COMBINATORIAL EFFECTS OF DIET-MICROBIOTA INTERACTIONS ON HOST METABOLISM

Metabolic diseases and colorectal cancer (CRC) are increasingly prevalent conditions influenced by complex interactions between diet, host genetics, the gut microbiota, and interorgan communication. Here, we describe findings from three studies that collectively elucidate novel mechanisms by which diet-microbiota interactions shape host metabolism, diet-host genetics shape oncological outcomes, and how colorectal tumors themselves impact systemic physiology, including brain function. In murine models, manipulation of dietary fiber and high-fructose corn syrup (HFCS) demonstrated antagonistic effects on glucose tolerance that were microbiota-dependent but independent of body weight. Through integrated microbial and metabolomic profiling, Dubosiella newyorkensis was identified as a key driver of glucose intolerance in a lipid-dependent manner. Its human homologue, Clostridium innocuum, similarly promoted glucose dysregulation and was enriched in individuals consuming low-fiber diets and at risk for diabetes. These findings highlight that specific microbiota-lipid interactions play critical roles in mediating host metabolic dysfunction. Parallel investigations into CRC revealed that dietary fiber and its microbial fermentation product, acetate, may modulate tumor biology through the host enzyme ACSS2, which converts acetate to acetyl-CoA—a substrate for lipid synthesis and histone acetylation. Loss of ACSS2 in human CRC tumors correlated with increased expression of metastasis-related genes, including those involved in epithelial-mesenchymal transition. However, dietary fiber manipulation and Acss2 loss in mouse models did not significantly impact systemic glucose metabolism or tumor burden, suggesting significant metabolic plasticity in CRC and underscoring the need to dissect context-specific dependencies. Expanding beyond metabolic and oncological endpoints, CRC was also shown to impair cognitive function in mice through non-CNS tumor effects. Cognitive deficits were found to be tumor site-specific and mediated via TRPV1-expressing peripheral neurons, indicating a novel axis of tumor-to-brain communication. These findings suggest that tumors can affect distant organ systems, such as the brain. Altogether, these studies reveal new paradigms in host-microbiota-diet interactions, metabolic regulation in cancer, and gut-brain communication. Understanding these integrative pathways may inform dietary, microbial, and pharmacological strategies for mitigating metabolic disease, cancer progression, and cancer-associated cognitive impairment.

Author dc:creator

• Sharma, Prateek, Varun

Advisors dc:contributor.advisor

• Wellen, Kathryn, E
• Thaiss, Christoph, A

• Biology
• Microbiology

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/62382

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/62382