Brain-gut-microbiome axis in neurodegeneration: Current controversies and future research directions

The brain-gut-microbiome axis (BGMA) has emerged as a central regulator of neural health and disease, extending far beyond the traditional view of gastrointestinal function. Increasing evidence reveals that microbial communities within the gut shape brain physiology through immune, metabolic, and neuroendocrine signaling, with profound implications for neurodegeneration, depression, and cognition. While probiotics have been widely investigated, the complexity of microbiome-host interactions demand a broader conceptual framework that incorporates diet, microbial metabolites, host genetics, and environmental exposures. Here, we review the current understanding of microbiome-driven modulation of neurodegenerative diseases, mood disorders, and cognitive performance. We highlight controversies regarding causality versus correlation, heterogeneity in human studies, and challenges in translating animal findings to clinical practice. Finally, we outline promising directions in multi-omics, personalized microbiome interventions, and novel therapeutic strategies targeting microbial metabolites and host-microbiome signaling pathways.

The concept that “all disease begins in the gut” has gained new relevance in the age of microbiome research. The BGMA is no longer viewed as a peripheral curiosity but as a central regulator of neural development, cognition, and vulnerability to psychiatric and neurodegenerative disease. Recent advances in microbiome science, spanning from developmental neuroscience to glial biology, reveal that microbial signals shape brain health across the lifespan. Yet, despite the enthusiasm, the field stands at a comma after crossroads, balancing compelling mechanistic insights with unresolved controversies and translational challenges.^[1] The gut microbiome, comprising trillions of microorganisms, functions as a dynamic ecosystem that communicates bidirectionally with the central nervous system (CNS). This communication occurs through neural (vagus nerve), immune, endocrine, and metabolic pathways collectively known as the BGMA. Disruptions in this axis dysbiosis have been implicated in a spectrum of neurological and psychiatric conditions, ranging from Parkinson’s disease (PD) and Alzheimer’s disease (AD) to major depressive disorder (MDD) and age-related cognitive decline.^[1] While early studies focused on the use of probiotics to modulate the microbiome, emerging research suggests that probiotic supplementation alone provides limited or inconsistent outcomes. The field is now moving “beyond probiotics,” toward mechanistic insights into microbial metabolites (e.g., short-chain fatty acids (SCFAs) and tryptophan derivatives), microbial-host immune crosstalk, and dietary microbiome interactions that collectively shape brain function. This editorial synthesizes recent advances, debates, and gaps in understanding, with particular emphasis on neurodegeneration, depression, and cognition.^[2] The mechanisms of microbiome–brain communication include microbial metabolites acting as neuromodulators. Short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate regulate blood-brain barrier integrity, microglial maturation, and neuroinflammation. Butyrate, in particular, acts as a histone deacetylase inhibitor influencing epigenetic regulation of neuronal genes.^[3] In tryptophan metabolism, gut microbes influence serotonin synthesis through tryptophan hydroxylase activity and generate kynurenine metabolites that can be either neuroprotective (kynurenic acid) or neurotoxic (quinolinic acid).^[4] Bile acid derivatives interact with farnesoid X receptor and TGR5, impacting neuroinflammation, while lipopolysaccharides (LPS) from Gram-negative bacteria can activate systemic inflammation linked to neurodegeneration.^[5] Dysbiosis alters systemic immune responses by modifying regulatory T-cell balance and cytokine production. Chronic low-grade inflammation is a recognized driver of both depression and neurodegenerative disease, suggesting that microbial-induced immune priming may underlie vulnerability to CNS disorders.^[6] Neural and endocrine signaling include; vagus nerve, hypothalamic pitutary adrenal axis and enteroendocrine signaling. Vagus nerve, which is a major conduit for gut–brain communication, transmitting microbial metabolite signals directly to the brain. In the hypothalamic-pituitary-adrenal (HPA) axis, microbial imbalance influences stress responses by altering cortisol release through enteroendocrine signaling. Microbially modulated gut peptides (GLP-1, PYY) affect satiety, metabolism, and brain energy balance. In Parkinson’s disease (PD), gastrointestinal symptoms often precede motor manifestations by years, implicating the gut as an early site of pathology. a-synuclein aggregates have been shown to propagate from the enteric nervous system to the brain through the vagus nerve in animal models.^[7] Reduced abundance of SCFA-producing bacteria and increased Enterobacteriaceae are consistent findings in PD patients, linking dysbiosis to neuroinflammation and motor dysfunction.^[8] In Alzheimer’s disease (AD), gut dysbiosis is associated with increased pro-inflammatory taxa (e.g., Escherichia/Shigella) and decreased anti-inflammatory taxa (e.g., Eubacterium rectale). Amyloid-like proteins produced by bacteria may cross-seed with amyloid-b in the brain, accelerating aggregation. SCFAs, particularly butyrate, demonstrate neuroprotective roles by reducing amyloid plaque burden and enhancing synaptic plasticity in preclinical models.^[9] Emerging data implicate microbiome disturbances in Huntington’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, though mechanistic clarity remains limited compared to PD and AD.

Major depressive disorder (MDD) is one of the most prevalent psychiatric conditions worldwide, and growing evidence implicates gut dysbiosis as a contributing factor. Several mechanisms have been proposed, including alterations in microbial metabolites, immune activation, and neurotransmitter availability. Compelling preclinical findings show that germ-free mice display exaggerated stress responses and depression-like behaviours, which can be reversed by microbial recolonization.^[10] Fecal microbiota transplantation from patients with depression induces depressive phenotypes in rodents, strongly suggesting a causal role.^[11] In human trials, probiotic supplementation has shown modest benefits, though results remain inconsistent, reflecting the heterogeneity of microbial signatures across individuals.^[12] Together, these findings indicate that dysbiosis contributes to MDD through metabolic, immune, and neurochemical pathways. However, the complexity of host-microbe interactions mean probiotics alone are insufficient; more targeted strategies are required. Parallel to neurodegeneration, psychiatric disorders such as depression also bear the microbial imprint. Gut dysbiosis can shift tryptophan metabolism toward kynurenine neurotoxins, reduce serotonin availability, and promote systemic inflammation, mechanisms increasingly recognized in MDD. Likewise, microbial richness correlates with cognitive resilience, while depletion impairs hippocampal plasticity. These findings underscore that mood and memory are not confined to synapses alone but resonate from microbial ecosystems within the gut.^[12]

Despite the growing enthusiasm surrounding the BGMA, several controversies remain unresolved: Despite striking findings, several controversies cloud the field. First, causality remains elusive: is dysbiosis a driver of disease or a consequence of lifestyle and pathology? Second, human studies often yield conflicting microbial “signatures,” reflecting methodological differences and population heterogeneity. Third, the gap between mechanistic animal studies and translational human applications remains wide. Finally, the probiotic narrative persists, overshadowing more sophisticated therapeutic strategies. Most human studies are cross-sectional, making it difficult to determine whether dysbiosis precedes disease onset or arises as a consequence of altered diet, lifestyle, or medication use.^[13] Microbiome signatures linked to depression or neurodegeneration vary substantially across cohorts, reflecting differences in sequencing approaches, geographic background, dietary habits, and comorbidities.^[14] Animal models provide mechanistic insights but differ in microbiome composition, limiting the generalizability of findings to humans. For example, the role of short-chain fatty acids in mood regulation is robust in mice but inconsistent in human studies.^[3] Probiotics are often marketed as “psychobiotics,” but their effects are inconsistent, likely because they target only a small fraction of the gut microbiome and may not address systemic host–microbe signaling pathways.^[2] To move beyond reductionist models and probiotic-centered interventions, future research must take a more nuanced and mechanistic approach: To unlock the therapeutic potential of the BGMA, research must move decisively beyond probiotics. The future lies in metabolite-driven therapies targeting short-chain fatty acids, bile acids, or tryptophan derivatives; diet-microbiome strategies tailored to individual profiles; and glial-centered approaches that recalibrate microglial and astrocytic responses to microbial cues. Longitudinal human studies, integrating host genetics with microbiome ecology, will be essential to establish causality and identify reliable biomarkers. Rather than whole-microbe supplementation, targeting key microbial metabolites such as SCFAs, tryptophan derivatives, or bile acid metabolites could yield more consistent outcomes.^[5] Dietary modulation remains one of the most accessible strategies to shape the microbiome. Fiber-rich and polyphenol-rich diets promote beneficial taxa and SCFA production, which may support cognitive and emotional resilience.^[3]

Recent studies highlight the microbiome’s influence on microglia and astrocytes, positioning glial biology as a key therapeutic target in both depression and neurodegeneration. Interventions that recalibrate glial responses may help attenuate neuroinflammation and synaptic dysfunction. Well-designed longitudinal human cohorts are needed to establish causality and identify early microbial biomarkers of disease risk. Moreover, individualized strategies that account for host genetics, baseline microbiome composition, and lifestyle factors are essential to improve therapeutic efficacy.^[2] Conclusively, the BGMA represents a paradigm shift in understanding neurological and psychiatric diseases. Moving beyond probiotics, current research emphasizes microbial metabolites, immune crosstalk, and host-diet-microbe interactions as central determinants of neurodegeneration, depression, and cognition. Despite controversies regarding causality and translation, the field is advancing toward precision interventions that harness microbiome–host interactions for brain health. Future research must prioritize mechanistic studies, longitudinal cohorts, and innovative therapeutics to fully realize the potential of microbiome-based strategies in neurology and psychiatry.