Insights into the direction and extent of gut microbiome dysbiosis in Alzheimer’s disease and mild cognitive impairment

In a recent study published in PLOS ONE, researchers performed a meta-analysis to determine the association between intestinal microbiota and Alzheimer’s disease (AD).

Background

The gut microbiota primarily impacts neurological function through the gut-brain axis, a means of interaction between the brain and the abdominal organs, through the nervous system and neuromodulator production. Neurodegeneration includes immunological activation through a defective gut barrier, neuroinflammation, and blood-brain barrier impairments.

AD, a neurodegenerative illness, is characterized by gradual cognitive decline and memory loss. The initial stage of AD is characterized by mild cognitive impairments (MCI). There is no definite cure for AD; however, studies have documented cognitive improvements using non-pharmacological treatments such as probiotics and fecal microbial transplantation (FMT) in the initial stages, indicating a potential role of gut microbiota in AD and MCI pathophysiology. However, the extent and direction of gut microbial imbalance among AD patients are not well-characterized.

About the study

In the present meta-analysis, researchers reported on the contribution of gut microbes to Alzheimer’s disease and associated mild cognitive impairments.

The team searched databases such as Cochrane, EBSCO, Scopus, and MEDLINE for case-control and interventional 16S and metagenomic studies on AD gut microbiota published in English between 1 January 2010 and 31 March 2022.

In addition, the included records’ references were searched, and data were extracted independently by two researchers on the location, sample size, mean age, female proportion, eligibility criteria, sequencing platforms, and bioinformatics tools used.

The primary study outcomes were altered alpha-diversity and microbial taxa abundance, analyzed by inverse variance-weighted random-effects modeling. The secondary study outcomes emphasized linear discriminant analysis effect sizes (LEfSe) and qualitative beta-diversity ordination. Bias risks were evaluated using suitable methods for the study types, and subgroups were analyzed in the case of considerable heterogeneity in the included studies.

Only studies assessing the gut microbiota profiles of AD patients by metagenomic sequencing and documenting outcomes such as alpha- and beta-diversity ordination, linear discriminant analysis effect sizes (LEfSe), and microbial taxa abundance were analyzed. AD was diagnosed using the National Institute on Aging and Alzheimer’s Association (NIA-AA) or Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. Individuals who did not satisfy the AD criteria but reported cognitive decline and memory loss were grouped with individuals having MCI. Individuals consuming antibiotics within 14 days of specimen collection and those with a history of medical conditions such as genetic or neurological diseases, depression, or cancer were excluded from the analysis.

Results

In total, 2,235 records were identified initially, of which 42 underwent full-text screening, and 17 studies comprising 679 and 632 AD patients and controls, respectively, were considered for the final analysis. The mean age of the participants was 71 years, and 62% were female. The included studies of high quality with low risk of bias. An overall reduction in gut microbial richness was observed among AD patients, although Bacteroides species were consistently higher among United States (US) residents and lower among Chinese individuals.

The findings indicated that location, lifestyle, and diet considerably impact the intestinal microflora and the pathogenesis of AD. Further, Phascolarctobacterium species increased significantly only in the initial stage of mild cognitive impairment. Among AD patients, a small but significant decrease occurred in alpha diversity, measured using the Simpson and Shannon index; however, the studies were significantly heterogeneous, and subgroup analysis yielded similar results for Chinese individuals.

In addition, a significant, moderate decrease occurred in Chao indices and species richness for AD patients. The LEfSe analysis showed an increased abundance of Actinobacteria, Proteobacteria, Bifidobacteriaceae, Clostridiaceae, Enterobacteriaceae, Lactobacilleae, Ruminococcaceae, and Akkermansia. On the contrary, the relative abundance of Bacteroidetes, Firmicutes, Bacteroidaceae, Lachnospireae, Prevotellaceae, Alistipes, and Anaerostipes decreased among AD patients.

Conclusions

Overall, the study findings showed that AD progression is related to more significant impacts on species richness than evenness in the intestinal microbiota and that regional differences in lifestyle and diet can affect the gut composition, especially Bacteroides abundance.

In addition, increased Phascolarctobacterium and decreased Bacteroides counts among individuals with MCI indicated that gut microbial dysbiosis commences in the MCI stage. Thus, gut microbiota studies can enable prompt diagnosis and early intervention in neurodegenerative diseases such as AD.

The LEfSe synthesis showed an increased abundance of propionate, lactate, and acetate producers such as Bifidobacterium, Lactobacillus, and Akkermansia, which have correlated negatively with clinical cognition indicators in previous studies. However, the findings must be interpreted with caution due to potential confounding by polypharmacy.

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.