# Alterations and mechanistic insights of gut microbiota and its metabolites in type 2 diabetes mellitus and Alzheimer's disease

## TL;DR

This review explores how gut bacteria and their products contribute to both type 2 diabetes and Alzheimer's disease, suggesting shared mechanisms and possible treatments.

## Contribution

The paper uniquely proposes a framework for dual therapeutic targeting of T2DM and AD through gut microbiota-derived metabolites.

## Key findings

- Gut microbiota dysbiosis impacts T2DM and AD by modulating metabolic and inflammatory pathways.
- Key bacteria like Akkermansia muciniphila and metabolites such as SCFAs and TMAO regulate both diseases through complex mechanisms.
- Signaling pathways like TLR4/NF-κB and PI3K/Akt are involved in linking insulin resistance and neuroinflammation in T2DM and AD.

## Abstract

Epidemiological studies suggest a link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), possibly due to gut microbiota dysbiosis, although the exact mechanisms are unclear. This narrative review uniquely addresses how gut microbiota‐derived metabolites mediate overlapping pathologies of insulin resistance, neuroinflammation, and amyloidogenesis in T2DM and AD, proposing a framework for dual therapeutic targeting. This narrative review provides an in‐depth examination of the roles and mechanisms of gut microbiota and their metabolites in the context of T2DM and AD. This study indicates that gut microbiota dysbiosis significantly impacts the pathogenesis and progression of both diseases by modulating metabolic pathways, immune functions, and inflammatory responses. Key bacteria, such as Akkermansia muciniphila (which releases outer membrane vesicles), Lactobacillus, and Bifidobacterium, as well as their metabolites like short‐chain fatty acids (SCFAs), bile acids (BAs), lipopolysaccharide (LPS), vitamins, and Trimethylamine N‐oxide (TMAO) regulate T2DM and AD through complex mechanisms. Multiple signaling pathways, including G‐protein coupled receptor 41/43 (GPR41/43), phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt), Toll‐like receptor 4 (TLR4)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), and endoplasmic reticulum (ER) stress‐mediated pathways, are also involved. These findings offer insights into the pathogenesis and potential targeted therapies for T2DM and AD.

This narrative review uniquely addresses how gut microbiota‐derived metabolites mediate overlapping pathologies of insulin resistance, neuroinflammation, and amyloidogenesis in type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), proposing a framework for dual therapeutic targeting. This study indicates that the key bacteria, such as Akkermansia muciniphila (which releases outer membrane vesicles), Lactobacillus, and Bifidobacterium, as well as their metabolites like short‐chain fatty acids (SCFAs), bile acids (BAs), lipopolysaccharide (LPS), and Trimethylamine N‐oxide (TMAO) regulate T2DM and AD through complex mechanisms. These include Toll‐like receptor 4 (TLR4)/activated B cells (NF‐κB)‐driven neuroinflammation, phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt)‐mediated insulin resistance, and microbial amyloid cross‐seeding, which collectively bridge the two diseases. Multiple signaling pathways, such as G‐protein coupled receptor 41/43 (GPR41/43), PI3K/Akt, TLR4/NF‐κB, and endoplasmic reticulum (ER) stress‐mediated pathways, are critically involved in these processes.

This narrative review uniquely addresses how gut microbiota‐derived metabolites mediate overlapping pathologies of insulin resistance, neuroinflammation, and amyloidogenesis in type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), proposing a framework for dual therapeutic targeting.This study indicates that the key bacteria, such as Akkermansia muciniphila (which releases outer membrane vesicles), Lactobacillus, and Bifidobacterium, as well as their metabolites like short‐chain fatty acids (SCFAs), bile acids (BAs), lipopolysaccharide (LPS), vitamins, and Trimethylamine N‐oxide (TMAO) regulate T2DM and AD through complex mechanisms.These include Toll‐like receptor 4 (TLR4)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB)‐driven neuroinflammation, phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt)‐mediated insulin resistance, and microbial amyloid cross‐seeding, which collectively bridge the two diseases. Multiple signaling pathways, such as G‐protein coupled receptor 41/43 (GPR41/43), PI3K/Akt, TLR4/NF‐κB, and endoplasmic reticulum (ER) stress‐mediated pathways, are critically involved in these processes.

This narrative review uniquely addresses how gut microbiota‐derived metabolites mediate overlapping pathologies of insulin resistance, neuroinflammation, and amyloidogenesis in type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), proposing a framework for dual therapeutic targeting.

This study indicates that the key bacteria, such as Akkermansia muciniphila (which releases outer membrane vesicles), Lactobacillus, and Bifidobacterium, as well as their metabolites like short‐chain fatty acids (SCFAs), bile acids (BAs), lipopolysaccharide (LPS), vitamins, and Trimethylamine N‐oxide (TMAO) regulate T2DM and AD through complex mechanisms.

These include Toll‐like receptor 4 (TLR4)/nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB)‐driven neuroinflammation, phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt)‐mediated insulin resistance, and microbial amyloid cross‐seeding, which collectively bridge the two diseases. Multiple signaling pathways, such as G‐protein coupled receptor 41/43 (GPR41/43), PI3K/Akt, TLR4/NF‐κB, and endoplasmic reticulum (ER) stress‐mediated pathways, are critically involved in these processes.