mTOR inhibition enhances synaptic and mitochondrial function in Alzheimer's disease in an APOE genotype-dependent manner.

Apolipoprotein ε4 (APOE4) carriers develop brain metabolic dysfunctions decades before the onset of Alzheimer's disease (AD). A goal of the study is to identify if rapamycin, an inhibitor for the mammalian target of rapamycin (mTOR) inhibitor, would enhance synaptic and mitochondrial function in asymptomatic mice with human APOE4 gene (E4FAD) before they showed metabolic deficits. A second goal is to determine whether there may be genetic-dependent responses to rapamycin when compared to mice with human APOE3 alleles (E3FAD), a neutral AD genetic risk factor. We fed asymptomatic E4FAD and E3FAD mice with control or rapamycin diets for 16 weeks from starting from 3 months of age. Neuronal mitochondrial oxidative metabolism and excitatory neurotransmission rates were measured using in vivo 1H-[13C] proton-observed carbon-edited magnetic resonance spectroscopy, and isolated mitochondrial bioenergetic measurements using Seahorse. We found that rapamycin enhanced neuronal mitochondrial function, glutamate-glutamine cycling, and TCA cycle rates in the asymptomatic E4FAD mice. In contrast, rapamycin enhances glycolysis, non-neuronal activities, and inhibitory neurotransmission of the E3FAD mice. These findings indicate that rapamycin might be able to mitigate the risk for AD by enhancing brain metabolic functions for cognitively intact APOE4 carriers, and the responses to rapamycin are varied by APOE genotypes. Consideration of precision medicine may be needed for future rapamycin therapeutics.

Sanitation in urban areas may limit the spread of antimicrobial resistance via flies.

Synanthropic filth flies are common where sanitation is poor and fecal wastes are accessible to them. These flies have been proposed as mechanical vectors for the localized transport of fecal microbes including antimicrobial resistant (AMR) organisms and associated antimicrobial resistance genes (ARGs), increasing exposure risks. We evaluated whether an onsite sanitation intervention in Maputo, Mozambique reduced the concentration of enteric bacteria and the frequency of detection of ARGs carried by flies collected in household compounds of low-income neighborhoods. Additionally, we assessed the phenotypic resistance profile of Enterobacteriaceae isolates recovered from flies during the pre-intervention phase. After fly enumeration at study compounds, quantitative polymerase chain reaction was used to quantify an enteric 16S rRNA gene (i.e., specific to a cluster of phylotypes corresponding to 5% of the human fecal microflora), 28 ARGs, and Kirby Bauer Disk Diffusion of Enterobacteriaceae isolates was utilized to assess resistance to eleven clinically relevant antibiotics. The intervention was associated with a 1.5 log10 reduction (95% confidence interval: -0.73, -2.3) in the concentration of the enteric 16S gene and a 31% reduction (adjusted prevalence ratio = 0.69, [0.52, 0.92]) in the mean number of ARGs per fly compared to a control group with poor sanitation. This protective effect was consistent across the six ARG classes that we detected. Enterobacteriaceae isolates-only from the pre-intervention phase-were resistant to a mean of 3.4 antibiotics out of the eleven assessed. Improving onsite sanitation infrastructure in low-income informal settlements may help reduce fly-mediated transmission of enteric bacteria and the ARGs carried by them.

Prebiotic inulin enhances gut microbial metabolism and anti-inflammation in apolipoprotein E4 mice with sex-specific implications.

Gut dysbiosis has been identified as a crucial factor of Alzheimer's disease (AD) development for apolipoprotein E4 (APOE4) carriers. Inulin has shown the potential to mitigate dysbiosis. However, it remains unclear whether the dietary response varies depending on sex. In the study, we fed 4-month-old APOE4 mice with inulin for 16 weeks and performed shotgun metagenomic sequencing to determine changes in microbiome diversity, taxonomy, and functional gene pathways. We also formed the same experiments with APOE3 mice to identify whether there are APOE-genotype dependent responses to inulin. We found that APOE4 female mice fed with inulin had restored alpha diversity, significantly reduced Escherichia coli and inflammation-associated pathway responses. However, compared with APOE4 male mice, they had less metabolic responses, including the levels of short-chain fatty acids-producing bacteria and the associated kinases, especially those related to acetate and Erysipelotrichaceae. These diet- and sex- effects were less pronounced in the APOE3 mice, indicating that different APOE variants also play a significant role. The findings provide insights into the higher susceptibility of APOE4 females to AD, potentially due to inefficient energy production, and imply the importance of considering precision nutrition for mitigating dysbiosis and AD risk in the future.

Gut microbiome association with brain imaging markers, APOE genotype, calcium and vegetable intakes, and obesity in healthy aging adults.

Introduction: Advanced age is a significant factor in changes to brain physiology and cognitive functions. Recent research has highlighted the critical role of the gut microbiome in modulating brain functions during aging, which can be influenced by various factors such as apolipoprotein E (APOE) genetic variance, body mass index (BMI), diabetes, and dietary intake. However, the associations between the gut microbiome and these factors, as well as brain structural, vascular, and metabolic imaging markers, have not been well explored. Methods: We recruited 30 community dwelling older adults between age 55-85 in Kentucky. We collected the medical history from the electronic health record as well as the Dietary Screener Questionnaire. We performed APOE genotyping with an oral swab, gut microbiome analysis using metagenomics sequencing, and brain structural, vascular, and metabolic imaging using MRI. Results: Individuals with APOE e2 and APOE e4 genotypes had distinct microbiota composition, and higher level of pro-inflammatory microbiota were associated higher BMI and diabetes. In contrast, calcium- and vegetable-rich diets were associated with microbiota that produced short chain fatty acids leading to an anti-inflammatory state. We also found that important gut microbial butyrate producers were correlated with the volume of the thalamus and corpus callosum, which are regions of the brain responsible for relaying and processing information. Additionally, putative proinflammatory species were negatively correlated with GABA production, an inhibitory neurotransmitter. Furthermore, we observed that the relative abundance of bacteria from the family Eggerthellaceae, equol producers, was correlated with white matter integrity in tracts connecting the brain regions related to language, memory, and learning. Discussion: These findings highlight the importance of gut microbiome association with brain health in aging population and could have important implications aimed at optimizing healthy brain aging through precision prebiotic, probiotic or dietary interventions.

Persistent Ascaris Transmission Is Possible in Urban Areas Even Where Sanitation Coverage Is High.

In low-income, urban, informal communities lacking sewerage and solid waste services, onsite sanitation (sludges, aqueous effluent) and child feces are potential sources of human fecal contamination in living environments. Working in informal communities of urban Maputo, Mozambique, we developed a quantitative, stochastic, mass-balance approach to evaluate plausible scenarios of localized contamination that could explain why the soil-transmitted helminth Ascaris remains endemic despite nearly universal coverage of latrines that sequester most fecal wastes. We used microscopy to enumerate presumptively viable Ascaris ova in feces, fecal sludges, and soils from compounds (i.e., household clusters) and then constructed a steady-state mass-balance model to evaluate possible contamination scenarios capable of explaining observed ova counts in soils. Observed Ascaris counts (mean = -0.01 log10 ova per wet gram of soil, sd = 0.71 log10) could be explained by deposits of 1.9 grams per day (10th percentile 0.04 grams, 90th percentile 84 grams) of child feces on average, rare fecal sludge contamination events that transport 17 kg every three years (10th percentile 1.0 kg, 90th percentile 260 kg), or a daily discharge of 2.7 kg aqueous effluent from an onsite system (10th percentile 0.09 kg, 90th percentile 82 kg). Results suggest that even limited intermittent flows of fecal wastes in this setting can result in a steady-state density of Ascaris ova in soils capable of sustaining transmission, given the high prevalence of Ascaris shedding by children (prevalence = 25%; mean = 3.7 log10 per wet gram, sd = 1.1 log10), the high Ascaris ova counts in fecal sludges (prevalence = 88%; mean = 1.8 log10 per wet gram, sd = 0.95 log10), and the extended persistence and viability of Ascaris ova in soils. Even near-universal coverage of onsite sanitation may allow for sustained transmission of Ascaris under these conditions.