|
The gut is a complex environment; its mucosal barrier serves as the critical frontier between trillions of microbes and diverse food antigens and toxins within the gut lumen and the body’s immune system. The gut barrier is comprised of a single layer of epithelial cells, bound by cell-cell junctions. An impaired gut barrier, i.e., ‘leaky gut’, is believed to be a major contributor to the initiation and/or progression of systemic chronic inflammation, which in turn fuels the progression of various chronic diseases such as diabetes, atherosclerosis and arthritis.
Although their impact on cultured cell lines have been reported previously, no studies have investigated the impact of nicotine, e-cigarettes and cannabis on physiologically relevant models, and little or nothing is known regarding how these toxins impact the gut barrier. This proposal seeks to study the impact of 3 toxins-- nicotine, e-cigarettes (vaping) and cannabis on this critical frontier.
Our lab has recently described the importance of a novel molecular mechanism, a specialized signaling program called the stress-polarity signaling (SPS) pathway. This pathway acts as a S.W.A.T team that is deployed by the cells in the gut lining under duress to fortify the cell-cell junctions against stress-induced collapse. Preliminary studies with a novel stem-cell based organoid model system that recapitulates the complexity of the human gut barrier, the so-called ‘gut-in-a-dish’ have shown that nicotine, e-cigarettes and cannabis erode the integrity of the gut barrier via their ability to suppress the SPS-pathway. Going forward, the proposed studies capitalizes on the strengths and expertise of two investigators to determine the effects of the 3 toxins (alone or in combination) on the integrity of the gut barrier and the SPS-pathway using the gut-in-a-dish model. Additionally, the SPS-pathway will be assessed in the colonic biopsies from veterans undergoing routine colonoscopy who take one or more of the substances.
These studies are expected to provide mechanistic insights into the gut barrier-protective/destroying effects of nicotine, e-cigarettes and cannabis on the front line of host-defense, i.e., the gut barrier. We anticipate that this project will help improve public health guidelines by further refining cannabis-related laws and establish thresholds for smoking and vaping that is compatible with healthy living. |
