While there are many postulates for the etiology of post-viral chronic fatigue and other symptomatology, little is known. We draw on our past experience of these syndromes to devise means which can expose the primary players of this malady in terms of a panoply participating biomolecules and the state of the stool microbiome. Using databases established from a large dataset of patients at risk of colorectal cancer who were followed longitudinally over 3 decades, and a smaller database dedicated to building a Long PASC cohort (Post-Acute Sequelae of COVID-19), we were able to ascertain factors that predisposed patients to (and resulted in) significant changes in various biomarkers, i.e., the stool microbiome and serum cytokine levels, which we verified by collecting stool and serum samples. There were significant changes in the stool microbiome with an inversion from the usual Bacillota and Bacteroidota species. Serum cytokines showed significant differences in MIP-1β versus TARC (CC chemokine ligand 17) in patients with either PASC or COVID-19 (p < 0.02); IL10 versus IL-12p70a (p < 0.02); IL-1b versus IL-6 (p < 0.01); MCP1 versus TARC (p < 0.03); IL-8 versus TARC (p < 0.002); and Eotaxin3 versus TARC (p < 0.004) in PASC. Some changes were seen solely in COVID-19, including MDC versus MIP-1α (p < 0.01); TNF-α versus IL-1-β (p < 0.06); MCP4 versus TARC (p < 0.0001). We also show correlates with chronic fatigue where an etiology was not identified. These findings in patients with positive criteria for PASC show profound changes in the microbiome and serum cytokine expression. Patients with chronic fatigue without clear viral etiologies also have common associations, including a history of tonsillectomy, which evokes a likely immune etiology.

Earlier analyses evaluating patterns of gut microbiota in individuals from different geographies and age groups are heterogeneous in methodology, precluding broader conclusions about the relationship between the gut microbiome and geographic region, age, and clinical health. Here, we systematically conducted a meta-analysis of 16s rRNA gut microbiome sequencing data representing 10,878 samples across North America, Europe, Africa, Asia and Oceania. Our analysis included 27 countries and three age groups (neonate to age 17, or AG01; ages 18 to 64, or AG02; 65 and above, or AG03). We identified that Firmicutes, Bacteriodetes, and Proteobacteria constitute core phyla across geographic regions. A differing predominance of top families alongside core family Lachnospiracaeae across regions comprised unique microbiome signatures. Countries also differed in their relative abundances of Bifidobacterium, Faecalibacterium, Lactobacillus and Bacteroides. We found in our age analyses that Proteobacteria and Actinobacteria were the most abundant phyla in AG01, and Actinobacteria abundance declined across all continents with increasing age. The relative abundance of Bacteriodetes increased between AG01 and AG02. Enrichment of asthma-associated Enterobacterieaceae in AG01 was highest for North America, followed by Europe and then in Asia. We discuss the correlation of these gut microbial patterns in the context of dietary patterns, populations health, clinical health trends, and healthy aging.

Cocaine use disorder remains a major global health concern, with growing evidence that the gut microbiome modulates drug-related behaviors. This study examines the microbiome’s role in cocaine-induced psychomotor activation and context-dependent reward responses using germ-free (GF) and antibiotic-treated (ABX) models. In GF mice, the absence of a microbiome blunted cocaine-induced psychomotor activation (p = 0.013), which was restored after conventionalization. GF mice also showed reduced cocaine-conditioned place preference (CPP) (p = 0.002), which normalized after conventionalization. Dopaminergic function, critical for psychomotor responses and reward, was microbiome-dependent, with increased dopamine levels (p = 0.009) and normalized turnover ratios after conventionalization. In the ABX model, microbiome depletion reduced both cocaine-induced locomotion and CPP responses (p ≤ 0.009), further supporting the role of gut microbes in modulating psychomotor and reward behaviors. ABX-treated mice also showed significant declines in microbial diversity, shifts in bacterial structure, and dysregulation in metabolic, immune, and neurotransmitter pathways (p ≤ 0.0001), including alterations in short-chain fatty acids and gamma-aminobutyric acid metabolism. These findings highlight the gut microbiome’s critical role in regulating cocaine’s psychomotor and rewarding effects, offering insights into potential therapeutic strategies for cocaine use disorder.