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

Behavioural investigation of normal and mutant human presenilin functions in caenorhabditis elegans

Presenilins are well known as sites of mutations responsible for early-onset Alzheimer's disease. The normal functions of presenilins and the mechanisms by which presenilins cause Alzheimer disease are not yet known. Conservation of cellular and molecular functions between the C.elegans and human genes makes it a powerful experimental model organism to investigate cellular mechanisms of Alzheimer's disease and neurodegenerative disorders in general. Mutations in the C.elegans presenilin1homologue, sel-12, decrease Notch signaling activity, which results in an egg-laying deficit in these animals. It has been well established that pathogenic PS1 mutations impair Notch signaling; however, in the first part of this thesis we showed that a recently discovered PS1Δs₁₆₉ human mutation rescued the egg-laying deficit associated with Lin12/Notch pathway, suggesting that in this pathogenic PS1 mutation Notch processing remained intact. In the second part of this thesis the behavioural phenotypes of a mutation in the C.elegans presenilin homologue, sel-12, were studied. Our results revealed that a mutation in the sel-12 gene causes chemotaxis deficits toward volatile and water-soluble stimuli in sel-12 mutant animals. Reintroducing the sel-12 or the wild-type human presenilin gene decreased those behavioural phenotypes, indicating that the observed chemotaxis deficits were dependent on sel-12 activity. However, rescuing with the human PS1C₄₁₀Y mutation, which has a severe effect on Notch processing, did not ameliorate the chemotaxis deficit; in contrast, rescuing with PS1Δs₁₆₉ rescued both volatile and water-soluble chemotaxis impairments suggesting that the chemotaxis deficit causing by sel-12 mutation depends on the Notch pathway.Medicine, Faculty ofGraduat

Early Life Exposure to Human Milk Oligosaccharides Reduces Allergic Response in a Murine Asthma Model

Background. Studies suggest that early-life gut microbiota composition and intestinal short-chain fatty acids (SCFAs) are linked to future asthma susceptibility. Furthermore, infancy offers a critical time window to modulate the microbiota and associated metabolites through diet-microbe interactions to promote infant health. Human milk oligosaccharides (HMOs), nondigestible carbohydrates abundant in breast milk, are prebiotics selectively metabolized by gut microbiota that consequently modify microbiome composition and SCFA production. Methods. Using a house dust mite mouse model of allergy, we investigated the impacts of early oral treatment of pups with biologically relevant doses of 2′-fucosyllactose (2′-FL) and 6′-sialyllactose (6′-SL), two of the most abundant HMOs in human milk, in amelioration of allergic airway disease severity. Results. We found that administration of 2′-FL and 6′-SL during early life reduced lung histopathology scores, circulating IgE, cytokine levels, and inflammatory cell infiltration, all hallmark symptoms of allergic asthma. HMO supplementation also increased the relative abundance of intestinal Bacteroidetes and Clostridia, known SCFA producers within the gut. Indeed, we detected increased SCFA concentrations in both the intestine and blood of adult mice who received HMOs prior to weaning. Conclusion. We propose a model in which orally administered HMOs delivered during early life shift the microbiota toward increased production of SCFAs, which dampens the allergic immune responses behind allergy and asthma. Overall, these data suggest the potential for HMO supplementation to protect infants against asthma development later in life, with possible benefits against additional atopic diseases such as eczema and food allergies