Gastroenterology Spotlight

Patients with both obesity and Crohn’s disease exhibit a decreased diversity of microorganisms and characteristic changes in bacterial phyla, as well as evidence of abnormal gut bacterial translocation and inflammation.^7,8 This translocation is an independent link to both obesity and Crohn’s disease. Central to IBD pathogenesis is mucosal barrier dysfunction, bacterial translocation, and loss of intestinal immune homeostasis.⁸ This has been linked to adipocyte and pre-adipocyte activation, with ensuing alterations in pro-inflammatory cytokine expression and immune homeostasis.⁵ Increased gut bacterial translocation is pertinent given its independent links to both obesity and Crohn’s disease; both conditions have a reduction in bacterial diversity with accompanying dysbiosis.⁷

Moreover, adipocytes stimulate activation of pro-inflammatory cells and produce mediators that increase systemic inflammation and influence mucosal homeostasis.⁹ Patients with IBD also show a unique locally restrictive form of visceral adipose tissue (VAT) — creeping fat — where mesenteric fat hyperplasia is limited to areas of inflamed bowel.¹⁰ Creeping fat is thought to be more immunologically active than other VAT, and the extent of creeping fat correlates closely with the extent of histological inflammation and degree of lymphocyte or macrophage infiltration.¹⁰

In addition to potential complementary pathologies, obesity might affect response to treatment for GI conditions, independent of drug exposure. For example, population pharmacokinetic studies of biologic agents approved for use in IBD, including infliximab, adalimumab, certolizumab pegol, golimumab, and vedolizumab, have identified high body weight as a risk factor associated with increased drug clearance, resulting in a short half-life and low trough drug concentrations.¹¹

Ultimately, obesity and IBD – a potential proxy for other inflammatory GI conditions – create a vicious cycle involving intestinal barrier dysfunction and microbiota alteration, that, in turn, leads to the onset and maintenance of mucosal and systemic inflammation. Addressing obesity is thus essential for improving GI health. Dietary interventions and weight reduction, potentially with weight loss medications such as GLP-1/GIP receptor agonists, can alleviate microbiome dysfunction and also improve metabolic parameters, which can lead to resolution or improvement of obesity-associated GI conditions.