts: fostering a microbiome that naturally activates PPARs could be a gentle way to keep inflammation at bay. This might involve diet plans or next-generation probiotics engineered to secrete PPAR-activating metabolites in the intestine. Similarly, understanding PPARs’ role in mesenteric fat may inspire therapies aimed at “reprogramming” creeping fat from a pro-inflammatory tissue to a healing one–perhaps by local PPARγ stimulation to increase anti-inflammatory adipokine release.
Of course, challenges remain. Much of the current mechanistic understanding of PPAR signaling in IBD is derived from in vitro models and animal studies, and thus, its translational relevance to human disease must be interpreted with caution and validated in robust clinical trials. Additionally, PPAR-targeted drugs must be fine-tuned to avoid unwanted systemic effects. Long-term safety data in the context of IBD (where patients may be young and on therapy for life) will be needed. Also, CD is heterogeneous; PPAR modulation may dramatically help some patients but be less effective in others, so identifying predictors of response is crucial. As we accumulate more clinical trial data and real-world experiences, these questions will be answered.
In conclusion, the role of PPARs in CD exemplifies the growing realization that metabolic pathways are inseparable from immune regulation in chronic inflammatory disorders. PPARα and PPARγ act as guardians of gut immune homeostasis by sensing metabolic cues and appropriately tuning immune and epithelial cell function. Their impairment can tip the scales toward uncontrolled inflammation, whereas their activation can restore equilibrium. With an armamentarium of PPAR agonists (both old and new) at our disposal, gastroenterology stands at the cusp of translating these insights into novel therapies. The coming years will likely see PPAR-focused treatment strategies moving from bench to bedside–potentially inaugurating a new era of immunometabolic therapy for CD, wherein nurturing the body’s own regulatory pathways leads to deeper and more durable remission for patients. Such an approach, especially if personalized, holds promise to tackle facets of CD that remain difficult to manage with current therapies, bringing us closer to the goal of complete mucosal healing and disease modification in CD.
Notes
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Data Availability Statement
Not applicable.
Author Contributions
Conceptualization: Bashiri K. Supervision: Mattar MC, Meighani A, Mason AL. Visualization: Bashiri K. Writing - original draft: Bashiri K. Writing - review & editing: Mattar MC, Meighani A, Mason AL. Approval of final manuscript: all authors.
Additional Contributions
The authors thank the Center of Excellence for Gastrointestinal Inflammation and Immunity Research at the University of Alberta for providing critical feedback and resources for this study.