Gut-brain axis under attack: Links between diabetes, environmental toxicants, and neurodegeneration

Table 1 Functional mechanisms linking gut microbiota, diabetes, and heavy metal exposure to brain dysfunction

Mechanism category	Effect of diabetes	Effect of heavy metals	Combined effect	Functional brain outcome	Ref.
Gut dysbiosis	Promotes growth of pro-inflammatory microbes (e.g., proteobacteria), reduces SCFA producers	Disrupts microbial diversity; increases LPS-producing taxa (e.g., Sutterella)	Amplified dysbiosis; synergistic expansion of harmful taxa (e.g., Sutterella)	Linked to memory impairment and hippocampal dysfunction	[1,8]
Intestinal barrier dysfunction	Hyperglycemia weakens tight junctions, increases gut permeability	Damages epithelial integrity; leads to endotoxemia and systemic inflammation	Exacerbated permeability; elevated systemic LPS and IL-6 levels	Systemic inflammation impacts CNS, contributes to cognitive decline	[7]
Neuroinflammation	Chronic low-grade inflammation; IL-6 and TNF-α elevated	Induces proinflammatory cytokines (e.g., IL-1β, TNF-α); activates microglia	Enhanced neuroinflammation; additive increase in COX-2, NF-κB, and cytokines	Microglial overactivation leads to neuronal injury and reduced plasticity	[23]
PI3K-Akt signaling impairment	Reduced insulin signaling; PI3K-Akt downregulated in hippocampus	Inhibits PI3K-Akt pathway via oxidative stress, reduces BDNF expression	Marked reduction in neuroprotective signaling; increased neuronal apoptosis	Neuronal survival and plasticity compromised; memory deficits ensue	[37]
Neurotransmitter imbalance	Impaired glutamate/GABA balance, reduced acetylcholine levels	Exacerbates glutamate excitotoxicity; reduces acetylcholine and BDNF	Severe neurotransmitter imbalance; impaired cognition and synaptic function	Cognitive impairment due to disrupted synaptic transmission	[8]

SCFA: Short-chain fatty acid; LPS: Lipopolysaccharide; IL: Interleukin; CNS: Central nervous system; TNF-α: Tumor necrosis factor-alpha; COX-2: Cyclooxygenase-2; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K: Phosphoinositide 3-kinase; Akt: Protein kinase B; BDNF: Brain-derived neurotrophic factor; GABA: Gamma-aminobutyric acid; BDNF: Brain-derived neurotrophic factor.