Growth differentiation factor 15 - a new molecular target in inflammatory bowel disease: Progress and challenges

Abstract

The study by Ruiz-Malagón et al marks a significant advancement in understanding the role of growth differentiation factor 15 (GDF15) in inflammatory bowel disease (IBD). Using both in vivo and in vitro models, the researchers detected elevated circulating GDF15 levels in patients with both ulcerative colitis (UC) and Crohn’s disease (CD), and its level correlates with markers of inflammation and intestinal permeability. Utilizing colonic organoids and T84 cells, they demonstrated that GDF15 increases intestinal permeability by reducing the expression of zonula occludens-1 (ZO-1) and claudin 1. They concluded that targeting GDF15 may offer a promising strategy to preserve intestinal barrier integrity and potentially reducing immune overactivation. However, results from a small-sample sized study (CD patients 21, UC patients 18, and healthy controls 23) signals interpretation with caution. Genetic approaches are needed to validate the findings that GDF15 alters the intestinal barrier and increases permeability by decreasing the levels of ZO-1 and claudin 1. GDF15 serves as a double-edged mediator with context-dependent protective or pathogenic roles, and clarifying this duality is a critical goal for translational research. Overall, the study represents a critical step in understanding the pathogenesis of IBD, highlighting both progresses made and the work still required for clinical translation.

Key Words: Growth differentiation factor 15; Double-edged mediator; Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease

Core Tip: The study by Ruiz-Malagón et al represents an important step toward elucidating the pathogenesis of inflammatory bowel disease, suggesting that growth differentiation factor 15 (GDF15) may contribute to disease development. GDF15 functions as a context-dependent mediator with both protective and pathogenic effects, and clarifying this duality remains a key objective for translational research. Current findings, derived largely from small observational cohorts, should be interpreted with caution and require validation in larger, independent populations. Ultimately, well-designed randomized controlled trials will be essential to establish more definitive evidence.

INTRODUCTION

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGF-β) superfamily, its circulating concentration fluctuates substantially with changes in the physiological and pathophysiological conditions. GDF15 serum levels rise in response to cell stress, such as renal and heart failure, chronic liver disease, cancer cachexia, chronic inflammatory diseases, and mitochondrial diseases[1]. Many studies highlight its role in inflammation and tissue repair.

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic immune-mediated condition characterized by recurrent and remitting inflammation of the gastrointestinal tract[2]. Although the etiology and mechanism of IBD remains incompletely understood, it is broadly recognized to involve a complex interplay of genetic susceptibility, dysregulated immune responses, gut microbiota alterations, and environmental exposures[3].

PROGRESS IN GDF15

GDF15 was first identified in 1997 as macrophage inhibitory cytokine-1 for its inhibition of macrophage activity. Further, the study showed that pro-inflammatory cytokines, including interleukin (IL)-1β, IL-2, and tumor necrosis factor α, itself, could induce GDF15 expression, suggesting that GDF15 might be an autocrine signal that inhibits a pro-inflammatory response[4]. Its anti-inflammatory effect might rely on leading macrophages to M2-like polarization[5]. While several studies reported that GDF15 suppresses inflammation by impairing production of pro-inflammatory cytokines and recruitment of immune cells to the organs during sepsis[6], and it plays a protective role in inflammation-driven states and promotes survival in the settings of acute inflammation[7,8]. Some studies described GDF15 as a pathogenic factor[9,10].

Glial cell line derived neurotrophic factor (GDNF)-family receptor α-like was described in 2017 as the receptor for GDF15, it is an orphan receptor of GDNF family, with an exclusive expression in the mouse area postrema (AP) and nucleus tractus solitarii (NTS)[11]. A recent study reported that beyond the AP/NTS region, GDNF-family receptor α-like (GFRAL) immunoreactivity was observed in other brain regions as well as in peripheral tissues, including liver, small intestine, and muscle[12]. GDF15-mediated activation of GFRAL recruits the tyrosine kinase rearranged during transfection (RET) as a co-receptor, and subsequently triggers the downstream intracellular signal pathways, which are consistent with GDNF signaling[13] (Figure 1). The unique action of GDF15/GFRAL at AP/NTS neurons activates the parabrachial nucleus-central amygdala circuit, mediating food and taste aversion and driving anorexia and weight loss[14]. Thus, targeting the GDF15/GFRAL/RET signaling pathway offers a potential therapeutic opportunity for eating disorders, metabolic diseases, and cachexia associated with cancer[15-17].

Figure 1 Mechanism of growth differentiation factor 15. Growth differentiation factor 15 (GDF15) binds to its receptor glial cell line derived neurotrophic factor-family receptor α-like, which forms a signaling complex with the co-receptor rearranged during transfection on the cell membrane. Ligand-receptor engagement activates downstream intracellular signal-transduction pathways, mediating the biological effects of GDF15. IL: Interleukin; TNF-α: Tumor necrosis factor α; CDF15: Growth differentiation factor 15; GFRAL: Glial cell line derived neurotrophic factor-family receptor α-like; RET: Rearranged during transfection.

Although GFRAL has been traditionally considered brainstem-restricted, recent evidence indicates a broader distribution. Fichtner et al[12] demonstrated that GFRAL is expressed in both the brain and peripheral tissues of mice, including the small intestine. RT-qPCR, western blotting, and immunohistochemistry revealed low but detectable levels of GFRAL mRNA and protein in intestinal tissues. These findings suggest that GDF15 may exert local effects in the gut via GFRAL-dependent or alternative pathways, though the functional relevance of intestinal GFRAL remains to be elucidated.

All in all, the precise biological role of GDF15 is not fully elucidated despite its identification over 20 years ago. It acts both locally (autocrine/paracrine) and systemically (endocrine), with effects on cell differentiation, survival/apoptosis, proliferation, and also on metabolic regulation[7]. As immunoregulation disturbances are central in the pathogenesis of IBD, assessing GDF15 in IBD may reveal a promising pathway for improving the overall management of patients with this disease. Thus, several recent studies have looked at circulating GDF15 levels in IBD, and its associations with disease activity, severity, and other markers[18-23].

GDF15 AND IBD

To date, six observational studies have evaluated the role of GDF15 in IBD. Tonkic et al[18], Koureta et al[19], Kučerka et al[21], and Ruiz-Malagón et al[23] detected higher GDF15 levels in patients with both CD and UC compared to the control group, but Ramasamy et al[20] reported no difference of GDF15 levels between UC patients and healthy controls. Yamamoto et al[22] detected higher serum GDF15 levels in CD patients with low skeletal muscle index relative to CD patients with normal skeletal muscle index. Besides, Kučerka et al[21] reported significant relationships between GDF15 levels, patient age, and IL-6 levels in IBD. Koureta et al[19] also found that GDF15 levels were positively correlated with flares in CD, and GDF15 was positively correlated to IL-6 levels only in UC but not in CD. Besides, they reported that median GDF15 levels were higher in both UC and CD patients receiving azathioprine without concomitant biologic therapy. In contrast, CD patients treated with biologic agents, corticosteroids, and/or mesalazine showed comparable median GDF15 levels. No significant differences in GDF15 concentrations were observed among UC patients receiving different treatment regimens (Table 1).

Table 1 Main clinical results of the recent studies.

Ref.	Diagnosis	Number of patients (male/female)	Number of controls (male/female)	Disease status	Direction of GDF15 change	Circulating GDF15 level (pg/mL)
Yamamoto et al[22], 2022	Patients: CD with low skeletal muscle index. Controls: CD without low muscle index	33 (17/16)	45 (33/12)	In remission (CDAI: 97.6 ± 59.5 vs 93.4 ± 53.6)	↑	1511.0 ± 1646.3 vs 688.2 ± 575.3
Ramasamy et al[20], 2023	Patients: UC. Controls: Dyspepsia with no systemic inflammation	80 (48/32)	39 (23/16)	20/80 in remission (defined by Truelove-Witts criteria)	↑	576.515 (416.51-937.91) vs 520.14 (343.99-686.28)
Tonkic et al[18], 2024	Patients: IBD. Controls: Healthy volunteers	90 (53/37): CD 48, UC 42	67 (43/24)	CD in remission [CDAI: 55 (34-84)]; UC with mild disease [Mayo score: 3 (2-5)]	↑	800 (512-1154) vs 412 (407-424)
Kučerka et al[21], 2024	Patients: IBD. Controls: Individuals without any chronic inflammatory disease	100 (60/40)	50 (21/29)	In remission (defined as the resolution of abdominal pain and the resolution of altered bowel habits)	↑	751 (400-3406) vs 527 (400-1171)
Koureta et al[19], 2025	Patients: IBD. Controls: Healthy individuals	CD 122 (78/44)	44	In remission (HBI 2.1 ± 1.8)	↑	686.5 (655) vs 556 (271)
		UC 71 (46/25)	44	Mild [clinical Mayo score 3 (5)]	↑	807 (744) vs 556 (270)
Ruiz-Malagón et al[23], 2025	Patients: IBD. Controls: Healthy volunteers from the colon cancer screening program with non-pathological findings	CD 21 (10/11)	23 (12/11)	Not reported	↑	Levels of GDF15 in plasma from IBD patients were significantly increased compared to HC. When stratified, both CD and UC patients maintained significantly higher levels. Data was not reported
		UC 18 (7/11)	23 (12/11)	Not reported	↑

Crohn’s disease activity index range is divided in four categories which are: Remission (< 150), mild to moderate (150-220), moderate to severe (220-450), and severe (> 450). Mayo score: It is used to assess the severity of ulcerative colitis, a score of 0-2 indicates remission, 3-5 is mild, 6-10 is moderate, and 11-12 is severe activity. Harvey-Bradshaw index, remission is a score of 0-4, mild is 5-7, moderate is 8-16, and severe is > 16. CDF15: Growth differentiation factor 15; CD: Crohn’s disease; UC: Ulcerative colitis; IBD: Inflammatory bowel disease; CDAI: Crohn’s disease activity index; HBI: Harvey-Bradshaw index; HC: Healthy control.

CLINICAL IMPLICATIONS

Based on these findings, GDF15 might play a role in the pathophysiology of IBD. GDF15 can act as a biomarker of disease activity and severity, because it correlates with clinical activity, endoscopic severity, C-reactive protein (CRP), IL-6, hospitalization, etc., it may serve as a marker to monitor disease, predict flares or poor prognosis[18,21,22]. What worth noting is that elevated GDF15 seems to parallel elevated CRP and IL-6 in IBD patients, that could mean GDF15 is part of the response to inflammation, possibly a feedback attempt to limit damage. But direct mechanistic evidence is still limited[21]. In addition, Ruiz-Malagón et al[23] reported a positive relationship between plasma GDF15 levels and intestinal permeability by using both in vivo and in vitro models, and then utilizing colonic organoids and T84 cells, they demonstrated that GDF15 increases intestinal permeability by reducing the expression of zonula occludens-1 (ZO-1) and claudin 1. These findings suggest that GDF15 may play a pathogenic role in the pathophysiology of IBD, and that therapeutic inhibition of GDF15 could represent a potential strategy to attenuate disease activity in the future. If validated as a predictive marker for disease flare-ups or complications in IBD[18,21], GDF15 could play a pivotal role in guiding personalized therapeutic strategies and enabling earlier, more targeted interventions to enhance patient outcomes. Strategies might involve enhancing its protective functions, such as barrier preservation, mucin production, and autophagy, while mitigating any potential pro-inflammatory or harmful effects.

CONTEMPORARY CHALLENGES IN GDF15 AND IBD

Firstly, it remains unclear whether GDF15 functions merely as a biomarker, being upregulated secondary to inflammation and mucosal injury, or whether it exerts an active causal role in the pathogenesis and progression of IBD, either by exacerbating inflammation or by mediating protective, tissue-repairing effects. While the in vitro study by Ruiz-Malagón et al[23] has provided preliminary insights, the specific mechanisms by which GDF15 acts on human intestinal epithelial cells, immune cell subsets, or the gut microbiota in the context of IBD remain incompletely understood. Secondly, while GFRAL remains the only well-established receptor for GDF15, other potential targets, particularly in peripheral tissues, have been hypothesized to mediate its effects[12], it remains unclear which receptors mediate GDF15 activity within the intestinal mucosa, which cellular populations (including epithelial, immune, and stromal cells) respond to its signaling, and which intracellular pathways, such as those of the TGF-β family or nuclear factor kappa B, are engaged in mediating its local effects. Thirdly, given the limited sample sizes of the available studies, it remains to be determined whether GDF15 can predict disease flares, therapeutic response, long-term outcomes, or complications more accurately than existing biomarkers, and what diagnostic cut-offs, sensitivity, and specificity values might apply.

FUTURE DIRECTIONS

The currently available results should be interpreted with caution and validated in larger, independent cohorts. Robust and well-designed randomized controlled trials are needed to provide more convincing evidence. Besides, fecal calprotectin is a key biomarker reflecting the inflammatory burden in IBD and is considered as important as CRP and serum albumin[24]. However, recent studies have failed to demonstrate a clear association between fecal calprotectin and GDF15 levels. This may be partly due to the small sample sizes and the inclusion of patients with mild disease activity or in clinical remission, which could mask potential correlations. To clarify this relationship, future studies should incorporate disease activity, age and smoking stratification and larger, more representative cohorts. Moreover, a recent mouse study[25] demonstrated that GDF15 deficiency aggravated dextran sulfate sodium-induced mucosal injury, impaired mucus production, and altered the abundance of mucin-metabolizing bacteria, including Muribaculum intestinale, Duncaniella dubosii, Akkermansia muciniphila, and Bacteroides vulgatus. These results suggest that GDF15 is crucial for maintaining mucosal integrity and microbial homeostasis. Nonetheless, its interaction with the gut microbiota in IBD remains largely uncharacterized. As dysbiosis is a key contributor to IBD pathogenesis, elucidating the GDF15-microbiota axis may provide new insights into disease mechanisms and therapeutic targets.

This elegant study by Ruiz-Malagón et al[23] demonstrated that GDF15 increases intestinal permeability by reducing the expression of ZO-1 and claudin 1 in colonic organoids and T84 epithelial cells. ZO-1 and claudin 1 are key components of tight junctions (TJs), which play a central role in maintaining intestinal barrier integrity. However, intestinal permeability is also influenced by other factors such as mucus layer thinning, epithelial injury, apoptosis, and cellular stress. Including these additional aspects would provide a more comprehensive understanding of how GDF15 regulates epithelial barrier function. Furthermore, genetic approaches, such as gene transfection, overexpression, or knockout models, are warranted to validate the mechanistic finding that GDF15 disrupts TJs by downregulating ZO-1 and claudin 1.

COST-EFFECTIVENESS CONSIDERATIONS

A reliable assessment of cost-effectiveness requires clinical trial data and formal economic evaluation conducted in parallel with therapeutic development. At present, the cost-effectiveness of GDF15-targeted therapy for IBD cannot be determined due to the absence of phase III efficacy, safety, and pricing data. Its economic value will ultimately depend on its comparative efficacy and safety relative to existing treatments, its effectiveness in specific patient subgroups (e.g., severe or refractory cases), and its pricing strategy. Incorporating health-economic measures, such as quality of life, healthcare utilization, and biomarker data, into future clinical studies will be essential to establish a credible cost-effectiveness profile once therapeutic efficacy is demonstrated.

CONCLUSION

The study represents a critical step in understanding the pathogenesis of IBD, that is GDF15 might play a pathogenic role in IBD, highlighting both progresses made and the work still required for clinical translation. GDF15 appears to function as a double-edged mediator, capable of exerting both protective and pathogenic effects depending on the biological context, and elucidating this duality remains a central challenge in translational research.