These immune cells reside in the nervous system; in the CNS glia are involved in the production, potentiation, and resolution of neuroinflammation. Also known as glial cells or neuroglia, glia support neuronal functions, e.g. synapse formation, neuronal plasticity, neurotransmission, injury response, and protection from neurodegenerative disorders. Glia release cytokines and chemokines that are potential mediators of neurotoxicity ( Table 3 ). The most plentiful glia are astrocytes, which are “master regulators of synapse formation, ion homeostasis, and neurovascular coupling” (13).

In response to changes in their environment, in addition to producing cytokines and chemokines, microglia express antigenic markers, regulate neurotransmitters, and undergo morphological changes (61). Once activated, microglia can cause neuronal damage by producing reactive oxygen species and nitric oxide—both neurotoxic—and cross-reacting with astrocytes to magnify the effect, resulting in loss of neurotrophic functions. Microglia have been proposed to promote neuroinflammation and neurotoxicity; however, recent research suggests that their impact can be context-dependent, contingent upon their polarization phenotype, activation status, and cellular context (62). These effects are modulated through neuron-microglia communication facilitated by various neurotransmitter receptors expressed on microglia. Notably, receptors for neurotransmitters such as glutamate, GABA, norepinephrine, cannabinoid, and acetylcholine play significant roles in mediating these interactions. Microglia may modulate neurotransmitter release, thus, coordinating either positive or negative feedback loops tailored to the needs of the organism. Moreover, these interactions may extend to indirect effects on neighboring microglia, further expressing the role of neuron-microglia communication.

The relationship between the microbiota-gut-brain-immune interface, microbial metabolites, and glia is a potent regulator of GI and actionable target in neuroinflammatory and neurodegenerative disorders (12). In chronic neuroinflammation, pro-inflammatory cytokines are habitually upregulated and glia are overactive, resulting in damage to neurons, synapse function, cortical tissue, and functional connectivity—commonly observed in neurological disorders (57, 63). The multidirectional relationship of the microbiota-gut-brain-immune interface governs this chronic neuroinflammation, which may start at any point, including moving from the gut into the CNS, which often results in systemic inflammation. Systemic inflammation is a core feature of chronic neuroinflammation. Neuroinflammatory diseases arecharacterized by elevated C-reactive protein (CRP), TNF-α, and IL-1β (23). The overactivation of glia that drives pathogenesis is affected by the gut microbiome and implicated in neuroinflammation and subsequent neurological disorders (e.g. Alzheimer’s and Parkinson’s), as well as gut microbiome composition (dysbiosis) and intestinal inflammation and permeability (‘leaky gut’) (18, 23, 64). Neurodegenerative disorders are likely multifactorial in cause, and a key element of this is the gut microbiota due to their production of neuroactive metabolites (5). In specific, gut microbiota that produce the endotoxin lipopolysaccharides (LPS) may contribute to amyloid deposition and neuroinflammation in Alzheimer’s (65). LPS interacts with the microbiota-gut-brain-immune interface via Toll-like receptor (TLR) 4 and the NF-κB pathway, stimulating an inflammatory cascade, triggering leaky gut, and leading to neuroinflammation (18, 23, 64–66).

Interleukins (ILs) are a category of cytokines: some of which have pro-inflammatory/immune reaction stimulating effects while others have anti-inflammatory/homestasis stimulating effects. Therefore, the change in the concentrations of these cytokines (the cytokine milleau) can have great effects on neuroinflammation. ILs are a promising target for treating neuroinflammation and subsequent neurodegeneration (67). Many of the Preventative and Therapeutic Interventions discussed below alter the cytokine milleau, meaning this is at least in part their method of action.

TLRs are pattern recognition receptors (PRRs) that recognize molecules and patterns of molecular structure, pathogen-associated molecular patterns (PAMPs), from bacteria that are extracellular or have been engulfed into vesicular pathways via phagocytosis. They signal through cytokines such as ILs. TLRs could be used as targets to quench neuroinflammation, according to research from preclinical to clinical trials (68). Futher, small phytocompounds such as curcumin have been shown to target TLRs (68). The dose and other details for such an intervention have yet to be elucidated and show the possiblity of a hormetic response, meaning higher doses are actually detrimental.

No matter the cause(s), dysbiosis fosters a damaging, inflammatory environment via the microbiota-gut-brain-immune interface via LPS and other stimulators of the inflammatory cascade, i.e. pro-inflammatory cytokines and chemokines, T-helper cells, and monocytes (5). Further, dysbiosis contributes to aberrant HPA axis activation that can result in cortisol dysregulation, which exacerbates leaky gut (5). Therefore, dysregulation of the microbiota-gut-brain-immune interface can create a circular inflammatory feedback loop between dysbiosis, leaky gut, and chronic systemic and CNS inflammation.

The hallmarks of Alzheimer’s disease are amyloid-beta and hyperphosphorylated tau protein accumulation with neuronal degeneration, which is thought to develop decades prior to symptoms. The microbiota-gut-brain-immune interface has been implicated in its pathogenesis with human studies finding dysbiosis in the gut microbiomes of those with Alzheimer’s (69–71). For example, the gut microbiomes of those with Alzheimer’s compared to healthy controls has decreased Bacillota (formerly Firmicutes) and Bifidobacterium and increased Bacteroidota (formerly Bacteroidetes), and Escherichia and Shigella (two inflammatory genus) as well as lower abundance of the species Eubacterium rectale (E. rectale is believed to be anti-inflammatory), all of which correlates with increased pro-inflammatory cytokines in Alzheimer’s (72, 73). However, these compositional changes have not been confirmed in cohorts in other countries, such as China, indicating a role for the environment and/or the need for higher resolution data, likely at the species or strain level (74, 75). There is a need for further research, especially that better control for potential confounders, to be able to use this as a screening tool for research or clinically.

In Parkinson’s disease, misfolded α-synuclein accumulates in the neuronal cell body with motor impairments at least in part due to progressive dopaminergic neuron damage, resulting in decreased dopamine (5, 76). Of note, digestive symptoms are common in Parkinson’s and typically develop prior to hallmarks of the disease. This points to a key role of the microbiota-gut-brain-immune interface and lends some support for a causative role via temporality à la the Bradford Hill criteria (5, 21, 77). While it is not yet clear that α-synuclein causes neuronal loss (it may be an intermediate step or a symptom), the vagus nerve may transmit pathology to the brainstem, resulting in deposition of α-synuclein (78, 79). In fact, correlations have been established between α-synuclein and composition of the gut microbiome, which have been supported by a recent meta-analysis (76). Specifically, compared to healthy controls, the gut microbiomes of those with Parkinson’s have: depletion of Prevotellaceace that are involved in SCFA production, which leads to leaky gut and endotoxin exposure; depletion of important SCFA producers belonging to the Lachnospiraceae family and of which key players include Blautia, Roseburia, and L-Ruminococcus; increased Enterobacteriaceae, which can raise LPS and eventually lead to neuroinflammation; and enrichment of Lactobacillus, Akkermansia, and Bifidobacterium (5, 76). However, it is unclear if these changes are the cause or consequence of disease at present.

Gut dysbiosis appears to promote the pathogenesis of Multiple Sclerosis (MS) via the microbiota-gut-brain-immune interface: leaky gut, leading to immune activation, leading to systemic inflammation, leading to disruption of the blood brain barrier, leading to neuroinflammation, leading to neurodegeneration (52, 80). The impetus for this cascade and the leaky gut that drives it is currently unknow but dysbiosis has been found in MS patients and is mechanistically plausible (52, 80–83). While it is possible that this may actually be a consequence of the disease process rather than its cause, the research to date does not clearly support this concept. Further, the types of MS seem to have their own distinct versions of dysbiosis (52, 80–83). When compared to healthy controls, the gut microbiomes of those with MS have fewer SCFA-producing bacteria, Butyricimonas, Faecalibacterium, Clostridium cluster IV and XIVa, Faecalibacterium prausnitzii, and Blautia species and more Akkermansia muciniphila, Ruthenibacterium lactatiformans, Hungatella hathewayi, Eisenbergiella tayi, and Clostridium perfringens (82–84).

In a 2022 systematic review involving 52 studies and 5,496 participants with Alzheimer’s disease, Parkinson’s disease, MS, amyotrophic lateral sclerosis, and stroke, the strongest overlap was seen between Parkinson’s disease and MS with 8 shared genera (85). Interestingly, Parkinson’s also shared 6 genera with stroke. While there was overlap between Alzheimer’s and Parkinson’s the sample size is small, making this an unreliable association at present. Among these CNS disorders, Akkermansia, Faecalibacterium, and Prevotella were most commonly indicated. Again, this work is done at high order (low resolution) and is still mostly correlational and, therefore, may not be causative. However, these overlapping trends may better inform researchers and clinicians about preventative and interventional measures that could be more broadly applicable to neuroinflammatory disorders. Thus, this may represent a research priority for funding agencies. Key relationships for all of these disorders are highlighted in Supplementary Table S1 Observed Functional Relationships with the Gut Microbiota and Neurodegenerative Disorders; of note, only bacterial taxa have been characterized sufficiently at present.

Much of the excitement around the research on the microbiota-gut-brain-immune interface, especially around altering the gut microbiome, is the possibility of preventative and therapeutic interventions. This is especially poignant in neurodegenerative disorders, where there is little to offer in terms of such interventions. Most of the research has been in animal models with limited human studies, however. Translating these findings into the clinic requires further investigation in general and in how best to personalize such interventions to maximize their impact for an individual.

Nutrition is an important, modifiable risk factor that has a major role in the microbiota-gut-brain-immune interface, affecting each aspect of the interface. Gene-diet interactions have been linked to the microbial theory of inflammation, neuroinflammation, and neurodegenerative disorders like dementia (86, 87). Diet induced changes to the gut microbiome are key in the microbiota-gut-brain-immune interface. Gut microbiome changes are associated with shifts in the production of SCFAs and secondary bile acids, which in turn can impact inflammation and the release of neurotransmitters like serotonin (35). Therefore, resolving inflammation, dysbiosis, and leaky gut are likely to prevent and/or manage neurodegenerative disorders. The quantity of MACs present in the diet is linked to the production of SCFAs (88). A diet with adequate calories, rich in MACs promotes health in the microbiota-gut-brain-immune interface, while a high calorie, low MACs diet is associated with cognitive decline (25, 89, 90). SCFAs clearly play a role in this, especially in light of their role as fuel for colonocytes, preventing leaky gut and the inflammatory cascade (25, 89, 90). Polyphenols may also play a key role and have been shown continually and repeatably to be health-promoting elements of a healthy diet (25, 91, 92). Thus, diets low in MACs, high in fat/protein (i.e. Western-style diets) are associated with gut dysbiosis and inflammation (25, 93). While some research on ketogenic diets, which are often low in MACs, has shown promise in reducing neuroinflammation and improving cognitive function in animal models of Alzheimer’s and Parkinson’s diseases, microbiome research poorly translates from animal models, which are overly simplistic. Therefore, the results in humans are often greatly attenuated or even lost due to a much more complex physiology, meaning they are no longer meaningful let alone clinically meaningful. This necessitates research in humans, which is currently lacking for ketogenic diets.

The nutrients and nutraceuticals often recommended for brain health mostly support the gut microbiome and the barrier function of the gut and blood brain barrier (94). However, any individual food is more than the sum of its parts—the concept of the ‘food matrix’ (95–98). Therefore, focusing on nutrients alone is insufficient to promote a healthy diet. Instead, an emphasis on the inclusion of whole, minimally processed foods and limiting ultra-processed foods is necessary and likely better able to support the microbiota-gut-brain-immune interface and prevent the inflammatory cascade and consequently neurodegeneration. Dietary patterns that embody this include the Mediterranean diet and the Mediterranean-DASH Diet for Neurodegenerative Delay (MIND) diet.

The Mediterranean diet is a style of dietary pattern that emphasizes vegetables, fruit, olive oil, and low-moderate alcohol intake (i.e. red wine) and is considered to be health promoting. It is also rich in polyphenols and omega-3 fatty acids, the latter of which is required for the resolution of the inflammatory response via resolvins and are associated with reduced neuroinflammation (99, 100). This dietary pattern has been linked to lower risk of neurodegenerative disorders and cognitive impairment and better global cognition and episodic memory (101). Many of the disorders that are seen to be decreased in those on this type of diet (coronary artery disease, hypertension, diabetes, metabolic syndrome, dyslipidemia) are also risk factors for cognitive impairment and involve the microbiota-gut-brain-immune interface (99).

The MIND diet is a version of the Mediterranean diet with an emphasis on neuroprotection and cardioprotection through anti-inflammatory foods that has been shown to slow cognitive decline with aging (99, 101, 102). It consists of high intake of whole plant foods emphasizing berries and green leafy vegetables, nuts, beans, fish, poultry, and olive oil while limiting animal foods, processed foods, and foods high in saturated fat. The focus on the food matrix likely plays a role in the MIND diet’s effect on the microbiota-gut-brain-immune interface, potentially making it a more comprehensive tool.

Adherence to both the Mediterranean and MIND diets are associated with decreases in all-cause dementia independent of genetic risk and numerous studies support reduction in the risk of Alzheimer’s disease specifically (19, 86, 103). Both the Mediterranean and MIND diets are associated with reduced pathology in Alzheimer’s (104). Evidence to date demonstrates support for the Mediterranean and MIND diets in the prevention of a multitude of disease states, and the MIND diet appears to impart the greatest neuroprotection. However, there are limitations to this research: small cohorts, lacking a gold-standard to measure dietary adherence, potential for reverse causality because of short durations/follow-up (86, 105). In an attempt to account for this, a recent population-based study by de Crom et al. found an association between both diets and reduced dementia risk; however, there is still potential for confounding from lifestyle (105).

Perhaps the most underrepresented region in gut microbiome research is Sub-Saharan Africa. With its immense genetic, cultural, and environmental diversity, increasing research in this region will greatly advance our understanding of unique microbial interactions and the related implications for human health. Research in this area is limited largely due to barriers such as insufficient research infrastructure, funding scarcity, access to advanced technologies, and ethical issues such as informed consent and sharing samples (176, 177). In addition to addressing these barriers to gut microbiome research, promoting collaborative research in this field within Africa will lead to priceless insights into the diverse human population in this continent as well as a more complete comprehension of the human microbiome globally.

Gut microbiome research remains comparatively limited in Latin America as a region. In contrast, some countries have made advances in this field; however, even these are still lagging behind high-income countries. Major barriers include funding scarcity, insufficient research infrastructure, and inadequate expertise pipelines. Collaboration between Latin American and international researchers can help bridge this gap and foster knowledge exchange to enhance gut microbiome research regionally and globally (178).

Due to the large population in Southeast Asia, this region represents one of the most significant for global health research, generally, and gut microbiome research, specifically. Despite this, this region continues to lag behind in gut microbiome research. Barriers include a dearth of well-established research institutions (insufficient research infrastructure) and funding scarcity. As in Latin America, collaboration may fill some of this gap; however, regional capacity building will also be required (179). Both are necessary to advance gut microbiome research in this region and lead to a wholistic understanding of the gut microbiome globally.

The final key, underrepresented region in gut microbiome region is the Middle East with relatively limited gut microbiome research (180, 181). Barriers in this region include political instability, funding scarcity, and ethical issues including cultural norms and sharing data. Again, international collaboration can overcome some of this with the ultimate need for local capacity building.

Capacity building is a key step in addressing the underrepresentation of LMICs in gut microbiome research. To build capacity locally, investments will need to be made to provide training and support to local researchers, equipping them with the latest technology, and developing collaborations between HIC and LMIC institutions. An example of this being success is reported by Maduka et al. in 2017, where African researchers were empowered through bioinformatics training and development of the necessary infrastructure (182).

Another element of support is international partnerships and exchange programs, which can cultivate knowledge exchange and resource sharing. It is common to see large-scale collaborations in HICs (e.g. the Human Microbiome Project), which have facilitated data and resource sharing to advance gut microbiome research with comprehensive datasets and groundbreaking discoveries (141, 183). Some of these HIC projects have promoted international collaboration (i.e. Earth Microbiome Project, American Gut Project, MetaHIT Consortium) and could serve as models for bringing LMICs in as well (184–186).

Additionally, community engagement is indispensable to ensuring appropriate, diverse representation in gut microbiome research. To conduct research in these populations, culturally appropriate approaches must be used, which require respecting cultural practices and beliefs (187). Further, such approaches (e.g. culturally sensitive recruitment strategies and community-based participatory research design) promote diversity, equity, and inclusion in the research and the study population, enhancing the applicability of the findings (188). To assure fair and equitable development of this emerging field, such ethical considerations must be prioritized including as they relate to sharing of data and resources as well as the informed consent process, particularly when vulnerable populations (i.e. those in LICs) are involved.

The generalizability of gut microbiome research can also be improved by the inclusion standardization, longitudinal study designs, and multi-omics analysis. Standardizing methodologies ensures the comparability and reproducibility of gut microbiome research findings (189, 190). To establish guidelines for data generation, processing, and analysis and facilite harmonization across studies, the International Human Microbiome Standards project was established (173, 186); this data will lay the foundation for personalized and innovative methods of prevention, treatment, and management of disease. Longitudinal studies are necessary to understand how the gut microbiome evolves over time and how this relates to health outcomes and/or the pathogenesis of disease. Further, such long-term studies are likely to elucidate unknown relationships between alterations of the gut microbiome and disease development that cannot be studies through observational or cross-sectional studies. Finally, integrating multi-omics data (e.g. genomics, epigenomics, metagenomics, metabolomics) will provide a wholistic understanding of the interactions among the microbiota-gut-brain-immune interface, revealing novel biomarkers and therapeutic targets for numerous disease states. The combination of these will advance personalized healthcare globally.