The Weight of Disease — Understanding the Impact of Obesity on IBD Treatment

Vol. 30, Issue 4 (December 2025)

Chandler Shapiro, MD
Resident Physician, Internal Medicine
Rush University, Medical Center
Chicago, Illinois, USA

 

Brittany Doll, MD
Resident Physician, Internal Medicine
Rush University, Medical Center
Chicago, Illinois, USA

 

Zoë Post, MD, MSc
Advanced IBD Fellow Physician
Northwestern Medicine
Chicago, Illinois, USA

 

Veena Nannegari, MD
Assistant Professor, Department of Internal Medicine
Division of Digestive Diseases and Nutrition
Rush University, Medical Center
Chicago, Illinois, USA
 

Introduction

In recent years, there has been increasing discussion in the gastroenterology community regarding obesity and its impact on inflammatory bowel disease (IBD), specifically the intricate interplay between disease progression and treatment response. According to the U.S. Centers for Disease Control and Prevention, the prevalence of obesity rose from 30.5% between 1999 and 2002 to 41.9% between 2017
and March 2020. Meanwhile, the prevalence of severe obesity increased from 4.7% to 9.2%.¹ Similarly, the prevalence of obesity in patients with IBD has been rising over time. Recent studies indicate that 20% to 40% of patients with IBD are overweight, while 15% to 40% are classified as obese. Additionally, around 2% to 3.2% of these patients fall into the category of severe obesity.²

There has been growing concern that obesity may negatively affect the management of IBD, particularly regarding the efficacy of tumor necrosis factor alpha (TNF-α) inhibitors. It is thought obese individuals—defined as having a body mass index (BMI) >30.0 kg/m²—with IBD may be more susceptible to both primary and secondary loss of response to anti-TNF-α treatments compared to their non-obese counterparts.³ While the exact mechanism by which obesity influences anti-TNF efficacy remains unclear, it is hypothesized that excess adipose tissue leads to higher baseline inflammation due to increased cytokine production. Additionally, obesity may alter the pharmacokinetics of anti-TNF drugs, affecting their absorption and clearance.^{4, 5}

As obesity becomes more prevalent within the IBD population, it is essential to further investigate the condition’s impacts on disease pathogenesis, treatment outcomes, comorbidities, and drug effectiveness. A deeper understanding of these factors could lead to more personalized and effective management strategies for IBD patients who also struggle with obesity.

Effect of Obesity on the Pathogenesis of IBD

Adipose tissue is an essential endocrine organ that plays a key role in energy metabolism by secreting hormones, known as adipocytokines. Adipose tissue can be classified into two main types: white adipose tissue (WAT) and brown adipose tissue (BAT). While BAT is primarily involved in temperature regulation, WAT is critical for energy storage, insulin signaling, and lipid homeostasis. WAT is located both subcutaneously and viscerally, and its expansion results in obesity.⁶

Adipose tissue is dependent on oxygen for its metabolic functions; however, when adipose tissue increases in size secondary to obesity, a hypoxic microenvironment for the adipose cells can develop. This occurs largely due to an increased distance and density between the capillaries and adipose cells restricting the diffusion of oxygen. As a result, hypoxia-inducible factor 1 (HIF-1) expression is activated. Downstream effects of HIF-1 include the upregulation of genes for pro-inflammatory cytokines and subsequent proliferation of inflammatory cells.⁷ Furthermore, a chronic hypoxic state can lead to cell death, which causes macrophage activation and infiltration of the adipose tissue. Macrophages further promote the inflammatory response by secreting cytokines, including IL-6 and TNF-α.⁷ Under these mechanisms, obese individuals have a higher level of baseline inflammation and TNF-α levels; thus, obesity is considered a chronic, low inflammatory state. Supporting this conclusion is a prior study demonstrating that obese individuals have a 2.5-fold increase in TNF-α messenger RNA levels.⁸ TNF-α is a key pro-inflammatory mediator implicated in the pathogenesis of IBD and its levels within the colonic mucosa have been linked to disease activity and severity. Therefore, the elevated levels of TNF-α observed in obesity are thought to contribute to a heightened risk of developing IBD.

The Western diet, characterized by its high fat content and refined sugar, serves as a significant catalyst for the prevalence of obesity in Western countries. Growing evidence suggests that this diet is also a major environmental factor driving the development of IBD, primarily due to its impact on gut microbiota. Specifically, studies indicate that a high-fat intake promotes the growth of harmful bacteria while simultaneously reducing the population of beneficial gut bacteria. This effect is similarly observed with excessive consumption of red meat and sodium. Such an imbalance in the gut microbiome contributes to intestinal inflammation by disrupting the intestinal epithelial barrier and triggering the release of bacterial endotoxins.⁹ A 2011 systematic review highlighted that higher dietary intake of polyunsaturated fatty acids (PUFAs), omega-6 fatty acids, and meat, is associated with an increased risk of both ulcerative colitis (UC) and Crohn’s disease (CD).¹⁰ PUFAs and omega-6 fatty acids are primarily found in plant and seed oils, including safflower, soybean, and canola.

Obesity and the Western diet seem to play important roles in the pathogenesis of IBD, though their relationship is complex and bidirectional. It remains challenging to discern whether dietary factors primarily drive obesity or whether obesity itself contributes to an increased risk of developing IBD. Interestingly, research has shown that obesity is linked to an elevated risk of developing CD but not UC.^{11, 12} A pooled analysis of five prospective cohort studies identified that with every 5 kg/m² increase in baseline BMI, the risk of developing CD rose by 16%.¹²

Obesity-Related Complications in IBD

A recent cross-sectional, case-control study compared lean individuals with IBD to lean controls without IBD to further investigate the increased incidence of metabolic-associated steatotic liver disease (MASLD) in lean populations, given concerns patients are already at higher risk due to chronic systemic inflammation. The study found that the prevalence of MASLD was 21.3% in the lean IBD group, compared to 10% in the non-IBD group, after adjusting for metabolic risk factors and prior systemic steroid use. These findings suggest that IBD may act as an independent risk factor for MASLD. Additionally, the study assessed the prevalence of liver fibrosis, a known major risk factor for MASLD, and again observed a higher prevalence in the lean IBD group (4.7% vs. 0%).¹³ Comparable results were reported in a 2022 study which found IBD to be an independent predictor of MASLD and an independent risk factor for advanced liver fibrosis.¹⁴ Martínez-Domínguez et al. adjusted for prior systemic steroid use due to the role of elevated serum cortisol levels in promoting weight gain and obesity, which occurs through increased appetite, altered fat distribution, and disruptions in lipid and glucose metabolism. Given that steroids are commonly used to manage acute IBD flares and some patients become steroid-dependent, this factor further explores the risk of obesity-related complications which may already be present in lean individuals with IBD. Patients with IBD have been shown to have an increased incidence of type 2 diabetes mellitus, hyperlipidemia, obstructive sleep apnea, hypertension, atherosclerotic cardiovascular disease, and cerebrovascular accidents; therefore, it is reasonable to assume that patients with both IBD and obesity would face an even greater risk for these obesity-related complications.^15-18

Treatment of Obesity in IBD

Despite the high rates of obesity and associated metabolic syndromes seen in the IBD population, the utilization rate of anti-obesity medications remains notably low at only 2.8%.¹⁵ Stone et al. suggests that this low utilization may be linked to the prevailing belief that IBD patients are often malnourished, leading to concerns that further weight loss could be detrimental.¹⁹ However, as discussed in this article, obesity can adversely affect the management and pathogenesis of IBD and should thus be treated. One previous study investigated the impact of GLP-1 receptor agonists on the progression of IBD and found that patients treated with these medications had a lower risk of adverse clinical outcomes. These outcomes were measured by primary indicators, such as the need for oral corticosteroids, TNF-α inhibitors, hospitalizations, and IBD-related surgeries.²⁰ A comprehensive review of existing literature suggests that GLP-1 receptor agonists warrant further investigation as a potential treatment for IBD, given their ability to regulate key pathways involved in the disease’s pathogenesis such as the structure and function of tight junctions, as well as the gut microbiome.^20-23 Additionally, weight-loss medications including naltrexone, bupropion, and phentermine-topiramate have demonstrated anti-inflammatory properties that may be advantageous for individuals with IBD.¹⁹ A phase 2 clinical trial evaluating the safety and effectiveness of phentermine-topiramate in obese patients with ulcerative colitis is near completion, and further investigations into sodium-glucose linked transporter 2 inhibitors have shown promise in improving IBD in animal models.^{24, 25} If we assume that patients with IBD are malnourished, it is reasonable to anticipate adverse outcomes for those opting for more aggressive weight loss interventions, such as bariatric surgery. However, a case-control study indicated that this surgical procedure is both safe and effective for patients with IBD, as their outcomes were comparable to those of the control population.²⁶

In an effort to standardize the treatment of obesity in IBD, the European Society for Clinical Nutrition and Metabolism (ESPEN) and United European Gastroenterology (UEG) jointly developed evidence-based guidelines for the management of obesity in IBD. These guidelines emphasize the need for a multidisciplinary team to be involved in nutritional assessments, routine screenings, lifestyle modifications, pharmacological interventions, and surgical options for patients with IBD. Due to the limited number of randomized controlled trials available to inform these guidelines, an expert review panel with at least 91% consensus contributed to the development of good practice points (GPPs) to guide recommendations.²⁷

TNF-α Therapy in Obese Patients with IBD

Anti-TNF-α agents have become regarded as the mainstay treatment for moderate to severe IBD.¹ These biologic therapies take advantage of the TNF-α proinflammatory pathway by interfering with cytokine signaling and downregulation of the immune response involved in the pathogenesis of IBD. Infliximab, a monoclonal anti-TNF-α antibody, was the first biologic to obtain U.S. Food and Drug Administration (FDA) approval for IBD treatment and, given its studied clinical efficacy, it continues to be regarded as the leading biologic therapy for patients with IBD.² More recent FDA-approved anti-TNF-α agents include adalimumab and golimumab.

It has been hypothesized that observed poor treatment responses in obese individuals with IBD may be due to the “TNF sink” phenomenon.²⁸ This phenomenon involves the rapid absorption and clearance of anti-TNF, leading to a shorter half-life and lower drug concentrations in the serum. As previously stated, adipose tissue increases TNF-α concentrations and local tissue inflammation, and thus patients with obesity are thought to have significantly higher amounts of TNF-α molecules. The abundance of TNF molecules in the system rapidly depletes the serum drug concentration and, despite extensive binding of anti-TNF agents, a substantial quantity of TNF remains unbound, perpetuating a pro-inflammatory environment.^{2, 7} It is important to note, anti-TNF-α agents used for IBD follow either standardized fixed or weight-based dosing. Given the pharmacokinetics, there is likely a need for dose intensification in obese IBD patients to mitigate the “TNF sink” effect and combat low trough levels.

Conclusion

The complex relationship between obesity and IBD presents significant challenges for disease management and treatment outcomes. Obesity, with an increasing prevalence among the IBD population, appears to exacerbate disease pathogenesis by increasing baseline inflammation. It also heightens the risk of both primary and secondary treatment failure for biologic therapies through its effect on proinflammatory cytokines, complicating the therapeutic response to anti-TNF-α agents. Furthermore, IBD itself seems to elevate the risk of obesity-related comorbidities, further complicating patient care and management.

While numerous studies have explored the relationship between elevated BMI and the effectiveness of anti-TNF-α treatment, the results remain inconclusive. A 2020 pooled meta-analysis concluded that obesity increased the odds of anti-TNF-α treatment failure in UC but not CD, whereas other studies reported no significant impact on infliximab response in either condition.^{5, 29-32} Currently, the evidence is insufficient to warrant adjustments to the standard weight-based or fixed dosing guidelines for anti-TNF-α medications based on BMI. Further studies should explore potential adjustments to dosing strategies to create a tailored approach in managing IBD in the context of obesity. While treatment strategies such as pharmacological interventions and weight-loss therapies show promise, more research is needed to refine these strategies and understand their full potential in improving outcomes for these patients. Investigating the “TNF sink” phenomenon and the role of obesity-induced inflammation may offer valuable insights into optimizing treatment protocols. Ultimately, a deeper understanding of how BMI influences IBD outcomes could help create more personalized treatment approaches, improving both the quality of life and long-term health outcomes for patients affected by IBD and obesity.

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