Beth A. McCormick

Gut microbiome differences in Alzheimer’s disease (AD) are typically cataloged taxon by taxon, yet bacterial competition and cross-feeding make species’ roles dependent on the entire community. We analyzed 274 stool metagenomes from 119 older adults (18 with AD) as communities, retaining 22 recurring across 1,000 runs. Using our AI framework, we identified 15 species differing in abundance in AD, particularly the commensal Phocaeicola vulgatus (Cohen’s d –0.91, 95% CI [-1.23, –0.59]), a finding robust to repeated sampling. It correlated negatively with its sister species, Phocaeicola dorei ( r –0.57), suggesting possible niche competition; this replicated in an independent cohort ( r –0.43). P. vulgatus was depleted in AD and the opportunistic pathogen Bacteroides fragilis enriched, shifting their balance toward B. fragilis ( d –0.70), a modestly reproduced AD-associated pattern ( d –0.24). Our findings suggest that AD-associated gut microbiome variation extends beyond taxon-specific abundance to the balance between specific species within a community matrix.

Alzheimer's disease (AD) is a highly prevalent and progressive neurodegenerative disease and the most common cause of dementia in older adults with no known prevention or cure. 1 AD pathology is ch...

Alzheimer’s Disease Analysis Model Generation 1 (ADAM-1) is a multi-agent reasoning large language model (LLM) framework designed to integrate and analyze multimodal data, including microbiome profiles, clinical datasets, and external knowledge bases, to enhance the understanding and classification of Alzheimer’s disease (AD). By leveraging the agentic system with LLM, ADAM-1 produces insights from diverse data sources and contextualizes the findings with literature-driven evidence. A comparative evaluation with XGBoost revealed a significantly improved mean F1 score and significantly reduced variance for ADAM-1, highlighting its robustness and consistency, particularly when utilizing human biological data. Although currently tailored for binary classification tasks with two data modalities, future iterations will aim to incorporate additional data types, such as neuroimaging and peripheral biomarkers, and expand them to predict disease progression, thereby broadening ADAM-1’s scalability and applicability in AD research and diagnostic applications.

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. We sought to determine if features of the urinary microbiome differed between positive and negative urinalysis (UAs) and symptomatic and asymptomatic patients with positive UAs. The same urine sample used for clinical testing was sequenced and analyzed for bacterial taxa, metabolic pathways, and known bacterial virulence factors. After exclusion for anatomical abnormalities and filtering for sequencing quality, 152 samples were analyzed (5 negative UAs, 147 positive UAs, among which 68 were asymptomatic, and 79 symptomatic). Positive UA samples showed significantly lower alpha diversity (2.29 versus 0.086, p < 0.01) and distinct community composition based on beta-diversity (PERMANOVA on Bray-Curtis distance p < 0.01). Alpha and beta diversity did not significantly differ between asymptomatic and symptomatic patients. Machine learning classifiers combining clinical covariates other than specific signs and symptoms and microbiome features (taxa, metabolic pathways, or virulence factors) revealed mostly microbiome features as predictive of symptomatic UTI over clinical features.

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. We demonstrate the causal role of the microbiome in modulating this phenotype using fecal matter transplantation and administration of consortia of succinate-producing bacteria. Administration of succinate production–deficient microbes shows a reduced response in a Pou2f3-dependent manner despite similar intestinal colonization. Finally, antibiotic-treated mice prophylactically administered with succinate-producing bacteria show increased protection against C. difficile–induced morbidity and mortality. This effect is nullified in Pou2f3−/− mice, confirming that the protection occurs via the TC pathway. We propose that activation of TCs by the microbiota in the colon is a mechanism evolved by the host to counterbalance microbiome-derived cues that facilitate invasion by pathogens.

The gastrointestinal (GI) tract is the reservoir for multidrug resistant (MDR) pathogens, specifically carbapenem-resistant (CR) Klebsiella pneumoniae and other Enterobacteriaceae, 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 Enterobacteriaceae, including multidrug-resistant clinical isolates, in vitro at concentrations resembling those of commonly prescribed antibiotics. We then genetically modify the probiotic bacterium Escherichia coli Nissle 1917 (EcN) to produce MccI47 from a stable multicopy plasmid by using MccI47 toxin production in a counterselection mechanism to engineer one of the native EcN plasmids, which renders provisions for inducible expression and plasmid selection unnecessary. We then test the clinical relevance of the MccI47-producing engineered EcN in a murine CR K. pneumoniae colonization model and demonstrate significant MccI47-dependent reduction of CR K. pneumoniae abundance after seven days of daily oral live biotherapeutic administration without disruption of the resident microbiota. This study provides the first demonstration of MccI47 as a potent antimicrobial against certain Enterobacteriaceae, and its ability to significantly reduce the abundance of CR K. pneumoniae in a preclinical animal model, when delivered from an engineered live biotherapeutic product. This study serves as the foundational step toward the use of engineered live biotherapeutic products aimed at the selective removal of MDR pathogens from the GI tract.

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. This occurred only after colonization of the alimentary tract with normal gut microflora, which induced Ern2 expression. ERN2 acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although ERN1 can also splice Xbp1 mRNA, it did not act redundantly to ERN2 in this context. By regulating assembly of the colon mucus layer, ERN2 further shaped the composition of the gut microbiota. Mice lacking Ern2 had a dysbiotic microbial community that failed to induce goblet cell development and increased susceptibility to colitis when transferred into germ-free WT mice. These results show that ERN2 evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.

Preventing aberrant inflammation is essential to maintaining homeostasis in the mammalian intestine. Although P-glycoprotein (P-gp) expression in the intestine is critical for protecting the intestinal epithelium from toxins and damage due to neutrophil infiltration, its regulation in the intestine is poorly understood.

Interferon γ (IFNγ) is an essential and pleiotropic activator of human monocytes, but little is known about the changes in cellular metabolism required for IFNγ-induced activation. We sought to elucidate the mechanisms by which IFNγ reprograms monocyte metabolism to support its immunologic activities. We found that IFNγ increased oxygen consumption rates (OCR) in monocytes, indicative of reactive oxygen species generation by both mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Transcriptional profiling revealed that this oxidative phenotype was driven by IFNγ-induced reprogramming of NAD+ metabolism, which is dependent on nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ salvage to generate NADH and NADPH for oxidation by mitochondrial complex I and NADPH oxidase, respectively. Consistent with this pathway, monocytes from patients with gain-of-function mutations in STAT1 demonstrated higher-than-normal OCR, whereas chemical or genetic disruption of mitochondrial complex I (rotenone treatment or Leigh syndrome patient monocytes) or NADPH oxidase (diphenyleneiodonium treatment or chronic granulomatous disease [CGD] patient monocytes) reduced OCR. Interestingly, inhibition of NAMPT in healthy monocytes completely abrogated the IFNγ-induced oxygen consumption, comparable to levels observed in CGD monocytes. These data identify an IFNγ-induced, NAMPT-dependent, NAD+ salvage pathway that is critical for IFNγ activation of human monocytes.