Evaluation of the Safety and Efficacy of Fecal Microbiota Transplantations with Oral Capsules in Alzheimer’s Disease Patients Using Metagenomic Sequencing

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Numerous studies have shown that the gut microbiota is closely related to the occurrence and development of Alzheimer's disease, suggesting that alterations in gut microbiota may represent a therapeutic strategy. However, the role and mechanisms of the gut microbiota in AD remain unclear, and standard research protocols for the gut microbiota are not uniform. The clinical safety and efficacy of oral capsule fecal microbiota transplantation, ( FMT) in patients with AD are not yet established, and related clinical studies are lacking. Objective: This study aimed to investigate the safety and effects of FMT capsule on cognitive im-pairment in patients with mild to moderate Alzheimer's disease and to explore the re-lationship between cognition and gut microbiota by evaluating changes in gut microbial gene expression after FMT. Methods: In this study, 18 patients with clinically and radiologically confirmed mild to moderate AD aged 60-80years old were enrolled in this prospective single-arm clinical observation study. All subjects received allograft FMT (intestinal bacteria capsules with strict do-norscreening and in line with international FMT donor standards) three times at 0, 30 and 60 days. Serum and fecal samples were collected at 0, 30, 60 and 90 days, and MoCA, MMSE scores, HAMD, HAMA, ADL and fecal metagenomics sequencing were evalu-ated.During FMT and follow-up, safety was assessed by recording adverse events (AEs), vital signs, and laboratory parameters. Results After the intervention of FMT capsule, various cognitive and behavioral scores in FMT1 and FMT2 groups were not significantly changed, MMSE and MoCA scores in FMT3 group were significantly higher than those in FMT0 group (P < 0.05), in addition, HAMD scores and HAMA scores in FMT3 group were significantly lower than those in FMT0 group (P < 0.05). Cognitive scores and depression scores improved compared with those before transplantation.Fecal microflora analysis showed that FMT intervention could increase α diversity and reshape the overall structure of intestinal flora in AD patients (β diversity analysis).The proportion of dominant bacteria at phyla level changed.Genus level microbial diversity improved;Dynamic up-regulation of target functional flora at species level; A total of 12 species were identified by LEfSe analysis.The adverse reactions were mainly gastrointestinal reactions, and no serious adverse events were observed. Conclusion: In this study, FMT capsules can alter the intestinal microbiome structure and achieve intestinal microbiome remodeling, which may be a potential mechanism for microbiome capsules to improve AD related phenotypes.It is well tolerated and safe in the treatment of patients with mild to moderate Alzheimer's disease.Despite the limited sample size and lack of control group, the results still provide clinical evidence for targeted inter-vention of the gut-brain axis in AD, but larger, randomized, double-blind place-bo-controlled trials are needed to further verify its efficacy and mechanism.