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Background: Alzheimer's disease (AD) prevalence is increasing, but its etiology remains elusive. Gut microbes can contribute to AD pathology and may help identifying novel markers and therapies against AD. Methods: A randomized crossover pilot study of modified Mediterranean-ketogenic diet (MMKD) and American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 63.4±3.7yr), of which 11 have mild cognitive impairment (MCI), while 6 are cognitively normal (CN). Subjects undergo MMKD and AHAD intervention for 6-weeks separated by 6-weeks washout periods. Gut microbiome, fecal short-chain fatty acids (SCFAs), and markers of AD in cerebrospinal fluid (CSF) including amyloid β (Aβ)-40 and As-42, total tau, and phosphorylated tau-181 (tau-p181) are measured at before and after diet interventions. Findings: At baseline, MCI and CN subjects show no notable difference in microbiome diversity but several unique microbial signatures are detected in MCI subjects. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in MCI subjects. Several bacteria are differently affected by the two diets with distinct patterns between CN and MCI subjects. Notably, the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium reduces on MMKD, while AHAD increases Mollicutes. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. Conversely, AHAD increases acetate and propionate while reducing butyrate. Interpretation: The data suggest that specific gut microbial signatures may predict the MCI and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers. Funding Statement: The work was supported by National Institutes of Health grant P30AG049638; R01AG055122 (SC), the Department of Defense funding W81XWH-18-1-0118 (HY), as well as the funds and services provided from Center for Diabetes, Obesity and Metabolism, Wake Forest Baptist Medical Center and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health funded Wake Forest Clinical and Translational Science Institute (WF CTSI) through Grant Award Number UL1TR001420. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study was approved by the Institutional Review Boards of the Wake Forest School of Medicine and was conducted in the Wake Forest Clinical Research Units. All protocols related to the cohorts involved in the study have been reviewed and approved by the Institutional Review Board of the Wake Forest School of Medicine. All experiments and samplings were carried out in accordance with ethical and biosafety protocols approved by the Institutional guidelines.

Background Alteration of the gut microbial population (dysbiosis) may increase the risk for allergies and other conditions. This study sought to clarify the relationship of dysbiosis with allergies in adults. Methods Publicly available American Gut Project questionnaire and fecal 16S rRNA sequence data were analyzed. Fecal microbiota richness (number of observed species) and composition (UniFrac) were used to compare adults with versus without allergy to foods (peanuts, tree nuts, shellfish, other) and non-foods (drug, bee sting, dander, asthma, seasonal, eczema). Logistic and Poisson regression models adjusted for potential confounders. Odds ratios and 95% confidence intervals (CI) were calculated for lowest vs highest richness tertile. Taxonomy associations considered 122 non-redundant taxa (of 2379 total taxa) with ≥ 0.1% mean abundance. Results Self-reported allergy prevalence among the 1879 participants (mean age, 45.5 years; 46.9% male) was 81.5%, ranging from 2.5% for peanuts to 40.5% for seasonal. Fecal microbiota richness was markedly lower with total allergies (P = 10− 9) and five particular allergies (P ≤ 10− 4). Richness odds ratios were 1.7 (CI 1.3–2.2) with seasonal, 1.8 (CI 1.3–2.5) with drug, and 7.8 (CI 2.3–26.5) with peanut allergy. These allergic participants also had markedly altered microbial community composition (unweighted UniFrac, P = 10− 4 to 10− 7). Total food and non-food allergies were significantly associated with 7 and 9 altered taxa, respectively. The dysbiosis was most marked with nut and seasonal allergies, driven by higher Bacteroidales and reduced Clostridiales taxa. Interpretation American adults with allergies, especially to nuts and seasonal pollen, have low diversity, reduced Clostridiales, and increased Bacteroidales in their gut microbiota. This dysbiosis might be targeted to improve treatment or prevention of allergy., Highlights • Allergy history vs. fecal microbiota metrics was assessed in 1879 American adults. • Fecal microbiota had markedly fewer species and altered composition with allergies. • Markedly higher Bacteroidales, lower Clostridiales with nut and seasonal allergies. American adults with allergies, especially to nuts and seasonal pollen, have low diversity, reduced Clostridiales, and increased Bacteroidales in their gut microbiota. This dysbiosis might be targeted to improve treatment or prevention of allergy.