Gut microbes shape microglia and cognitive function during malnutrition

Fecal-oral contamination promotes malnutrition pathology. Lasting consequences of early life malnutrition include cognitive impairment, but the underlying pathology and influence of gut microbes remain largely unknown. Here, we utilize an established murine model combining malnutrition and iterative exposure to fecal commensals (MAL-BG). The MAL-BG model was analyzed in comparison to malnourished (MAL mice) and healthy (CON mice) controls. Malnourished mice display poor spatial memory and learning plasticity, as well as altered microglia, non-neuronal CNS cells that regulate neuroimmune responses and brain plasticity. Chronic fecal-oral exposures shaped microglial morphology and transcriptional profile, promoting phagocytic features in MAL-BG mice. Unexpectedly, these changes occurred independently from significant cytokine-induced inflammation or blood-brain barrier (BBB) disruption, key gut-brain pathways. Metabolomic profiling of the MAL-BG cortex revealed altered polyunsaturated fatty acid (PUFA) profiles and systemic lipoxidative stress. In contrast, supplementation with an ω3 PUFA/antioxidant-associated diet (PAO) mitigated cognitive deficits within the MAL-BG model. These findings provide valued insight into the malnourished gut microbiota-brain axis, highlighting PUFA metabolism as a potential therapeutic target

Commensal microbes modulate gut-systemic impacts of malnutrition : from neurocognitive function to NAFLD

Fecal-oral contamination promotes the persistence of early-life malnutrition. Systemic consequences of malnutrition include stunting, poor immune function, metabolic shifts, and neurocognitive impairment, but the underlying pathology and precise role of fecal microbes remain largely unknown. To address these knowledge gaps, I have utilized an established murine model (MAL-BG) that combines malnutrition and iterative exposure to fecal commensals. MAL-BG mice exhibit altered behavioural and cognitive deficits—poor spatial memory and learning plasticity—putatively linked to aberrant microglia phagocytosis. Microglial alterations occurred independently from neuroinflammation and blood-brain barrier (BBB) disruption, but were linked to systemic lipoxidative stress. Fecal-oral contamination exacerbated systemic, malnutrition-induced oxidative stress within the gut, brain, and liver. Beyond oxidative damage, malnourished livers exhibit fatty liver features. Largely studied in the context of obesity, undernutrition can also trigger NAFLD (non-alcoholic fatty liver disease). A combination of histology, liver metabolomics, and microbiome analyses were performed to assess the impact of diet and gut microbes in the pathology and reversal of undernutrition-induced fatty liver. Intriguingly, fatty liver histology was only observed in the early-life, but not adult, MAL-BG model despite similar liver metabolomic profiles. These findings indicate a crucial window in early-life development that, when disrupted by nutritional deficits, likely shapes liver health trajectories. Importantly, dietary intervention largely mitigated aberrant metabolomic and microbiome features in MBG mice. Collectively, my doctoral work explores (1) gut-brain and (2) gut-liver interactions in the context of undernutrition and intervention. I anticipate my findings will not only provide valued insight into gut microbiota-systemic interactions, but also identify putative therapeutic targets to halt or reverse consequences of childhood malnutrition.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat

Adenosine A2a receptor inhibition increases the anti-tumor efficacy of anti-PD1 treatment in murine hepatobiliary cancers

Backgrounds & Aims: The efficacy of immune checkpoint inhibitor (ICI) therapy for liver cancer remains limited. As the hypoxic liver environment regulates adenosine signaling, we tested the efficacy of adenosine A2a receptor (A2aR) inhibition in combination with ICI treatment in murine models of liver cancer. Methods: RNA expression related to the adenosine pathway was analyzed from public databases. Peripheral blood mononuclear cells of 13 patients with hepatocellular carcinoma (HCC) were examined by flow cytometry. The following murine cell lines were used: SB-1, RIL175, and Hep55.1c (liver cancer), CT26 (colon cancer), and B16–F10 (melanoma). C57BL/6 and BALB/c mice were used for orthotopic tumor models and were treated with SCH58261, an A2aR inhibitor, in combination with anti-PD1 therapy. Results: RNA expression of ADORA2A in tumor tissues derived from patients with HCC was higher than in tissues from other cancer types. A2aR+ T cells in peripheral blood from patients with HCC were highly proliferative after immunotherapy. Likewise, in an orthotopic murine model, A2aR expression on T cells increased following anti-PD1 treatment, and the expression of A2aR on T cells increased more in tumor-bearing mice compared with tumor-free mice. The combination of SCH58261 and anti-PD1 led to activation of T cells and reductions in tumor size in orthotopic liver cancer models. In contrast, SCH58261 monotherapy was ineffective in orthotopic liver cancer models and the combination was ineffective in the subcutaneous tumor models tested. CD4+ T-cell depletion attenuated the efficacy of the combination therapy. Conclusion: A2aR inhibition and anti-PD1 therapy had a synergistic anti-tumor effect in murine liver cancer models. Impact and implications: Adenosine A2a receptor (A2aR)-expressing T cells in the liver increased in tumor-bearing mice and after anti-PD1 treatment. The combination of an A2aR inhibitor and anti-PD1 treatment had potent anti-tumor effects in two murine models of orthotopic liver cancer. Adenosine A2a receptor blockade promotes immunotherapy efficacy in murine models, highlighting putative clinical benefits for advanced stage liver cancer patients