Research Review: Exploring the Molecular Links Between NAFLD and IBD

The Question

The prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with inflammatory bowel disease (IBD) can reach 59%, depending on the diagnostic criteria.^2-3

The question: Why is there such a high prevalence of NAFLD in patients with IBD?

To help answer this question, Kwon, et al. set out to answer: What are the molecular links between NAFLD and IBD?

There are interactions between IBD and metabolic disorders, and their pathology shares common features, including metabolic tissue dysregulation, inadequate immune response, and inflammation. However, the possible pathophysiologic connections between these two categories of diseases remain largely undescribed, and this holds true for the causal relationship between NAFLD and IBD.

The Idea

Multiple metabolic factors (e.g., adiponectin signaling, irisin and FGF21 regulation, sirtuin pathways,etc.) and intestinal inflammation likely contribute to the high NAFLD prevalence in IBD patients, and elucidating these causal factors could reveal key therapeutic targets.

Because endotoxemia is common to IBD and metabolic disorders, the researchers hypothesized that an impaired intestinal barrier function caused by DSS treatment triggers lipopolysaccharide (LPS)-induced systemic inflammation that could disturb energy homeostasis. With this in mind, Kwon, et al. used DSS-induced colitis mouse models to explore the molecular mechanisms driving the pathogenesis of IBD-associated NAFLD.

The researchers focused on the colitis-associated alterations in:

• Lipid metabolism in the liver and adipose tissue
• Cholesterol and bile acid metabolism in the liver
• Browning and thermogenesis in adipose tissue

The Findings

Both young (8-week-old) and old (18-week-old) mice with DSS-induced colitis displayed NAFLD phenotype including hepatosteatosis and dyslipidemia, and had a similar pathological display of disrupted tight junctions and chronic inflammation in the colon.

The results suggest that lipid metabolic dysfunction in colitis is most likely due to the overall disruption of metabolic functions such as fatty acid oxidation, lipolysis, reverse cholesterol transport, bile acid synthesis, white adipose tissue browning and brown adipose tissue thermogenesis. Most of these functions are mediated via SIRT1/PGC-1α and LXRα—which were downregulated in the liver of mice with DSS-induced colitis.

The Conclusion

Kwon, et al. identified metabolic dysfunctions in the liver and adipose tissue that potentially drives the development of NAFLD in IBD patients, progressing scientists’ understanding of the common pathogenic factors the two diseases share, which could help elucidate promising targets for the development of therapeutics and approaches for disease prevention.

Technical Highlight

After acclimation, 8-week-old mice were randomly assigned to 4 groups: 0 (negative control), 1%, 2%, and 3% (w/v) DSS-treated group. Colitis was induced by oral administration of DSS (MW 36–50 kDa) from MP Biomedicals. Mice were treated with 3 cycles of DSS for 7 days and 7 days of drinking water between each cycle. During DSS and recovery cycles, the researchers recorded body weight, stool softness, and blood in the rectum or stool on a daily basis.

Researchers can confidently induce colitis in their animal model of choice and explore key molecular mechanisms driving pathology using high-quality dextran sodium sulfate from MP Bio.