Decoupled Signals: Exploring the Role of Microbial and Immune Signals in Regional Lipid Metabolism in the Large Intestine

Abstract

The mammalian intestine integrates dietary, microbial and immune-derived cues to regulate metabolic processes and maintain tissue homeostasis. These signals are sensed in a spatially restricted manner giving rise to region-specific functional specialization along the gastrointestinal tract. This architecture supports essential processes, including nutrient absorption and immune defense. In this work, I build on spatial transcriptomics experiments revealing spatial localization of select genes along the length of the intestine. Strikingly, many of these localization patterns were dampened in animals devoid of a microbiome. Among the genes to exhibit greater localization within the proximal region of the large intestine in the presence of the microbiome is Pparg. The gene Pparg is known to control the expression of several genes involved in lipid storage and mobilization. Here, I confirmed the proximal localization of PPARG at the level of protein expression. To identify potential regulators of this localization, I examined the effect of microbial and immune-derived signals on Pparg expression in intestinal organoids. I find that isolated microbial cues do not significantly alter Pparg expression. Similarly, I demonstrate that immune signal IL-13 is not sufficient to change Pparg expression. These findings suggest that Pparg localization is not directly driven by these candidate microbial or immune signals but rather relies on alternative, more complex mechanisms. This work provides novel insight into the establishment of regionalized metabolic functions, with implications for understanding intestinal inflammation and disease.