The gut–brain axis (GBA) is a biochemical link that connects the central nervous system (CNS) and enteric nervous system (ENS). Clinical and experimental evidence suggests gut microbiota as a key regulator of the GBA. Microbes living in the gut not only interact locally with intestinal cells and the ENS but have also been found to modulate the CNS through neuroendocrine and metabolic pathways. Studies have also explored the involvement of gut microbiota dysbiosis in depression, anxiety, autism, stroke, and pathophysiology of other neurodegenerative diseases. Recent reports suggest that microbe-derived metabolites can influence host metabolism by acting as epigenetic regulators. Butyrate, an intestinal bacterial metabolite, is a known histone deacetylase inhibitor that has shown to improve learning and memory in animal models. Due to high disease variability amongst the population, a multi-omics approach that utilizes artificial intelligence and machine learning to analyze and integrate omics data is necessary to better understand the role of the GBA in pathogenesis of neurological disorders, to generate predictive models, and to develop precise and personalized therapeutics. This review examines our current understanding of epigenetic regulation of the GBA and proposes a framework to integrate multi-omics data for prediction, prevention, and development of precision health approaches to treat brain disorders.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and App^NL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and App^NL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.

Mechanisms linking intestinal bacteria and neurodegenerative diseases such as Alzheimer’s disease (AD) are still unclear. We hypothesized that intestinal dysbiosis might potentiate AD, and manipulating the microbiome to promote intestinal eubiosis and immune homeostasis may improve AD-related brain changes. This study assessed sex differences in the effects of oral probiotic, antibiotics, and synbiotic treatments in the App^NL-G-F mouse model of AD. The fecal microbiome demonstrated significant correlations between bacterial genera in App^NL-G-F mice and Aβ plaque load, gliosis, and memory performance. Female and not male App^NL-G-F mice fed probiotic but not synbiotic exhibited a decrease in Aβ plaques, microgliosis, brain TNF-α, and memory improvement compared to no treatment controls. Although antibiotics treatment did not produce these multiple changes in brain cytokines, memory, or gliosis, it did decrease Aβ plaque load and colon cytokines in App^NL-G-F males. The intestinal cytokine milieu and splenocyte phenotype of female but not male App^NL-G-F mice indicated a modest proinflammatory innate response following probiotic treatment compared to controls, with an adaptive response following antibiotics treatment in male App^NL-G-F mice. Overall, these results demonstrate the beneficial effects of probiotic only in App^NL-G-F females, with minimal benefits of antibiotics or synbiotic feeding in male or female mice.

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and is a leading cause of death in the United States. Neuroinflammation has been implicated in the progression of AD, and several recent studies suggest that peripheral immune dysfunction may influence the disease. Continuing evidence indicates that intestinal dysbiosis is an attribute of AD, and inflammatory bowel disease (IBD) has been shown to aggravate cognitive impairment. Previously, we separately demonstrated that an IBD-like condition exacerbates AD-related changes in the brains of the App^NL-G-F mouse model of AD, while probiotic intervention has an attenuating effect. In this study, we investigated the combination of a dietary probiotic and an IBD-like condition for effects on the brains of mice. Male C57BL/6 wild type (WT) and App^NL-G-F mice were randomly divided into four groups: vehicle control, oral probiotic, dextran sulfate sodium (DSS), and DSS given with probiotics. As anticipated, probiotic treatment attenuated the DSS-induced colitis disease activity index in WT and App^NL-G-F mice. Although probiotic feeding significantly attenuated the DSS-mediated increase in WT colonic lipocalin levels, it was less protective in the App^NL-G-F DSS-treated group. In parallel with the intestinal changes, combined probiotic and DSS treatment increased microglial, neutrophil elastase, and 5hmC immunoreactivity while decreasing c-Fos staining compared to DSS treatment alone in the brains of WT mice. Although less abundant, probiotic combined with DSS treatment demonstrated a few similar changes in App^NL-G-F brains with increased microglial and decreased c-Fos immunoreactivity in addition to a slight increase in Aβ plaque staining. Both probiotic and DSS treatment also altered the levels of several cytokines in WT and App^NL-G-F brains, with a unique increase in the levels of TNFα and IL-2 being observed in only App^NL-G-F mice following combined DSS and probiotic treatment. Our data indicate that, while dietary probiotic intervention provides protection against the colitis-like condition, it also influences numerous glial, cytokine, and neuronal changes in the brain that may regulate brain function and the progression of AD.

Background: Previous studies have documented age‐related changes in behavior and cognitive functions and investigated the molecular changes in aging brain using inbred mouse strains such as C57BL/6, BALB/c etc. In this study using a genetically heterogenous mouse population (UM‐HET3) we investigated age‐related changes in motor and memory functions and their association with blood cell measures.Method: Both male and female UM‐HET3 mice at age of 11 months (middle‐aged) and 25 months (old) were used in this study. Complete blood count, grip‐strength, Rotarod, visual acuity, startle response, voluntary wheel running activity and contextual fear conditioning assays were performed on these mice. Further, a correlation analysis was performed on blood cells and contextual fear memory (CFM) to identify signatures associated with age related cognitive decline.Result: Our results showed significantly lower body temperature, decrease in hemoglobin, changes in blood related parameters (including RBC, hematocrit, platelets, MPV, WBC), reduced visual acuity, reduced grip strength (not normalized by BW) and impaired memory functions in older mice when compared to middle‐aged mice. We found no correlation between blood cells and CFM in middle‐aged mice, but the percentage of neutrophils (R = 0.794, p = 0.009) and lymphocytes (R = ‐0.734, p = 0.022) were found to be associated with CFM in older male mice. A reduced startle reactivity was also observed in older male and female mice which is likely to be the result of impaired hearing, although these mice were not tested for hearing loss. No statistical significance was observed in Rotarod performance and in wheel running activity when middle aged mice compared to old UM‐HET3 mice.Conclusion: Our study showed that UM‐HET3 mice exhibit age related impairment in sensory and memory functions as compared to middle aged mice. In older mice, reduced memory correlates with increased percentage of neutrophils and decreased lymphocytes in blood, suggesting a possible role of white blood cells in age‐related memory decline in UM‐HET3 mice. However, further studies are needed to understand the mechanisms driving age‐related decline in cognition with focus on changes in immune cells for developing therapies to slow down the rate of cognitive decline in normal aging as well as neurological disorders such as Alzheimer’s disease.