Role of AIM2 and cGAS-STING signaling in high fat high carbohydrate diet-induced gut dysbiosis associated neurodegeneration.

AIMS: Gut dysbiosis modulates CNS complications and cognitive decline through the gut-brain axis. The study aims to investigate the molecular mechanisms involved in gut dysbiosis-associated cognitive changes and the potential effects of probiotics in high fat-high carbohydrate diet-induced gut dysbiosis-associated neurodegeneration.

MATERIALS AND

METHODS

We used high fat, high-carbohydrate diet (HFHCD) and high-fat diet (HFD) to induce gut dysbiosis-associated neurodegeneration in C57BL/6 mice. IVIS imaging system and biochemical changes using ELISA measured intestinal inflammation. We used fecal samples for qPCR profiling of intestinal bacteria, and serum was used for inflammatory marker analysis using ELISA. Behavioral studies measured cognitive changes, while histopathology, immunohistochemistry, and western blot analysis of hippocampal samples measured protein changes.

KEY FINDINGS: The behavioral studies showed a significant decrease in cognitive function associated with gut dysbiosis in HFHCD and HFD animals. Gut dysbiosis was associated with intestinal inflammation and increased intestinal permeability, followed by systemic and neuroinflammatory changes. Molecular signaling studies showed the involvement of AIM2 inflammasome and cGAS-STING signaling pathways in neurodegeneration for HFHCD animals. Administration of probiotics restored the above processes and prevented gut dysbiosis-associated memory decline in mice.

SIGNIFICANCE: The study shows that alteration in microbial composition due to prolonged HFHCD could contribute to intestinal inflammation and increased intestinal permeability, facilitating the translocation of microbial toxins like LPS, leading to systemic inflammation, which eventually leads to neuroinflammation and neurodegeneration.