Executive functioning and processing speed as predictors of global cognitive decline in Alzheimer's disease.

Background: Better cognitive tools to predict disease progression in mild cognitive impairment (MCI) and Alzheimer's disease (AD) are needed.

Objective: In this prospective longitudinal cohort, we are testing if changes in the cognitive domains of executive functioning and processing speed can predict global cognitive decline.

Methods: We assessed patients with MCI, AD, and cognitively healthy controls (cHC) using NIH toolbox assessments for processing speed and executive functioning and overall cognitive decline by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog).

The urinary microbiome distinguishes symptomatic urinary tract infection from asymptomatic older adult patients presenting to the emergency department.

Older adults suffer from a high rate of asymptomatic bacteriuria (ASB), in which urinalysis may appear positive (presence of bacteria, white blood cells, and nitrates), often triggering initiation of antibiotics in acute care settings, without actual urinary tract infection (UTI) present. To investigate the urinary microbiome of older adults being tested for UTI, we enrolled a convenience sample of 250 older adult Emergency Department patients who had microscopic urinalysis ordered as part of their routine clinical care. Urinalysis results were classified as positive or negative, and patients were classified as being symptomatic or asymptomatic based on established diagnostic guidelines.

Multidimensional third-generation sequencing of modified DNA bases allows interrogation of complex biological systems.

DNA exists biologically as a highly dynamic macromolecular complex subject to myriad chemical modifications that alter its physiological interpretation, yet most sequencing technologies only measure Watson-Crick base pairing interactions. Third-generation sequencing technologies can directly detect novel and modified bases, yet the difficulty and cost of training these techniques for each novel base has so far limited this potential. Here, we present a method based on barcoded split-pool synthesis to generate reference standard oligonucleotides allowing novel base sequencing.

Microbiome functional gene pathways predict cognitive performance in older adults with Alzheimer's disease.

Disturbances in the gut microbiome is increasing correlated with neurodegenerative disorders, including Alzheimer's Disease. The microbiome may in fact influence disease pathology in AD by triggering or potentiating systemic and neuroinflammation, thereby driving disease pathology along the "microbiota-gut-brain-axis". Currently, drivers of cognitive decline and symptomatic progression in AD remain unknown and understudied.

Succinate-producing microbiota drives tuft cell hyperplasia to protect against Clostridioides difficile.

The role of microbes and their metabolites in modulating tuft cell (TC) dynamics in the large intestine and the relevance of this pathway to infections is unknown. Here, we uncover that microbiome-driven colonic TC hyperplasia protects against Clostridioides difficile infection. Using selective antibiotics, we demonstrate increased type 2 cytokines and TC hyperplasia in the colon but not in the ileum.

Executive Functioning and Processing Speed as Predictors of Global Cognitive Decline in Alzheimer Disease.

Introduction: There is a lack of cognitive tools to predict disease progression in mild cognitive impairment (MCI) and Alzheimer's disease (AD).

Methods: We assessed patients with MCI, AD, and cognitively healthy controls (cHC) using NIH toolbox assessments for attention/concentration and executive functioning and overall cognitive decline by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog).

Results: Among 183 participants over a median follow-up of 540 days, both between- and within-subjects variance in NIH toolbox and ADAS-Cog assessments increased from cHC to MCI to AD patients.

Microbiota encoded fatty-acid metabolism expands tuft cells to protect tissues homeostasis during infection in the large intestine.

Metabolic byproducts of the intestinal microbiota are crucial in maintaining host immune tone and shaping inter-species ecological dynamics. Among these metabolites, succinate is a driver of tuft cell (TC) differentiation and consequent type 2 immunity-dependent protection against invading parasites in the small intestine. Succinate is also a growth enhancer of the nosocomial pathogen in the large intestine.

Bacteroides Fragilis in the gut microbiomes of Alzheimer's disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice.

Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice.

Development of ADS051, an oral, gut-restricted, small molecule neutrophil modulator for the treatment of neutrophil-mediated inflammatory diseases.

Neutrophils are an essential component of the innate immune system; however, uncontrolled neutrophil activity can lead to inflammation and tissue damage in acute and chronic diseases. Despite inclusion of neutrophil presence and activity in clinical evaluations of inflammatory diseases, the neutrophil has been an overlooked therapeutic target. The goal of this program was to design a small molecule regulator of neutrophil trafficking and activity that fulfilled the following criteria: (a) modulates neutrophil epithelial transmigration and activation, (b) lacks systemic exposure, (c) preserves protective host immunity, and (d) is administered orally.

Differential effects of -enriched fecal microbiota transplant on energy balance in female mice on high-fat diet.

Estrogens protect against weight gain and metabolic disruption in women and female rodents. Aberrations in the gut microbiota composition are linked to obesity and metabolic disorders. Furthermore, estrogen-mediated protection against diet-induced metabolic disruption is associated with modifications in gut microbiota.

Microcin MccI47 selectively inhibits enteric bacteria and reduces carbapenem-resistant colonization when administered an engineered live biotherapeutic.

The gastrointestinal (GI) tract is the reservoir for multidrug resistant (MDR) pathogens, specifically carbapenem-resistant (CR) and other , which often lead to the spread of antimicrobial resistance genes, severe extraintestinal infections, and lethal outcomes. Selective GI decolonization has been proposed as a new strategy for preventing transmission to other body sites and minimizing spreading to susceptible individuals. Here, we purify the to-date uncharacterized class IIb microcin I47 (MccI47) and demonstrate potent inhibition of numerous , including multidrug-resistant clinical isolates, at concentrations resembling those of commonly prescribed antibiotics.

Microbial Metabolites Orchestrate a Distinct Multi-Tiered Regulatory Network in the Intestinal Epithelium That Directs P-Glycoprotein Expression.

P-glycoprotein (P-gp) is a key component of the intestinal epithelium playing a pivotal role in removal of toxins and efflux of endocannabinoids to prevent excessive inflammation and sustain homeostasis. Recent studies revealed butyrate and secondary bile acids, produced by the intestinal microbiome, potentiate the induction of functional P-gp expression. We now aim to determine the molecular mechanism by which this functional microbiome output regulates P-gp.

The epithelial-specific ER stress sensor ERN2/IRE1β enables host-microbiota crosstalk to affect colon goblet cell development.

Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1β, a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor, ERN1/IRE1α. How ERN2 functions at the host-environment interface and why a second paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2-/- mice, we found that ERN2 was required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon.

COVID-19 Variant Surveillance and Social Determinants in Central Massachusetts: Development Study.

Background: Public health scientists have used spatial tools such as web-based Geographical Information System (GIS) applications to monitor and forecast the progression of the COVID-19 pandemic and track the impact of their interventions. The ability to track SARS-CoV-2 variants and incorporate the social determinants of health with street-level granularity can facilitate the identification of local outbreaks, highlight variant-specific geospatial epidemiology, and inform effective interventions. We developed a novel dashboard, the University of Massachusetts' Graphical user interface for Geographic Information (MAGGI) variant tracking system that combines GIS, health-associated sociodemographic data, and viral genomic data to visualize the spatiotemporal incidence of SARS-CoV-2 variants with street-level resolution while safeguarding protected health information.

Dietary manipulation of the gut microbiome in inflammatory bowel disease patients: Pilot study.

Diet is a modifiable, noninvasive, inexpensive behavior that is crucial in shaping the intestinal microbiome. A microbiome "imbalance" or dysbiosis in inflammatory bowel disease (IBD) is linked to inflammation. Here, we aim to define the impact of specific foods on bacterial species commonly depleted in patients with IBD to better inform dietary treatment.

SepA Enhances Invasion of Epithelial Cells by Degrading Alpha-1 Antitrypsin and Producing a Neutrophil Chemoattractant.

spp. are highly adapted pathogens that cause bacillary dysentery in human and nonhuman primates. An unusual feature of pathogenesis is that this organism invades the colonic epithelia from the basolateral pole.

Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis.

Background: P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut lumen. Recent studies bring to light that P-gp also confers a critical link in communication between intestinal mucosal barrier function and the innate immune system. Yet, despite knowledge for over 10 years that P-gp plays a central role in gastrointestinal homeostasis, the precise molecular mechanism that controls its functional expression and regulation remains unclear.

The Nursing Home Older Adult Gut Microbiome Composition Shows Time-dependent Dysbiosis and Is Influenced by Medication Exposures, Age, Environment, and Frailty.

Older adults in nursing homes (NHs) have increased frailty, medication, and antimicrobial exposures, all factors that are known to affect the composition of gut microbiota. Our objective was to define which factors have the greatest association with the NH resident gut microbiota, explore patterns of dysbiosis and compositional changes in gut microbiota over time in this environment. We collected serial stool samples from NH residents.

Dysbiosis exacerbates colitis by promoting ubiquitination and accumulation of the innate immune adaptor STING in myeloid cells.

Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease.

The high prevalence of among nursing home elders associates with a dysbiotic microbiome.

disproportionally affects the elderly living in nursing homes (NHs). Our objective was to explore the prevalence of in NH elders, over time and to determine whether the microbiome or other clinical factors are associated with colonization.We collected serial stool samples from NH residents.