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

University of British Columbia

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.

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2022-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76232

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/