In PD post-mortem studies, α-syn aggregates have been found to have a craniocaudal gradient in the sympathetic chain and gastrointestinal tract, with the most severe pathology in the distal esophagus and stomach, and the least in the rectum (Gelpi et al., 2014). Measurable α-syn gradients suggest that pathology spreads from the enteric nervous system to the CNS via the vagus nerve (Gelpi et al., 2014; Braak et al., 2003a). In 2003, the “Braak hypothesis” postulated that Parkinson’s disease pathology may be secondary to neuro-invasion of an unknown pathogen via the olfactory nerve or enteric nervous system. Braak developed a staging system focusing on introductory lesion sites first within the dorsal motor nucleus of glossopharyngeal and vagus nerves, as well as the anterior olfactory nucleus. He hypothesized alpha-synuclein aggregation moved into the brain secondarily (Braak et al., 2003a; Braak et al., 2003b).

The phenomenon of transneuronal propagation—where pathological proteins spread from one neuron to another through the nervous system—has been explored in various neurodegenerative diseases. In mouse models of PD, a study by Kim S. et al. (2019) and Kim Y. H. et al. (2019) supported the hypothesis of transneuronal propagation of α-syn from the gut to the brain. It was found that injection of exogenous pre-formed α-syn fibrils (PFF) into the muscularis layer of the pylorus and duodenum stimulated PD-like aggregation and spread of pathologic endogenous α-syn from the myenteric plexus to the hippocampus and prefrontal cortex via the vagus nerve in a time-dependent manner (Kim S. et al., 2019; Kim Y. H. et al., 2019). This led to loss of dopaminergic neurons and PD-like cognitive deficits in the mice (Kim S. et al., 2019; Kim Y. H. et al., 2019). Further supporting the concept of transneuronal spread, both vagotomy and genome excision of endogenous α-syn prior to injection of α-syn PFFs prevented cognitive deficits and PD pathology from developing (Kim S. et al., 2019; Kim Y. H. et al., 2019). This is particularly relevant as human studies have shown that patients with truncal vagotomy have a lower risk of PD than controls (Svensson et al., 2015; Liu et al., 2017).

In Alzheimer’s disease, similar staging mechanisms have been developed with initial tau lesions in the transentorhinal cortex, moving into the entorhinal region and then more neocortical areas (Macedo et al., 2023). The olfactory bulb has been shown to be affected significantly by neurofibrillary tangles and has been considered a potential protein aggregation hub in AD by Braak et al. and others (Braak and Del Tredici, 2015; Mrdjen et al., 2019). This connection may serve as a pathway for protein aggregation, triggered by exogenous exposure through the nasal mucosa and cribriform plate via the olfactory bulb. While no research has yet demonstrated such clear transneuronal propagation, as seen in mouse models of PD, AD studies have highlighted transneuronal spread through early subcortical areas to the limbic and associated cortices (de Calignon et al., 2012). Additionally, a singular autopsy case of Juvenile Alzheimer’s disease highlighted NFTs in the olfactory epithelium (Shimizu et al., 2004), supporting the use of nasal mucosa as target tissue for measuring AD biomarkers (Kim S. et al., 2019; Kim Y. H. et al., 2019).

Signs and symptoms, as well as risk factors for each disease, seem to fit the general location of Braak’s hypotheses of introductory lesion sites (Braak et al., 2003b; Braak and Del Tredici, 2015). Gastrointestinal signs and symptoms in the GI tract, such as constipation, inflammation, and appearance of α-syn in colonic submucosa, have been repeatedly reported in PD patients (Braak et al., 2002; Shannon et al., 2012; Devos et al., 2013). Early studies, including Braak et al. (2002) and Shannon et al. (2012) observed intestinal α-syn in aged non-PD individuals and presymptomatic PD patients, respectively. These findings have led to the hypothesis that gastrointestinal involvement may precede central nervous system pathology in Parkinson’s disease. Recent research has further elucidated the role of the gut in PD. For instance, Wang C. et al. (2021) and Wang Q. et al. (2021) highlighted that PD may originate in the gut, where dysbiosis disrupts intestinal barrier integrity and affects neurotransmitter activity. This dysbiosis may lead to increased intestinal permeability, allowing bacterial endotoxins to enter the bloodstream and eventually affect the CNS. However, further research is needed to fully understand the role of the gut in Parkinson’s disease, including the underlying mechanisms and pathways involved. In addition, many insights into the gut-brain axis come from animal models, which may not fully replicate human disease.

Interestingly, genetic studies suggest that PD patients are more likely to have variations in genes associated with inflammatory bowel disease (IBD) such as Crohn’s Disease, including the leucine-rich repeat kinase genes (Rideout and Stefanis, 2014). However, there are drastic differences between the magnitude of inflammation in IBD (inflammation is visible on colonoscopy) and PD (typically normal on colonoscopy), suggesting that the type of inflammation in these two disorders may be different. In IBD, inflammation is typically characterized by mucosal damage, ulceration, and inflammatory infiltrates (Lee et al., 2021). In contrast, inflammation associated with PD is more subtle and characterized by changes in gut microbiota composition and increase in intestinal permeability (Bellini et al., 2023).

In Alzheimer’s, most research has noticed more proximal GI region inflammation, as there has been a link between periodontal infections and AD (Kurtzman et al., 2024; Jungbauer et al., 2022). One study showed periodontitis exposure is associated with a 1.7-fold increase in the risk of developing AD via retrospective analysis (Chen et al., 2017), and IgG levels to common periodontal microbiota are associated with risk of developing AD (Noble et al., 2014). This may indicate these pathologies were present prior to neurologic damage. Specific periodontal bacteria taxa such as Porphyromonas gingivalis can exacerbate neuroinflammation and amyloid-beta deposition (Popescu et al., 2024; Bello-Corral et al., 2023). PD also presents with some proximal GI dysfunction, including gastroparesis and dysphagia (Sharma et al., 2025).

Looking at mid-GI tract areas, specifically the stomach and proximal small intestine, both patients with AD and PD have shown a higher prevalence of positive H. pylori testing compared to controls (Huang et al., 2018; Baj et al., 2021; Shen et al., 2017). This is important as H. pylori is known to stimulate systemic inflammation, which can disrupt the blood–brain barrier and promote neuroinflammation, potentially contributing to neurodegenerative processes (Bravo et al., 2018). In AD, gastrointestinal changes primarily involve increased intestinal permeability and gut dysbiosis, contributing to systemic inflammation and neuroinflammation (Kuźniar et al., 2024). Distal GI changes in PD present as constipation and colonic mucosal alterations (Sharma et al., 2025).

It is known from other diseases that systemic inflammation can worsen neuroinflammation by influencing immunomodulation (Mou et al., 2022; Amanollahi et al., 2023). This is particularly important because neuroinflammation has been consistently defined as a hallmark of both AD and PD (Calsolaro and Edison, 2016; Araújo et al., 2022). Increased pro-inflammatory cytokine densities, such as IL-6, IL-1β, TGF-β, and TNF-α, have been seen in the serum of AD and PD patients (Lai et al., 2017; Qin et al., 2016) as well as CSF (Chen et al., 2018). Elevated levels of these cytokines can cross the blood–brain barrier, leading to the activation of microglia and astrocytes in the central nervous system, perpetuating a cycle of neuroinflammation and neuronal damage.

Microglia, the resident immune cells of the central nervous system, play a crucial role in neuroinflammation and neurodegenerative changes. M1 microglia are associated with the release of these pro-inflammatory cytokines and contribute to oxidative stress and neuronal damage. In contrast, M2 microglia are involved in anti-inflammatory responses, neuroprotection, and tissue repair (Guo et al., 2022). An increase in M1 microglia activation showed inflammation-mediated degeneration in the enteric nervous system and has been a major focus in neurodegenerative treatment for both diseases (Becker et al., 2018). Gut bacterial dysbiosis may cause systemic activation and subsequent neuroinflammation via M1 microglial activation, altering the normal intestinal immune response and the integrity of the gut barrier and blood-brain barrier (BBB) (Popescu et al., 2024). Furthermore, M2 microglia-activating drugs suppressed neuroinflammation and improved the quality-of-life assessments of PD patients (Wakade et al., 2018).

Interestingly, similar mechanisms of immune activation have been observed in traumatic brain injury (TBI), one of the risk factors for AD and PD (Newcombe et al., 2018; Gardner et al., 2017). Similar to what is seen in PD and AD, major external forces activate M1 microglia, causing an increase in inflammatory cytokines systemically and in the brain. This causes a decrease in blood–brain barrier integrity, contributing to brain pathology due to an increase in systemic immune cell CNS penetration and subsequent worsening of neuroinflammation (Zhang et al., 2018). A meta-analysis by Farrall and Wardlaw (2009) showed a high confidence interval between studies that found Alzheimer’s patients to have increases in BBB permeability compared to controls, and an overall increase in BBB permeability with aging. These immune effects are intuitive when discussing something like TBI due to direct neuronal damage; however, similar effects to the BBB have been observed in gut inflammatory states caused by GI diseases and microbiome dysbiosis (Bravo et al., 2018; Mou et al., 2022).

For example, inflammatory bowel diseases (IBD) led to an increase of peripheral macrophages and inflammatory myeloid cells in the hippocampus (Gampierakis et al., 2020). This suggests that individuals with gut inflammation may experience elevated BBB permeability (Gampierakis et al., 2020). Thus, direct interplay between systemic immunomodulation and neuroinflammation highlights the role of immune cells and cytokines in compromising BBB integrity. It has also been known that the microbiome can regulate systemic inflammation through metabolic pathways, and severe dysbiosis can significantly impact systemic immune regulation and inflammation (Mou et al., 2022; Chen et al., 2022; Thevaranjan et al., 2017). Dysbiosis alters the production of short-chain fatty acids, impairing the function of regulatory T cells and promoting a pro-inflammatory environment (Chen et al., 2022). In addition, dysbiosis increases intestinal permeability, leading to microbial translocation (Thevaranjan et al., 2017). Therefore, gut inflammation due to dysbiosis of bacterial species or improper diet could have major effects on BBB integrity if microglial activation occurs or if the gut inflammation causes a neuroinflammatory state (Shahbazi et al., 2023; Anand et al., 2022; Morys et al., 2024). This could be exacerbated by comorbidities or genetic predispositions to neuroinflammation, the most notable of which being the ApoE4 isoform of the APOE gene in AD, which increases the activation of pro-inflammatory M1 microglia (Dias et al., 2025). In PD, genetic mutations in the PINK1, PARKIN, and LRRK2 genes have also been associated with inflammatory pathways (Quinn et al., 2020; Sosero and Gan-Or, 2023). As an ongoing area of research, numerous gene loci have been identified as possible risk factors in PD and AD, but their impact on neuroinflammation specifically is not as well characterized (Huang et al., 2022; Jansen et al., 2019; Kunkle et al., 2019). In aggregate pathologies like PD and AD, the increases in neuroinflammation and BBB permeability would ultimately promote the spread of protein aggregates from peripheral nerves into introductory lesion sites in the CNS, as Braak hypothesized (Braak et al., 2003a; Braak et al., 2003b; Braak and Del Tredici, 2015).

Much of the microbiome’s effects on host homeostasis are due to short-chain fatty acids (SCFA), metabolites derived from bacterial fermentation of dietary fibers and polysaccharides in the gut that have been shown to fuel intestinal epithelial cells and regulate their function (Parker et al., 2020; Parker et al., 2020; Martin-Gallausiaux et al., 2021). Acetate, butyrate, and propionate are the primary SCFA molecules produced from gut bacteria by fermentation (Mann et al., 2024). These SCFAs play crucial roles in maintaining intestinal homeostasis, modulating immune responses, and supporting gut barrier function (Yamada et al., 2015; Silva et al., 2020; Hays et al., 2024). Among them, butyrate is particularly well-characterized due to its robust anti-inflammatory properties and neuroprotective effects (Hays et al., 2024; Singh et al., 2014).

In patients with Parkinson’s Disease (PD), quantitative analysis of fecal samples has revealed significantly reduced concentrations of acetate, propionate, and butyrate compared to healthy controls (Unger et al., 2016). These reductions exceeded the typical age-related decline, suggesting a disease-specific alteration in SCFA metabolism. These findings support the hypothesis that reduced butyrate levels may impact the enteric nervous system (ENS), potentially contributing to gastrointestinal dysmotility—a common non-motor symptom of PD (Unger et al., 2016).

In Alzheimer’s disease (AD), findings have been more heterogeneous. Some studies report increased salivary concentrations of acetate and propionate but decreased butyrate levels in both feces and brain samples (Iilmaz et al., 2017; Zhang et al., 2017). Yet other data show lower serum acetate concentrations in AD patients, highlighting the complexity and inconsistency in SCFA distribution across body compartments (Cui et al., 2020).

Mechanistically, butyrate plays a uniquely protective role among SCFAs. It has been shown to reduce pro-inflammatory cytokine release from dendritic cells and protect dopaminergic neurons, whereas these effects have not been as clearly demonstrated for acetate or propionate (Hays et al., 2024; Nastasi et al., 2015; Kidd and Schneider, 2010). In mouse models of TBI, butyrate treatment improved neurological function, decreased brain edema, and mitigated neurodegeneration and BBB dysfunction (Li et al., 2018). It has also been shown to enhance α-synuclein clearance, reduce amyloid uptake, and improve cognition and memory in PD and AD models (Qiao et al., 2020; Marizzoni et al., 2020; Wang et al., 2022). These findings support the importance of butyrate in neurodegeneration prevention due to its potential to impact inflammation and protein aggregation.

Genus-level analyses in both PD and AD cohorts have demonstrated reductions in known SCFA-producing bacteria, including Blautia, Roseburia, and Faecalibacterium (Lin et al., 2018; Zhao et al., 2018; Vascellari et al., 2020; Keshavarzian et al., 2015; Scheperjans et al., 2015; Tan et al., 2021; Hopfner et al., 2017; Liu et al., 2018; Bedarf et al., 2017; Weis et al., 2019; Cosma-Grigorov et al., 2020; Cirstea et al., 2020; Haran et al., 2019; Toh et al., 2022; Hill-Burns et al., 2017; Petrov et al., 2017; Lubomski et al., 2022; Li et al., 2017; Ueda et al., 2021). These genera are among the most consistent SCFA producers, and their decline may lead to reduced SCFA levels seen in feces and serum.

While it is challenging to attribute specific SCFA production to genera due to intra-genus variability, several reviews estimate SCFA preferences by examining metabolic pathways (Hays et al., 2024; Deleu et al., 2021). For instance, Roseburia and Faecalibacterium are more closely linked to butyrate production (Hays et al., 2024). In support of this, the species Roseburia intestinalis has demonstrated anti-inflammatory activity in colitis models, presumably due to its butyrate output (Ruan et al., 2022). Loss of such butyrate-producing bacteria may therefore contribute to gut inflammation and compromised intestinal barrier function in neurodegenerative conditions.

Conversely, changes in Blautia levels may exert different effects. Although often cited as a SCFA producer associated with acetate and propionate, increased levels of Blautia have been implicated in metabolic disorders, potentially due to acetate-driven insulin release (Ordoñez-Rodriguez et al., 2023). In studies on multiple sclerosis, Blautia levels were inconsistently altered, with some reporting increases and others decreases (Aresella et al., 2020; Ventura et al., 2019). This suggests Blautia’s role in disease may depend on the disease context or other microbial interactions.

Despite butyrate’s extensive characterization, recent reviews have indicated that acetate and propionate may also confer neuroprotective benefits in the context of AD and PD (Popescu et al., 2024; Alam et al., 2024; Yassin et al., 2025). Interestingly, although SCFA-producing bacteria are frequently altered in AD and PD, those increases often favor acetate and propionate production. Still, Blautia, a key producer of these acids, is reduced in many PD cohorts. This suggests that there may be optimal ranges for SCFA concentrations, and excesses or deficiencies may both contribute to disease risk. Targeted profiling of each SCFA’s role is necessary for deeper mechanistic insight. Together, these findings suggest that SCFA imbalances—particularly reduced butyrate and context-dependent shifts in acetate and propionate—may disrupt gut and brain homeostasis in PD and AD, supporting a key mechanistic link between microbial metabolism and neurodegenerative disease progression.

Vascellari et al. (2020) correlated microbiome changes with metabolic alterations by using gas chromatography–mass spectrometry (GC–MS) to analyze gut metabolites in PD patients at a family level. Their findings showed an increase in Bifidobacteriaceae corresponded with decreased pyroglutamic acid and glutamic acid, and increased Bacteroidaceae in PD patients was correlated with decreased linoleic acid. Increased Streptococcaceae and decreased Sphingobacteriaceae were both linked to higher cadaverine levels. No similar study was done in AD patients.

Glutamic acid is a neurotransmitter implicated in PD and AD pathogenesis (Figura et al., 2018; Chang et al., 2020). As a precursor of glutathione, reduction in glutamic acid may reflect an increase in oxidative stress in disease progression or secondary to microbial shifts that impact glutamate metabolism (Chang et al., 2020). Also, several studies have reported that the serum of PD patients showed decreased levels of several long-chain omega-6 polyunsaturated fatty acids (PUFAs), including linoleic acid (Hernando et al., 2019; Schulte et al., 2016). Like glutamic acid, linoleic acid has been associated with protective effects against oxidative stress, thus suggesting that reduction in PUFAs in PD may reflect excessive oxidative stressors leading to increased disease progression (Vascellari et al., 2020). Conversely, AD derived gut microbiota in a study of mice was shown to enhance proinflammatory pathways for PUFA metabolism in the brain (Chen et al., 2022). Thus, increased PUFAs in the gut could worsen AD pathogenesis due to microbiome dysbiosis. Interestingly, oxidized linoleic acid metabolites (OXLAMs) have been associated with AD pathogenesis, thus there could be negative effects to the oxidation process as well (Mercola and D’Adamo, 2023). Therefore, in both AD and PD, decreased PUFAs might actually reflect increased oxidative damage leading to the harmful oxidation products that worsen neurodegeneration.

The polyamine cadaverine is a product of bacterial and human co-metabolism and has been reported to have a toxic effect, likely due to oxidative stress produced by its catabolism (Vascellari et al., 2020; Santoru et al., 2017). Some studies suggest that cadaverine is involved in the inhibition of intestinal motility (Sanchez et al., 2017; de la Rivas et al., 2006), which may decrease the normal clearance of pathogens or toxic substances from the GI tract. Another study found an increase in cadaverine in patients with IBD, suggesting that higher levels of cadaverine may be associated with a proinflammatory environment (Santoru et al., 2017). The risk of periodontitis and AD may be facilitated by an increase in cadaverine due to its ability to interfere with cell signaling and cause leukocyte migration disruption (Amin et al., 2021).

Gram-negative bacteria represent a significant public health concern due to their high antibiotic resistance and frequent involvement in human disease (Oliveira and Reygaert, 2022). Among them, certain genera commonly found in the human gut, such as Alistipes and Bacteroides, have been increasingly implicated in inflammatory and neurodegenerative conditions. Alistipes, a relatively new genus within the Bacteroidetes phylum, has been associated with gut inflammation and psychological disorders including anxiety, depression, and myalgic encephalomyelitis/chronic fatigue syndrome (Parker et al., 2020; Parker et al., 2020). Several studies have reported increased abundance of Alistipes in both PD and AD (Lin et al., 2018; Li et al., 2019; Qian et al., 2018; Qian et al., 2020; Li et al., 2020; Toh et al., 2022; Vogt et al., 2017; Cammann et al., 2023; Haran et al., 2019; Hung et al., 2022). Similarly, Bacteroides has been frequently identified in inflammatory contexts. Bacteroides vulgatus and Bacteroides fragilis, for instance, have been isolated from patients with Crohn’s disease and are associated with intra-abdominal abscesses, appendicitis, and inflammatory bowel disease (Zafar and Saier, 2021). In AD and PD patients, Bacteroides shows variable trends, with some studies reporting increased abundance (Keshavarzian et al., 2015; Vogt et al., 2017; Cammann et al., 2023; Haran et al., 2019; Hung et al., 2022) and others showing reductions (Vascellari et al., 2020; Petrov et al., 2017; Zhuang et al., 2018).

The Enterobacteriaceae family, accounts for approximately 80% of gram-negative isolates and includes several other pathogenic genera such as Escherichia, Proteus, Enterobacter, Klebsiella, Citrobacter, Yersinia, Shigella, and Salmonella. A key structural component of these bacteria, shared with Alistipes and Bacteroides, is lipopolysaccharide (LPS), a potent endotoxin. At the gut level LPS activates TLR4 receptors that lead to a rapid release of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, via both MyD88-dependent and TRIF-dependent pathways, resulting in increased intestinal permeability, immune cell recruitment, and amplification of local and systemic inflammation (Gryka-Marton et al., 2025; Singh et al., 2022; Guo et al., 2015; Bruning et al., 2021). Figure 1 illustrates the pathways through which gut dysbiosis, driven by specific microbiota shifts observed in AD and PD, induces distinct patterns of cytokine release. The MyD88-dependent pathway is activated at the plasma membrane upon TLR4 engagement of LPS leading to the activation of NF-κB and MAPKs, resulting in the release of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6. The TRIF-dependent pathway is activated after TLR4 is internalized into endosomes, where it recruits TRAM and TRIF adaptors producing type I interferons and a delayed wave of pro-inflammatory cytokines, likely contributing to chronic inflammation and further immune cell recruitment (Perez-Pardo et al., 2019; Lin C. H. et al., 2019; Lin C. et al., 2019). When translocated from the gut into systemic circulation, LPS can trigger immune responses systemically and chronic low-grade TLR4-mediated inflammation as well (Di Vincenzo et al., 2024; Wei et al., 2024). This process, often referred to as metabolic endotoxemia, has been implicated in the development of type 2 diabetes, multiple sclerosis, and neurodegeneration in mouse models (Cani et al., 2008; Gambuzza et al., 2011). LPS may also prime microglia through TLR4/MyD88 signaling pathways, further amplifying neuroinflammation via further cytokine release (Wang et al., 2023; Ausseil et al., 2008).

LPS from Gram-negative bacteria can also activate TLR4 on immune cells such as dendritic cells (Banks et al., 2015). Activated dendritic cells contribute to both local and systemic immune activation by amplifying cytokine production and trafficking to lymphoid tissues. Once in circulation, these cytokines can affect distant organs, including the brain. Within the central nervous system, these circulating inflammatory mediators can promote activation of microglia and astrocytes, both of which secrete additional inflammatory factors that impair synaptic function and neuronal health (Erny et al., 2015; Ransohoff and Brown, 2012). Astrocytes also play a role in compromising BBB permeability, further enabling immune mediators to infiltrate the brain parenchyma (Braniste et al., 2014). In parallel, ependymal cells lining the brain ventricles, which regulate cerebrospinal fluid homeostasis, respond to these inflammatory cues and may facilitate neuroimmune signaling. The culmination of these processes is a feed-forward loop of neuroinflammation, increased BBB permeability, and progressive neuronal dysfunction (Engelhardt and Ransohoff, 2012). These interactions at the gut epithelium and blood–brain barrier are illustrated in Figure 2.

Increased levels of Escherichia/Shigella have also been reported in multiple studies of AD and PD (Zhao et al., 2018; Pietrucci et al., 2019; Vascellari et al., 2020; Hopfner et al., 2017; Toh et al., 2022; Cattaneo et al., 2017). These genera are associated with gut-brain axis pathology, including generalized anxiety disorder (Baske et al., 2024). While these increases in LPS-producing bacteria support the idea of LPS-induced inflammation, recent findings complicate this interpretation. Some commensals produce structurally distinct forms of LPS with lower immunogenicity, particularly due to differences in the lipid A domain, which can reduce TLR signaling and induce anti-inflammatory effects (d’Hennezel et al., 2017).

LPS itself is highly variable. Its structure can differ by genus, species, and even strain, and bacteria vary in how much LPS they produce. These differences contribute to diverse immune outcomes (Caroff et al., 2002). For example, Shigella flexneri LPS is about 100 times less immunostimulatory than E. coli LPS, whereas Pseudomonas testosteroni LPS is 60 percent more active (Laude-Sharp et al., 1990). These observations likely reflect evolutionary adaptations in commensal and pathogenic bacteria (Caroff et al., 2002).

This variability suggests that the inflammatory consequences of LPS depend not just on abundance but also on the types of LPS present. A shift toward highly immunogenic LPS-producing species may exacerbate systemic inflammation and neurodegenerative disease progression. Species-level analysis, especially focusing on the immune activation potential of LPS variants, could provide deeper insight into microbial contributions to neuroinflammation in AD and PD.

It is also important to consider intra-genus variability. Alistipes, Escherichia/Shigella, and Bacteroides are all gram-negative and capable of expressing LPS, but their impact likely varies based on species-specific antigens and metabolites. Elevated bacterial loads may enhance TLR activation, but additional factors such as LPS subtype or metabolic byproducts may shape the host immune response. Future research should aim to identify species and strains whose LPS profiles or associated metabolites directly contribute to neuroinflammatory states or pathological protein aggregation in AD and PD.