Events

Pharmaceutical Sciences Seminar Series

How Environmental Factors Regulate Gut Innate Immunity

(Drug ACTION Specific Seminar)

• Ta-Chiang Liu, PhD
• Washington University

Gut mucosal immunity is regulated by genetic and environmental factors. While the impact of host genetics can been established by both genome-wide association studies and genetically modified animal models, the impact of environmental factors have been more difficult to delineate.

We have shown that the functional status of an intestinal epithelial cell type with innate immune function, Paneth cells, can be regulated by both host genetics and environmental triggers. In patients with inflammatory bowel disease, defective Paneth cells correlated with more aggressive disease course. Therefore it represents a model by which mechanistic interrogation is possible.

Using large cohort human samples, mouse models, and organoid culture system, we showed that consumption of western diet (WD; high fat and high fructose contents) activates bile acid signaling pathway FXR in the gut epithelium and in the phagocytes, the later of which induces type I interferon (IFN) response. The parallel FXR and type I IFN signaling impairs Paneth cell function.

We also found that in patients with Crohn’s disease, those carrying the most prevalent polymorphism (ATG16L1 T300A) and exposed to a common environmental risk factor, cigarette smoking, develop Paneth cell defects. This was recapitulated in mouse models. We further identified that this was mediated in part, by autophagy deficiency in phagocytes, which activates LRRK2 kinase. Macrophages with activated LRRK2 kinase are prone to secrete proinflammatory cytokines TNF and PAI-1 that target Paneth cells. LRRK2 kinase inhibitor, currently under development for patients with Parkinson disease (LRRK2 is a Parkinson susceptibility gene), is able to reduce the inflammation. Thus, cigarette smoking impacts multiple innate immune cell types in genetically susceptible hosts to trigger inflammation.

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