Reductionist thinking in neuroscience resulted in a cerebrocentric perspective. The brain was thought to be the sole arbiter of cognitive and emotional life, metabolically isolated by the blood-brain barrier (BBB) and structurally unchangeable in adulthood. In contrast, systems science realizes that the human organism as a holobiont- a host plus its symbiotic microbial residents 1-2. That is, the human body is an ecosystem that contains not just human cells, but also bacteria, viruses, fungi, and archaea. It encodes a genome that is about 150 times larger than that of the human genome.

This second genome provides metabolic capacities that are not in human cells, including the synthesis of essential vitamins, the fermentation of indigestible fibers, and, crucially, the production of neuroactive molecules. The gut microbiome extends from the esophagus to the lower intestines. These enteric bacteria interact with the central, autonomic and peripheral nervous systems (CNS, ANS and PNS, respectively) as part of the microbiota-gut-brain axis (MGBA) 3. Interactions go both ways in a bidirectional network of communication. This bidirectional communication is a major brain–body network that integrates cues from the environment and the body’s internal state.

The center of this network is the sensory system in the gut or enteric nervous system (ENS). It has connections between chemosensory epithelial cells and sensory nerve fibers that convey interoceptive signals to the CNS. This network connects the emotional and cognitive centers of the brain with intestinal functions through the neural, endocrine and immune systems. So, our gut microbiome affects our behavior, health, intelligence and emotions. The gut also contains its own population of neuroendocrine cells known as enteroendocrine cells (EECs), which make up roughly 1% of the epithelium.

Despite their rarity, EECs are scattered across the intestinal tract and produce many hormones that regulate digestion, glucose homeostasis and appetite. EECs are key sensors of the gut microbiota and are mediators of gut–brain signaling. Microbiota-dependent fluctuations in circulating gut hormones occur with glucagon-like peptide 1 (GLP1), peptide YY (PYY), 5-hydroxytryptamine (5-HT), cholecystokinin (CCK) and insulin-like peptide. Most, if not all, of these hormones have targets in nerve fibers of the gastrointestinal tract (GIT), the hypothalamus and other areas of the brain.

The ENS is a separate branch of the ANS. It exists throughout the length of the GIT. The GIT is densely innervated by a network of 200–600 million neurons. These neurons innervate all regions of the GIT. The ENS influences the physiology and function of the GIT, while communicating with the CNS by both parasympathetic and sympathetic vagal pathways. The gut microbiota and ENS can be thought of as an entero-endocrine organ. It is part of the GIT, which is the largest endocrine organ in the human body.

The GIT is also a hub in communication networks in the human body. It contains the highest concentration of immune cells in the body. It is a network consisting of 200-600 million neurons and trillions of viruses, Bacteria, Archaea and Eukarya that make up the human gut microbiota. The composition of the gut microbiome is affected by diet 4. Dietary fiber is very important for good health. It feeds anaerobic bacteria that ferment fiber to produce short-chain fatty acids (SCFAs). This includes acetate, propionate and butyrate.

SCFAs as critical signaling molecules within this axis, capable of modulating key neurobiological processes relevant to neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) 5. SCFAs exert neuroprotective effects by mitigating neuroinflammation, promoting neurogenesis, enhancing synaptic plasticity, and preserving BBB integrity. These actions are largely mediated through epigenetic mechanisms. Butyrate functions as a histone deacetylase inhibitor to alter gene expression related to neuronal survival, inflammation, and metabolism.

SCFAs also influence DNA methylation dynamics via modulation of DNA methyltransferases and ten-eleven translocation enzymes. Emerging findings suggest their involvement in novel histone modifications, such as attaching propionate, butyrate, lactate and others. Moreover, gut- derived SCFAs are promising modulators of the brain’s epigenetic landscape. Elucidating their mechanisms helps to develop novel interventions, including dietary, probiotic, and epigenetic-based strategies, for the prevention and treatment of NDs.

Butyrate upregulates Brain-derived neurotrophic factor (BDNF), enhances long-term memory, and maintains the integrity of the blood-brain barrier. Propionate modulates reward circuitry, reduces neuroinflammation and influences catecholamine synthesis. Acetate is a substrate for glutamate and gamma aminobutyric acid (GABA) synthesis and a microglial maturation signal. Lactate promotes synaptic strength and upregulates BDNF.

SCFAs also provide metabolic fuel. Butyrate can enter the Krebs cycle, providing ATP for high-energy demand processes like neurite extension and synaptic transmission. This bioenergetic support is crucial in the hippocampus, where neurogenesis persists throughout adulthood. The brain must be flexible and able to change when needed. Neuroplasticity is the fundamental property of the nervous system to reorganize its structure, function, and connections in response to intrinsic or extrinsic stimuli. It is the biological basis of learning, memory, recovery from injury, and adaptation to the environment.

Neuroplasticity requires a protected environment. SCFAs, particularly butyrate, upregulate the expression of tight junction proteins (occludin, claudin-5) in the blood-brain barrier’s endothelial cells. A tight barrier prevents the infiltration of systemic toxins and pro-inflammatory cytokines that would otherwise impair synaptic function. Dysbiosis leads to reduced SCFA production, increased permeability (leaky brain), and subsequent neuroinflammation.

The interaction is dynamic. High-fat diet-induced obesity (which causes dysbiosis) leads to excessive synaptic stripping by microglia in the hippocampus, impairing memory. Returning to a healthy low-fat diet restores microbial balance and halts this pathological pruning, restoring cognitive function. The vagus nerve (Cranial Nerve X) consists of about 80% afferent fibers that relay visceral information to the brainstem. Vagus Nerve Stimulation enhances neuroplasticity by increasing the expression of BDNF and enhancing LTP in the hippocampus. Gut bacteria like Campylobacter jejuni and Lactobacillus rhamnosus can activate these vagal pathways directly. Vagal activation also dampens systemic inflammation, reducing cytokine levels that would otherwise inhibit neuroplasticity.

Neuroplasticity is required for the neuroendocrine immune system to reorganize its structure, function, and connections in response to intrinsic or extrinsic stimuli 7. It is the biological basis of learning, memory, recovery from injury, and adaptation to the environment. Many neurological and psychiatric disorders are not currently well treated by prescription drugs. Gut dysbiosis (an imbalance in microbial community structure or function) is a common thread linking depression, anxiety, autism spectrum disorder (ASD), Alzheimer's disease (AD), and Parkinson's disease (PD). Neuroplasticity is accomplished in part through epigenetics – the layer of control that is above genetics.

Epigenetics regulates gene expression without altering the DNA sequence. These mechanisms, including DNA methylation and histone modifications, allow environmental stimuli to shape long-term neural development and synaptic plasticity. For example, cytosine in DNA can have a methyl group (CH3) attached to it or removed from it. This can turn transcription to RNA either off or on. When methyl groups are added to CpG sites (often located in gene promoters), they generally act to repress transcription. This is achieved by creating a physical barrier that prevents transcription factors from binding to the DNA.

Methylated DNA recruits specific proteins, such as Methyl-CpG-binding domain proteins (MBDs), which in turn recruit histone-modifying enzymes (like HDACs) that convert DNA into a compact, inactive structure called heterochromatin. The removal of methyl groups, often by certain enzymes, opens up the DNA structure, making it accessible to transcription factors and RNA polymerase, thus enabling gene expression. DNA methylation is essential for normal development, X-chromosome inactivation, genomic imprinting, and the suppression of transposable elements.

While methylation can be a stable, long-term repression method, it is dynamic and can change in response to environmental factors or during development. While 5-methylcytosine (5mC) is the most common modification in mammals, other bases like N6-methyladenine (6mA) and N4-methylcytosine (4mC) also exist, particularly in prokaryotes.

DNA is wrapped around histone proteins. Acetylation of histone lysine residues relaxes the chromatin structure, making genes accessible for transcription. Enzymes called histone deacetylases (HDACs) remove these acetyl groups, condensing chromatin and silencing gene expression. Butyrate is a potent inhibitor of HDACs (specifically HDAC2). By inhibiting HDACs, butyrate prevents the deacetylation of histones, leading to a state of hyperacetylation. Butyrate leads to enhanced histone H3 acetylation specifically at the promoter regions of the Bdnf gene (Promoters PII and PIV). This epigenetic opening allows transcription factors like CREB (cAMP Response Element-Binding protein) to bind and drive the synthesis of BDNF mRNA. Similarly, the ketone body beta-hydroxybutyrate (BHBA) enhances BDNF expression by increasing the activating mark H3K4me3 and decreasing the repressive mark H2AK119ub at Bdnf promoters in hippocampal neurons.

This establishes a direct molecular pathway connecting dietary fiber intake (the substrate for butyrate production) to gene expression in the hippocampus, effectively linking diet to memory formation via the microbiome. These fibers are commonly found in plant-based foods like fruits, vegetables, whole grains, and legumes. Specialized bacteria, including Bifidobacterium, Bacteroides, Prevotella, and Faecalibacterium, break down these fibers. The major SCFAs, including acetate, propionate, and butyrate, are each synthesized by specific groups of gut microbes and serve distinct metabolic roles in the host. Butyrate strengthens the intestinal barrier and exerts anti-inflammatory effects by suppressing pro-inflammatory cytokine production in gut mucosal immune cells.

Butyrate also enters systemic circulation, influences energy metabolism in muscle and adipose tissue, and crosses the BBB to provide neuro protection via epigenetic mechanisms. As a primary metabolic substrate for colonocytes, butyrate functions as a potent inhibitor of class I HDACs, promoting chromatin relaxation at genes essential for barrier maintenance. Propionate influences neuroimmunity by restraining inflammasome activation and reducing oxidative stress. Also, propionate helps regulate satiety and energy balance through interactions with enteroendocrine cells and CNS pathways.

Acetate crosses the BBB, influencing CNS function by regulating neurotransmitter release and microglial activity. Acetate supports astrocyte function and glutamate recycling, reducing excitotoxicity and preserving synaptic integrity. Acetate contributes to hypothalamic metabolic regulation through histone lactylation. Mitochondrial function is supported by SCFAs through metabolic and signaling mechanisms. SCFAs enter the mitochondrial matrix, where they participate in β-oxidation and the TCA cycle, supplying energy and reducing equivalents.

SCFAs also regulate the levels of tryptophan 5-hydroxylase. It helps to produce serotonin, which is a vital neurotransmitter and hormone produced in the brainstem and gut, regulating mood, sleep, digestion, and appetite. Roughly 95% of the body's serotonin is in the GIT, stimulating bowel motility. It boosts mood and helps regulate anxiety. SCFAs also help produce tyrosine hydroxylase, which is essential for the synthesis of dopamine, noradrenaline, and adrenaline. This enables them to influence cerebral neurochemistry. Additionally, SCFAs have been demonstrated to modulate neurotrophic factors, including nerve growth factor, glial cell line-derived neurotrophic factor, and BDNF.

These factors are involved in the development, viability, proliferation, and differentiation of neurons and synapses in the brain. In a corresponding manner, all three SCFAs were observed to enhance the survival and growth of human brain progenitor cells and to promote mitosis. These findings provide insights into the potential role of SCFAs in regulating early nervous system development and hippocampal neurogenesis. The significance of SCFAs in shaping the development of the CNS. Also, SCFAs may be able to help attenuate long-term memory, cognition, and anxiety in various neurodevelopmental and neurodegenerative diseases.

The gut microbiome and MCBA are also affected by the oral microbiome 8. The oral–gut axis constitutes a pivotal route through which oral microbiota and their components modulate the gastrointestinal and systemic immune landscapes. Through swallowing, circulatory dissemination, immune cell trafficking, and the release of bacterial extracellular vesicles, components of oral bacteria, including whole cells, DNA, and lipopolysaccharides, can reach the GIT. Under permissive or pathological conditions, these microbial elements may penetrate mucosal barriers, allowing them to interact directly with intestinal epithelial cells, lamina propria immune cells, and mesenteric lymphoid tissues.

This interaction reshapes mucosal immune homeostasis and initiates systemic inflammatory cascades. Recent studies have revealed strong links between the oral microbiome and chronic diseases affecting distal organs, including metabolic, immune-mediated, and neurodegenerative conditions. Among the proposed mechanisms, the oral–gut axis not only represents a physical and physiological bridge between the oral cavity and the gastrointestinal tract but also embodies the complexity of interregional microbial crosstalk and immune integration.

After translocating to the gut, oral microbes can alter colonization patterns, disrupt microbial metabolism, and activate mucosal immune sensors, thereby promoting both local and systemic immune activation6. For example, pathogenic oral bacteria have been shown to disrupt gut microbial ecology, compromise epithelial barrier function, and engage mucosal immune sensors such as TLRs, collectively leading to local inflammation and immune activation in distal organs.

These processes are increasingly recognized in the pathogenesis of several diseases. The liver is anatomically and functionally connected to the gut via the portal vein, receiving approximately 70–75% of its blood supply from the GIT. This vascular connection enables continuous delivery of dietary nutrients, microbial metabolites, and translocated microbial products to the liver. Dysbiosis in the oral and gut microbiota has been increasingly linked to liver disease pathogenesis. Oral microbes can disrupt gut microbial homeostasis, compromise epithelial barrier integrity, and promote endotoxemia.

This facilitates the translocation of microbial components and metabolites to the liver through the portal circulation, initiating hepatic inflammation and immune dysregulation. The CNS is also susceptible to microbial influence through the oral–gut–brain axis. The gut–brain axis is known to regulate CNS function via neural, immune, endocrine, and metabolic pathways.

Expanding on this concept, oral microbiota may influence brain immune responses and neurophysiology, particularly in neurodegenerative disorders such as cognitive impairment, AD, and PD. Epidemiological studies have linked chronic oral inflammation, particularly periodontitis, to cognitive decline and increased risk of AD.

Notes

1 Thornton, Owen R. The Microbiota-Gut-Brain Axis as a Fundamental Regulator of Neuroplasticity: A Systematic Review and Meta-Analytic Synthesis at The University of North Carolina.
2 Smith, R.E. Our second brain. The enteric nervous system and gut microbiome at Meer.
3 Ohara, Takahiro E., and Elaine Y. Hsiao. Microbiota–neuroepithelial signalling across the gut–brain axis at Nature Reviews Microbiology.
4 Smith, R.E. Dietary fiber, the gut microbiome and health. There is an undeniable link between the brain, the gut and the immune system at Meer.
5 Xu, X. et al. Microbial SCFAs as epigenetic mediators: fine-tuning the gut-brain axis in neurodegenerative disorders at Science Direct.
6 Yassin, Lidya K., et al. Exploring the microbiota-gut-brain axis: impact on brain structure and function at Frontiers.
7 Li, Chunhao, Yue Fan, and Xingming Chen. Oral microbiota–driven immune modulation along the oral–gut axis: from local signals to systemic inflammation at Science Direct.