Inflammatory bowel disease (IBD) is a chronic inflammatory condition that includes ulcerative colitis (UC) and Crohn disease (CD), of which the exact etiology and pathophysiology have yet to be completely elucidated. The development of IBD is most likely multifactorial, with genetic, environmental, dietary, geographic, demographic (eg, race, age, sex, body habitus), lifestyle (eg, smoking), and medications all potentially contributing1-3.  

One key factor that has developed increasing research interest is the role of a patient’s body mass index (BMI), specifically those with obesity (BMI > 30 kg/m2), in the development of IBD. Traditionally, many clinicians associate patients with IBD with a low or normal BMI. This paradigm may be shifting, as obesity is increasingly being associated with IBD as a result of its overall pro-inflammatory effect.

Obesity has been associated with inducing multiple pro-inflammatory mediators, including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and leptin, which are secreted in increased numbers secondary to adipocyte hypertrophy.2 This increase in inflammatory mediators can be reflected in elevated levels of C-reactive protein (CRP) and fecal calprotectin (FCP).1   


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The inflammation induced by obesity may also predispose patients to increased permeability of the gastrointestinal tract (GIT) and subsequent bacterial translocation that can be a risk factor for IBD.1 Additional mechanisms linking obesity to IBD include changes in the gut microbiome, alterations in immune responses, and changes to mesenteric fat.1 Increases in “creeping fat” within the mesentery may lead to fibrosis, stricturing, and muscular hypertrophy seen in IBD.1,2

To further evaluate the potential link between obesity and the development of IBD, a group led by Chan et al recently published a pooled analysis of 5 prospective cohort studies in Clinical Gastroenterology and Hepatology.1 This study included 5 international cohorts of patients with IBD that were gathered from the Dietary and Environmental Factors IN-IBD (DEFINe-IBD) study.   

The total pooled cohort analysis included 601,009 patients from 9 countries. There was an increased risk of developing CD in patients with obesity (BMI > 30 kg/m2) with a pooled adjusted hazard ratio (aHR) of 1.34 (95% CI, 1.05-1.71; I2 = 0%) compared against those with a normal body mass (BMI 18.5-25.0 kg/m2). For every 5 kg/m2 increase in baseline BMI, there was a 16% increase in risk for CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). When the authors specifically evaluated patients in early adulthood (ages 18-20 years), there was a 22% increase in risk for CD for every 5 kg/m2 increase in BMI (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%).  Interestingly, there was no association between obesity and risk of developing UC. 

This recent study published by Chan et al in 2021 had similar findings to another study published in 2015 by Khalili et al2. This group analyzed data from the Nurses’ Health Study (NHS) II. Of the 111,498 women included, 153 were diagnosed with CD vs 229 with UC. When using BMI at age 18, women with a BMI > 30 kg/m2 had an increased risk of developing CD (age aHR, 2.48; 95% CI, 1.24-4.98) in adulthood compared against those with normal or overweight BMIs. This risk was not altered by multiple risk factors, including physical activity, smoking, and prior appendectomy (multivariate aHR, 2.33; 95% CI, 1.15-4.69).2 Similarly, this study also found no association between BMI and risk of developing UC. 

Interestingly, the European Prospective Investigation into Cancer and Nutrition (EPIC)-IBD study published by Chan et al in 2013 found contrasting results to the preceding 2 studies.3 In the EPIC study, 300,724 patients were followed prospectively. In this cohort, there were 177 patients who developed incident UC compared against 75 patients with incident CD. There were no significant associations found between increased BMI and the risk of developing UC or CD. The authors proposed that obesity may need to be evaluated using modalities different from BMI, including waist to hip ratio (WHR) and mesenteric fat, though the latter is difficult to quantitate and evaluate in routine practice. 

Some of the differences found in the preceding studies between UC and CD may be related to the deeper, transmural inflammation that is seen in CD. In addition, CD can be found anywhere within the GIT, compared with UC, which is confined to the colon, making it more susceptible to the effects of the pro-inflammatory state that obesity promotes. It can be challenging to directly compare studies evaluating obesity and the risk for IBD due to the variations in study design, relatively small sample sizes, and diverse patient populations. It is important to note in studies such as these how obesity is defined, as BMI is only one way to measure obesity in clinical studies. BMI may not be the best indicator of obesity. This is especially true in certain patients as they get older, based on changes in fat distribution. In these cases, WHR may be utilized more effectively.1 As newer studies are conducted in the future, it will be interesting to see if further pathophysiologic mechanisms will be identified, which may present new opportunities for drug targets.

References

  1. Chan SSM, Casey K, Olen O, et al. Obesity is associated with increased risk of Crohn’s disease but not ulcerative colitis: a pooled analysis of five prospective cohort studies. Clin Gastroenterol Hepatol.  Published online July 7, 2021. doi: 10.1016/j.cgh.2021.06.049
  2. Khalili H, Anathakrishnan AN, Konijeti GG, et al. Measures of obesity and risk of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2015;21(2):361-368. doi: 10.1097/MIB.0000000000000283
  3. Chan SSM, Luben RL, Olsen A, et al.  Body mass index and the risk for Crohn’s disease and ulcerative colitis: data from a European prospective cohort study (The IBD in EPIC study).  Am J Gastroenterol. 2013;108(4):575-582. doi: 10.1038/ajg.2012.453