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

Abstract

A recent study comprehensively summarized the environmental toxicants, microbiota, and diabetes linkage that increasingly interact to influence human susceptibility to neurodegeneration. Recent experiments show that simultaneous exposure to heavy metals and high blood sugar from diabetes causes more extensive neural dysfunction than either factor alone, partly through microbiota-driven inflammation and metabolic signaling. Multi-omics studies now indicate that gut dysbiosis, especially an increase in taxa such as Sutterella, is closely linked to changes in hippocampal proteins, oxidative stress, and disruption of the phosphoinositide 3-kinase/protein kinase B pathway, establishing a mechanistic link between peripheral metabolic damage and brain injury. These findings highlight the gut-brain axis as a key site where environmental pollutants, glucose imbalance, immune activation, and neurotransmitter issues interact to accelerate cognitive decline. The current opinion review explores how toxic metals and diabetes influence gut microbiota, promote neuroinflammation, affect neurotransmitter pathways, and alter neuronal proteomes. By understanding how environmental and metabolic stressors combine, novel insights could be achieved by integrating the gut microbiome with the brain axis, which is vital for reducing neurodegenerative risk in a world facing increasing pollution and metabolic challenges.

Key Words: Gut-brain axis; Diabetes mellitus; Heavy metals; Environmental toxicants; Gut microbiota dysbiosis; Neuroinflammation; Oxidative stress

Core Tip: Emerging evidence shows that when diabetes coincides with environmental metal exposure, it significantly impacts the gut-brain axis. Hyperglycemia and toxicants together lead to gut dysbiosis, intestinal barrier breakdown, and increased neuroinflammation. This results in worse cognitive and hippocampal damage than each factor alone. Specific microbiota changes link metabolic toxicity to brain dysfunction, suggesting the need for prevention through reduced exposure and better glycemic control.

INTRODUCTION

The gut microbiota critically shapes host metabolism, immunity, and brain function. For instance, gut bacteria have extensive metabolic capacity to transform environmental chemicals, and conversely, pollutant exposures can significantly change microbial community structure and function[1,2]. Ecological toxicants are increasingly recognized as modifiers of metabolic health: In vitro and animal studies show that contaminants (heavy metals, pesticides, endocrine disruptors, etc.) can perturb the gut microbiome and promote insulin resistance or adiposity. For instance, chronic exposure to arsenic and cadmium (Cd) in mice causes marked shifts in gut bacterial diversity and bile-acid metabolism[3]. Many heavy metals damage the intestinal barrier even at subtoxic levels, enabling lipopolysaccharide and other proinflammatory signals to leak into circulation. Such dysbiosis has also been associated with metabolic endotoxemia, insulin resistance and inflammation in type 2 diabetes[4]. Meanwhile, diabetes itself involves chronic low-grade inflammation and gut microbiome changes, which have been linked to cognitive deficits.

Both diabetes and toxic metal exposure disrupt the gut microbiome. In animal models, arsenic and Cd treatment significantly alter gut microbial composition, reducing diversity and depleting beneficial taxa (including butyrate producers) while perturbing bile-acid and amino-acid metabolomes[3]. Similarly, rodent models of diabetes showed an expansion of inflammatory bacteria and a loss of commensals. Wang et al[5] reported that Cd exposure was shown to reduce expression of tight-junction and barrier proteins in intestinal epithelia, increase gut permeability, and elevate local proinflammatory cytokines. Diabetes-related hyperglycemia also compromises gut barrier function, resulting in a “leaky gut” state that allows microbial products (lipopolysaccharide, peptidoglycan, flagellin) and inflammatory mediators to enter the bloodstream and reach peripheral organs[6].

Therefore, the current opinion review discusses how the intersection of metabolic dysfunction and environmental pollutants converges on the gut-brain axis. It highlights the emerging data showing that combined hyperglycemia and toxicant exposure produce supra-additive neural injury via gut-mediated mechanisms for discussing the clinical implications and intervention strategies to break this vicious cycle.

ENVIRONMENTAL TOXICANTS AND DIABETES: A CONVERGING RISK LANDSCAPE FOR THE BRAIN

Diabetes is increasingly recognized as a systemic disease with neurological complications, where chronic dysglycemia can impair cognition and accelerate neurodegenerative-like changes. In parallel, legacy environmental metals remain prevalent and biologically active, with neurotoxic potential and endocrine-disrupting properties. The primary public-health concern is not exposure to one factor in isolation, but rather the realistic scenario of combined stressors: Metabolic dysregulation occurring in populations simultaneously exposed to pollutants. The gut-brain axis offers an attractive unifying framework because it is positioned at the interface of exposure, immunity, metabolism, and neuroinflammation. Once in circulation, gut-derived factors and cytokines can activate microglia and astrocytes, triggering neuroinflammation. Systemic and neuronal oxidative stress are central consequences of both conditions. Indeed, in a rat model, Benloughmari et al[7] found that HgCl₂ exposure in diabetic rats produced significantly higher hippocampal tumor necrosis factor α and interleukin (IL)-6 levels, along with more severe spatial learning deficits, than in control rats. These Hg-exposed diabetics also showed reduced hippocampal brain-derived neurotrophic factor and acetylcholinesterase activity, indicating synaptic dysfunction. Likewise, Cd-exposed mice showed early increases in brain IL-6 and TNF, accompanied by memory impairment. Such inflammation is linked to oxidative neuronal injury and apoptosis, as well as to Alzheimer’s-type pathologies (amyloid and tau disturbances) in some toxin studies. Thus, diabetes and metals amplify each other’s pro-oxidant and inflammatory impact on the brain.

Disturbed microbiota can also skew levels of neuroactive metabolites[8,9]. Gut bacteria synthesize or consume neurotransmitters and precursors (gamma-aminobutyric acid, serotonin, glutamate) and influence host tryptophan metabolism. In diabetic animals, the dysbiotic gut shows altered short-chain fatty acid (SCFA) profiles and glutamate-related metabolites. Strikingly, Zhao et al[10] demonstrated that fecal microbiota transplantation from healthy mice into type 1 diabetic mice partly reversed these metabolite changes: It improved hippocampal glutamate and gamma-aminobutyric acid balance, suppressed microglial activation, and rescued learning/memory deficits. This suggests that toxicant- and diabetes-induced gut shifts may impair cognition via metabolic channels[11]. Metabolomic links have also been made between specific gut taxa and brain pathways. For instance, Song et al[12] found that bacterial changes in db/db mice correlated with hippocampal gene networks governing the tricarboxylic acid cycle, lipid metabolism, and G protein-coupled receptor signaling. Convergently, diabetes is known to downregulate neuronal growth and survival pathways. For example, hippocampal phosphoinositide 3-kinase (PI3K)- protein kinase B (Akt) signaling is reduced under diabetic and stress conditions[13], which may intersect with inflammatory signaling to impair neuroplasticity.

Recent advances have shown that the gut microbiome is crucial for health, and dysbiosis is linked to diseases such as inflammatory bowel disease, metabolic disorders, and neurological disorders[14]. Traditional treatments like probiotics and fecal transplants lack precision, making nanomedicine a promising alternative. For instance, metal-organic frameworks, versatile materials, interact with the gut microbiome and show significant promise in this field. The development of gastrointestinal-targeted, biocompatible, stimuli-responsive metal-organic frameworks, which can serve as scaffolds, controlled-release carriers, and metabolite scavengers, with therapeutic uses in antimicrobial therapy, probiotic delivery, and immunomodulation.

MULTI-OMICS EVIDENCE FOR AN “INTERACTION” PHENOTYPE

Ding et al[1] constructed a four-group mouse design (control, diabetes, lead exposure, diabetes plus lead), enabling the study of single exposures and their combined effects. Their results support an interaction phenotype in which lead exposure under diabetic conditions produces more severe neural impairment than either factor alone, as shown by behavioral deficits in the Morris water maze and increased astrocytic activation in hippocampal tissue (glial fibrillary acidic protein signal), with statistically significant interaction effects reported for glial fibrillary acidic protein outcomes. A notable metabolic observation is that lead exposure alone did not raise glucose, yet it appeared to exacerbate hyperglycemia when diabetes already existed. Importantly, the novelty of the study lies not in confirming that diabetes and lead independently impair cognition, but in demonstrating a biologically interactive phenotype in which metabolic vulnerability amplifies toxicant-induced neural injury. This interaction moves the field beyond additive risk models toward a convergence framework centered on gut-brain signal transmission[15].

The mechanisms of microbiome modulation suggest restoring a healthy gut ecosystem that mitigates gut-brain injury, as in diabetic models, where fecal microbiota transplantation or probiotic therapies have reversed cognitive and biochemical defects[16,17]. For instance, Zhao et al[10] showed that transplanting a healthy microbiome into T1D mice significantly restored learning and memory and reduced hippocampal inflammation. Probiotics, prebiotics or dietary fiber to boost beneficial SCFA-producing bacteria could similarly attenuate gut inflammation and endotoxemia. Metabolic control and neuroprotection: Tight glycemic control (diet, exercise, glucagon-like peptide-1 agonists, etc.) remains fundamental to reduce diabetes-driven gut leak and neuronal stress. Antioxidants (vitamins, polyphenols) and anti-inflammatory agents may counteract pollutant-induced oxidative injury[18]. For example, enhancing PI3K-Akt signaling or inhibiting nuclear factor kappa has been shown to protect neurons in diabetic models. Some conventional diabetes drugs (e.g., metformin, pioglitazone) also show neuroprotective and anti-inflammatory effects; their impact on the gut-brain axis warrants further study. Barrier protection: Strategies to strengthen intestinal or blood-brain barriers may prevent toxin translocation. Nutrients like glutamine or zinc that support tight junctions, as well as drugs targeting endotoxin receptors (e.g., toll-like receptor 4 antagonists), could be explored. Overall, an integrated approach addressing the microbiome, systemic metabolism and barrier integrity is needed (Table 1).

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.

Emerging studies highlight how co-morbid exposures amplify risk. Benloughmari et al[7] directly compared diabetic and non-diabetic rats receiving HgCl₂. In that study, only the diabetic Hg group showed severe memory loss and cytokine surges. This supra-additive effect suggests a “double-hit” where hyperglycemia primes the brain to pollutant injury. Similarly, Cd-treated mice developed gut dysbiosis, increased gut/brain cytokines and memory deficits even without diabetes; one predicts worse outcomes if diabetes were also present. In contrast, classical diabetic models (e.g., STZ rats) show moderate cognitive decline with gut dysbiosis and hippocampal metabolic derangements[19]. Where, their epidemiological investigations found that even low-level lead or Cd exposure correlates with cognitive impairment in older adults, and diabetic patients show accelerated age-related brain atrophy and cognitive decline[20].

THE MICROBIOTA SIGNAL AS A CANDIDATE BRIDGE

The gut microbiome is regulated through a dynamic interplay of host genetic factors, metabolic state, immune surveillance, dietary inputs, and environmental exposures. Under physiological conditions, host-derived mechanisms - such as mucus secretion, antimicrobial peptides, and epithelial integrity - shape microbial composition, favoring symbiotic taxa and restricting pathobionts[21]. Carreto-Binaghi et al[22] mentioned that immune regulation, including secretory IgA and toll-like receptors, continuously monitors and modulates microbial populations, fostering homeostasis. Such exposures are also linked to reduced intestinal barrier integrity, which modifies the host-microbe signaling environment. Consequently, gut dysbiosis related to simultaneous diabetic and toxicant exposure should be interpreted as a complex outcome of altered host-immune-environmental interactions[5]. This integrated regulatory framework is essential for understanding how microbiome perturbations affect metabolic and inflammatory signaling to the brain via the gut-brain axis[9].

Therefore, one of the most provocative findings from the multi-exposure study was the integration of gut microbiome data with brain proteome changes. By performing correlation analysis, researchers found that shifts in the fecal microbiota were tightly linked to changes in hippocampal protein expression[23]. Among all the bacterial taxa analyzed, Sutterella - a genus of gram-negative bacteria - emerged as the microbe most strongly associated with the altered hippocampal proteins, especially in the combined diabetes and lead group. Sutterella has attracted attention in prior research for its potential influence on the gut-brain-immune axis[1]. It has a double-edged role in immune modulation. On one hand, Sutterella can induce pro-inflammatory mediators (triggering IL-6 and tumor necrosis factor α production) and is known to degrade IgA antibodies in the gut mucosa, which could promote systemic inflammation by undermining intestinal immune defense. On the other hand, this bacterium can also stimulate the release of the anti-inflammatory cytokine IL-10 and alter tryptophan metabolism, thereby affecting levels of neuroactive compounds such as serotonin and kynurenine. These context-dependent effects mean Sutterella might exacerbate inflammation in some settings while moderating it in others. Importantly, Sutterella has been linked to both metabolic and neurological disorders.

Elevated abundance of Sutterella has been observed in individuals with type 2 diabetes of longer duration (those more prone to complications) and in neurological conditions; in these contexts, it correlates with markers of disease severity[24]. For example, higher Sutterella levels have been noted alongside greater amyloid burden and oxidative stress in Alzheimer’s disease patients. It has also been detected frequently in certain neurodevelopmental disorders (like autism) where gastrointestinal issues co-occur. Thus, the enrichment of Sutterella under combined diabetic and lead exposure is biologically plausible: This taxon’s known ability to provoke systemic inflammation (via lipopolysaccharide and cytokines) and impact neurotransmitter pathways makes it a strong candidate to carry signals from a dysbiotic gut to the brain[8].

TRANSLATIONAL IMPLICATIONS AND RISK STRATIFICATION

The study naturally informs a translational hypothesis: People with dysglycemia may represent a higher-susceptibility subgroup for pollutant-associated neurocognitive decline, because hyperglycemia can prime inflammation and weaken barrier defense. Chen et al[25] reported that people with dysglycemia (e.g., diabetes or chronically high blood sugar) represent a subgroup at higher risk of pollutant-associated cognitive decline. Chronic hyperglycemia can prime systemic inflammation and compromise barrier defenses (gut and blood-brain barriers), creating a more permissive environment for neurotoxic insults. Indeed, hyperglycemia in diabetes is linked to blood-brain barrier dysfunction and neuroinflammation, which contributes to cognitive deficits and dementia risk. This means that in individuals with poor glycemic control, environmental toxicants might trigger greater neurological injury than they would in metabolically healthy people[26]. Importantly, the implication is not that any single pollutant will deterministically cause neurodegeneration on its own, but rather that combined stressors add up via shared inflammatory and metabolic pathways. In other words, metabolic dysfunction and toxic exposures synergize to amplify neuroinflammatory damage beyond what either would do alone. For example, a recent mouse study showed that lead exposure under diabetic conditions produced significantly worse neural impairment (e.g., memory deficits and heightened astrocyte activation) than either factor alone. This synergy underscores the need to identify high-susceptibility individuals (like those with diabetes or prediabetes) in order to stratify risk for environmental neurohazards[27].

Because the gut microbiome and intestinal barrier mediate interactions between metabolic and environmental factors, they present a promising intervention point. Strategies include optimizing dietary fiber intake, prebiotics, and probiotics to foster a resilient microbiome and robust gut barrier. A high-fiber, microbiota-supporting diet can increase production of beneficial metabolites (like SCFAs), reduce systemic inflammation, and even ameliorate brain pathology[28]. Conversely, low-fiber diets that disrupt the microbiome have been shown to impair cognition via the gut-brain axis. Other approaches involve microbiota-directed therapies (e.g., fecal transplants or specific probiotic strains) and barrier-protective agents (to reinforce intestinal tight junctions or blood-brain barrier function). By modulating the gut-brain axis early, these interventions aim to prevent the downstream cascade of neuroinflammation and neuronal damage rather than “chasing” end-stage neurodegeneration. The three preventive pillars identified, reducing toxic exposures, optimizing metabolic control, and strengthening the gut–brain interface, are essential for lowering neurodegenerative risk in populations vulnerable to metabolic issues[29]. Each element targets distinct links external triggers, host susceptibility, and the interface connecting them.

A significant caution arises from focusing on individual microbes implicated in the disease process, as complex disorders like neurodegeneration are rarely linked to a single pathogen. In the highlighted study, the gut bacterium Sutterella was shown to have a strong association with neurodegenerative phenotypes under conditions of diabetes and lead exposure. However, it is argued that Sutterella may serve as a marker of broader dysbiosis rather than as a sole causal agent, given its dual roles in inflammation. Davoody et al[23] reported that the dual effects of Sutterella on host immunity and neuroinflammation are context-dependent, suggesting that it primarily functions as an ecological indicator of dysbiosis rather than as an isolated causal agent. It is recommended that a metabolite-first and function-first approach be adopted, prioritizing measurements of SCFAs, indoles, endotoxin markers, and targeted metagenomic pathways over taxonomic counts alone[4,6]. Where the impact of host phenotypes like glycemic control and immune markers on Sutterella’s effects indicates a stronger relationship than other microbial taxa linked to disorders[23,30]. Therefore, translational strategies should prioritize functional biomarkers that reflect the collective activity of the microbiome and immune system. By measuring inflammatory cytokine levels, gut and blood-brain barrier integrity, metabolite profiles, and key signaling pathways, the true impact of interventions on pathogenic mechanisms can be assessed. This perspective emphasizes that understanding microbial function rather than mere presence is critical for therapeutic outcomes. Furthermore, individuals with poor metabolic control should be classified as high risk for pollution-related cognitive decline. A multi-faceted approach is essential for effectively mitigating neurodegenerative risks influenced by metabolic and environmental stressors[31-34].

FUTURE DIRECTIONS AND RECOMMENDATIONS

Future studies should convert microbiome-brain associations into causality. Prioritize fecal microbiota transfer into germ-free or antibiotic-treated hosts. Use targeted colonization to test Sutterella as a mechanistic driver. Build “necessity” tests using selective depletion and reversal designs. These causal approaches follow the direction of human-to-mouse transfer logic used in diabetic neuropathy research. Mechanistic resolution should become metabolite-first, not taxonomy-first. Pair metagenomics with targeted metabolomics of SCFAs, bile acids, indoles, and endotoxin markers. Quantify microbial imidazole-propionate-like pathways that impair host signaling. Link each metabolite to PI3K-Akt readouts, oxidative stress, and microglial activation states. Cell Press reviews emphasize metabolites as blood-brain barrier-relevant effectors across brain cell types.

Barrier biology needs direct, standardized measurement in combined exposure models. Tracking intestinal permeability with fluorescein isothiocyanate dextran and tight-junction proteins will make a significant enhancement in this biomarker approach. Measuring the blood-brain barrier leak using tracer assays and endothelial transcriptomics will add significance to this approach. In addition, spatial single-cell profiling and interactions will play an important role in tracking its transcriptomic pathway[35]. Besides, the use of multi-omics layers to connect gut microbiota, circulation, and the brain proteome will enable the translation of longitudinal human cohorts and mechanism-guided trials, providing novel insights in this field. Collect metal burden, glycemic metrics, stool metagenomes, and cognitive trajectories together. Stratify by sex, age, kidney function, and antidiabetic drugs that reshape microbiota[36]. Test bundled interventions targeting glucose control plus microbiome and barrier protection. Use mechanistic endpoints, not cognition alone, to confirm pathway interruption.

CONCLUSION

The research on the gut-brain axis provided timely evidence that diabetes and heavy metals exposure can interact to intensify neural dysfunction, accompanied by gut dysbiosis and hippocampal proteome remodeling (Figure 1). By nominating Sutterella as a gut taxon most strongly linked to brain protein changes and validating inflammatory-metabolic disruption through cyclooxygenase-2, PI3K, and glutathione readouts, the study’s mechanistic findings help operationalize the gut-brain axis, where environmental and metabolic stressors converge. The most valuable next step is to establish causality through gnotobiotic and transfer designs and to identify the metabolite and barrier pathways that transmit intestinal signals to the brain. Achieving this would transform multi-omics association into intervention-ready biology, supporting new strategies to reduce neurodegenerative risk in an increasingly polluted and metabolically burdened world.

Figure 1 Schematic illustration of how hyperglycemia and heavy metals co-induce dysbiosis (e.g., Sutterella), gut barrier breakdown, microglial activation, and neuronal injuries. LPS: Lipopolysaccharide; TNF-α: Tumor necrosis factor α; COX-2: Cyclooxygenase-2; HIGH: Elevated blood glucose concentration.