The Potential Role of Gut Microbiota in Alzheimer’s Disease: From Diagnosis to Treatment

Abstract

Gut microbiota is emerging as a key regulator of many disease conditions and its dysregulation is implicated in the pathogenesis of several gastrointestinal and extraintestinal disorders. More recently, gut microbiome alterations have been linked to neurodegeneration through the increasingly defined gut microbiota brain axis, opening the possibility for new microbiota-based therapeutic options. Although several studies have been conducted to unravel the possible relationship between Alzheimer’s Disease (AD) pathogenesis and progression, the diagnostic and therapeutic potential of approaches aiming at restoring gut microbiota eubiosis remain to be fully addressed. In this narrative review, we briefly summarize the role of gut microbiota homeostasis in brain health and disease, and we present evidence for its dysregulation in AD patients. Based on these observations, we then discuss how dysbiosis might be exploited as a new diagnostic tool in early and advanced disease stages, and we examine the potential of prebiotics, probiotics, fecal microbiota transplantation, and diets as complementary therapeutic interventions on disease pathogenesis and progression, thus offering new insights into the diagnosis and treatment of this devastating and progressive disease.

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

“…Dysbiosis is normally accompanied by an altered gut immune response, favoring epithelial cell leakage, increased bacterial translocation, and enhanced systemic inflammation [ 379 ]. Though data are still inconclusive, gut bacteria family and genus shifts might represent promising tools as novel biomarkers for the diagnosis and progression of AD, and the restoration of gut microbiota balance a potential therapeutic approach [ 380 ]. Several bacterial metabolites are already used as fecal biomarkers to characterize dysbiosis in AD patients; for instance, higher levels of trimethylamine N-oxide (a microbial metabolite implicated in immune response activation), enhanced oxidative stress, and intestinal barrier dysfunction have been identified in MCI and AD patients compared to cognitively unimpaired individuals [ 381 , 382 ].…”

The Gut Microbiome–Brain Crosstalk in Neurodegenerative Diseases

“…Moreover, some recent studies have reported an altered gut microbiome composition in people with AD compared to HCs [ 10 , 17 , 18 , 19 ]. Aging itself impacts the gut microbiome composition, favoring proinflammatory bacteria, such as Bacillus fragilis, Bacteroides fragilis , and Faecalibacterium prausnitzii , to the detriment of more immune-regulatory bacteria [ 101 ]. Indeed, in patients with evidence of amyloid deposition, an increase in the proinflammatory taxa Escherichia and Shigella was associated with an increase in peripheral inflammatory markers such as interleukin-1β, NLR Family Pyrin Domain Containing 3, and C-X-C Motif Chemokine Ligand 2 (IL-1β, NLRP3, and CXCL2) [ 16 , 17 , 18 ].…”

“…As far as gut microbial products are concerned, an alteration in the gut’s production of SCFAs, including butyrate, propionate, and acetate, has been repeatedly reported in patients with AD [ 101 ]. A decrease in SCFAs has been associated with increased epithelial leakage and bacterial translocation, with a consequent increase in circulating Gram-negative bacteria and LPS [ 103 ], microglia activation, and Aβ deposition in the CNS [ 104 , 105 ].…”

“…Lastly, as outlined in the previous paragraph, strains of bacteria derived from the gut microbiome can produce amyloids and favor Aβ peptide aggregation [ 101 ]. The proteins curli, TasA, CsgA, FapC, and phenol soluble modulins produced by E. coli, B. subtilis, S. typhymurium, E. fluorescens , and S. aureus , respectively, are only some of the bacteria-derived amyloids with the ability to promote the formation of Aβ oligomers and fibrils in vitro [ 110 ].…”

“…FMT has shown promising results in C. difficile infection [ 128 ] and could potentially be applied to all the diseases associated with gut microbiome dysbiosis, including neurodegenerative diseases. The most robust results on the effects of FMT on neurodegenerative diseases have been obtained from studies on animal models [ 101 ]. FMT from mouse models of AD to GF or antibiotic-treated specific-pathogen-free (SPF) recipient mice resulted in impaired neurogenesis, memory impairment, increased levels of proinflammatory cytokines, and Aβ plaque deposition [ 129 , 130 ].…”