Gut Dysbiosis and Neurodegeneration: The Expanding Role of the Microbiome in Alzheimer’s Disease Pathogenesis and Therapy

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most prevalent form of dementia, affecting on the order of 50 million people worldwide. Clinically it manifests as insidious cognitive decline (including memory loss) and associated behavioural changes. Neuropathologically, AD is characterized by extracellular aggregation of amyloid-β (Aβ) into plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau. Chronic neuroinflammation and other pathologies (oxidative stress, vascular dysfunction, insulin resistance) are also recognized contributors to AD progression ^[1].  To date, no disease-modifying therapy exists: currently approved drugs provide only symptomatic relief (e.g. cholinesterase inhibitors, memantine) and fail to halt underlying neurodegeneration ^[2]. In recent years, the gut–brain axis has attracted considerable attention in neurodegenerative disease research ^[1]. The gut–brain (or microbiota–gut–brain) axis refers to a bidirectional communication network linking the central nervous system and the gastrointestinal tract via neural, endocrine, immune, and metabolic pathways ^[3]. The intestinal microbiota a diverse community of bacteria, archaea, viruses, and fungi residing in the gut plays a crucial role in this axis. Gut microbes generate bioactive metabolites (for example, short-chain fatty acids and neurotransmitter precursors), modulate peripheral and central immune signalling, and help maintain the integrity of the intestinal and blood–brain barriers ^[1,3]. Through these mechanisms, a balanced gut microbiome supports normal brain function and immune homeostasis. Accumulating evidence implicates gut dysbiosis (an imbalance or alteration in microbial composition) in AD pathogenesis. Multiple clinical studies have shown that the fecal microbiome profile of AD patients differs markedly from that of healthy older adults. Dysbiosis can lead to increased intestinal permeability and systemic inflammation. Leaky gut may allow bacterial components (e.g., LPS) or amyloid-like proteins to enter the circulation, triggering immune activation and cytokine release that can breach the blood–brain barrier and exacerbate neuroinflammation ^[3]. In experimental models, gut dysbiosis has been linked to increased brain Aβ production and plaque deposition, suggesting a feedforward cycle between peripheral microbial changes and central amyloid pathology ^[1]. Thus, impaired gut barrier function and chronic inflammation in dysbiosis may promote the core pathologies of AD. This review provides a comprehensive overview of the role of the gut–brain axis in AD, focusing on mechanisms by which gut dysbiosis may drive disease progression. We examine how microbial metabolites, immune signalling, and barrier dysfunction influence amyloid and tau pathology and neuroinflammation. We also survey emerging gut-targeted interventions – including dietary modulation (e.g. Mediterranean or ketogenic diets), probiotic and prebiotic supplementation, and even fecal microbiota transplantation – that have shown promise for ameliorating AD-related biomarkers or symptoms ^[3,4]. By elucidating the gut–brain connection in AD, we aim to identify novel therapeutic approaches for prevention and treatment of this devastating disorder.

Historical Background and Timeline

Early Concepts (17th–19th Centuries). The idea that the gut influences the brain has ancient roots. The microscopic gut organisms, later known as bacteria, were initially discovered by Antonie van Leeuwenhoek during the 17th century, but it was not until the 18th–19th centuries that physicians explicitly connected gut health with mental states. For example, 19th-century clinicians invoked nervous sympathy between the stomach and brain: dietary errors (rich food, alcohol) were thought to evoke negative moods and anxiety. James Johnson (1827) famously wrote that “strange antipathies… considered solely as obliquities of the intellect, have their source in corporeal disorder”. Physicians historically referred to the stomach as the “abdominal brain” or the “epicenter of organic function,” reflecting early recognition of gut-brain interplay. ^[5] foreshadowing modern gut–brain axis concepts. 20th Century and the Microbiome Revolution. By the early 20th century, Western medicine largely reversed this view: many gut disorders without apparent lesions were labelled psychosomatic, as scientists assumed mind-to-gut causality. However, in parallel, microbiology began to flourish. Elie Metchnikoff (1901–1904) hypothesized that Lactobacillus from yogurt could counteract gut “putrefaction” and aging, planting the seed for probiotics. Through the 20th century, terms like “probiotics” (coined in 1954) and “microbiota” (popularized in the 1990s) emerged. The Human Microbiome Project (2007) then catalogued human gut microbes, enabling detailed study of microbiome–disease links ^[5]. Gut–Brain Axis in AD (2010s–Present). Only in the 2010s did researchers directly test gut–brain links in AD. In 2017, Cattaneo et al. found that AD patients had higher levels of pro-inflammatory gut bacteria (e.g. Escherichia/Shigella) and lower anti-inflammatory Eubacterium compared to controls. The same year, Vogt et al. (2017) reported reduced microbial diversity in AD stool, with fewer Firmicutes and more Bacteroidetes. These and subsequent studies showed that even mild cognitive impairment (MCI) is associated with distinct gut microbiota profiles. Animal models also confirmed gut changes: transgenic AD mice differ markedly from wild-type controls in fecal microbiota composition ^[6]. Research has accelerated sharply: annual AD–microbiome publications climbed from ~2 in 2012 to ~393 in 2022 ^[7].

The Gut-Brain Axis: An Overview

1. Components of the Gut-Brain Axis
   The GBA is a complex network that includes:
   1. The Gut Microbiota: 

Microbes have coexisted with humans for millions of years, playing a fundamental role in physiological and metabolic processes. The human microbiota comprises trillions of microorganisms, with the gut microbiota being the most diverse and extensively studied. The gut hosts a diverse population of microorganisms, including yeasts, archaea, parasites such as helminths, viruses, and protozoa. Recent findings have identified an elementary layer of variability in the microbiome, specifically microbial genomic structural variants, which refer to the existence of a few genes that differ between otherwise identical bacterial strains. These variants are unique to the host microbiota and demonstrate a strong association with host metabolic health ^[8]. Bacteria dominate, chiefly from six phyla – Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia – with Firmicutes and Bacteroidetes constituting the majority (~75%) of the gut flora ^{[9, 10]}. Less abundant phyla (Actinobacteria, Proteobacteria, etc.) and genera (e.g. Bacteroides, Clostridium, Lactobacillus) are also present ^[9]. In addition to bacteria, the gut contains a resident virome (bacteriophages) and mycobiome (fungi such as Candida, Saccharomyces, Malassezia) and archaeal species (notably Methanobrevibacter smithii) ^{[9, 11]}. These non-bacterial members – often called “forgotten” microbiota – are increasingly recognized as modulators of gut ecology and may influence brain function by altering bacterial communities or producing unique metabolites ^{[9, 11]}. Gut microbes perform essential functions for the host, including fermenting dietary fibers to short-chain fatty acids (SCFAs), synthesizing vitamins, modulating immunity, and affecting host metabolism. They also synthesize neuroactive compounds: for example, certain bacteria produce neurotransmitters (γ-aminobutyric acid (GABA), serotonin precursors, dopamine) or their precursors ^[12]. These microbial signals can be conveyed to the CNS via vagal afferents or circulation. In contrast, pathogenic bacteria in dysbiosis can release pro-inflammatory molecules (e.g., lipopolysaccharide, LPS) that trigger systemic inflammation. Overall, the gut microbiota represents a dynamic organ-like component of the GBA, with diverse players (bacteria, viruses, fungi, archaea) and metabolites that can influence both local gut and distant brain physiology ^{[9, 11]}.

Figure 1. Gut-Microbiota-Participant Bacteria

The gastrointestinal tract differs from all other peripheral organs in that it has an extensive intrinsic nervous system, termed the enteric nervous system (ENS). The ENS is a “brain-in-the-gut”: a complex network of neurons and glia embedded in the gut wall that controls gastrointestinal functions independently but also communicates with the CNS. It comprises two main plexuses, the myenteric (Auerbach) plexus (between muscle layers, regulating motility) and submucosal (Meissner) plexus (in the mucosa, regulating blood flow and secretion) ^[13]. The ENS contains sensory neurons (mechanoreceptors, chemoreceptors) and motor neurons that coordinate peristalsis, blood flow, and epithelial secretion ^[12,13]. Notably, the ENS has its reflex circuits (intrinsic primary afferents, interneurons, motor neurons) that can function autonomously, but it is extensively connected to the CNS. For example, ENS activity modulates vagal afferent firing and can activate spinal sensory pathways. Conversely, CNS inputs (via vagus or sympathetic nerves) can adjust gut motility and secretion. The ENS also interacts with gut immunity: enteric neurons and glia can influence intestinal barrier function and immune responses. Emerging research links gut inflammation and microbiota composition with amyloid plaque formation in the brain, implicating ENS-mediated immune and inflammatory pathways in AD pathogenesis ^[14]. The ENS is not merely a digestive controller but a powerful player in neurological health and disease. Its intricate connection with the brain through the gut-brain axis suggests that understanding and modulating gut health may offer novel approaches to managing a range of neurological disorders. In summary, the ENS is a critical GBA component linking gut physiology to the brain ^[13].

1.3 The Vagus Nerve: 

The vagus nerve (cranial nerve X) is a principal conduit of gut–brain neural signalling. It is the longest cranial nerve, extending from the brainstem through the thorax to innervate the gut pmc.ncbi.nlm.nih.gov. Approximately 80% of vagal fibers are afferent (sensory), carrying information from the gut to the brain, while the remaining 20% are efferent (motor) parasympathetic fibers. Afferent vagal endings in the gut include mechanosensory receptors (intraganglionic laminar endings, responding to stretch and tension) and chemosensory endings (vagal villi), which can detect luminal nutrients, microbial metabolites, hormones and even immune mediators ^[12]. The vagus nerve plays a crucial role in the gut-brain axis (GBA), serving as the primary bidirectional communication pathway between the gut and the brain. It transmits signals from gut microbiota, enteroendocrine cells, and the enteric nervous system (ENS) to the brainstem, influencing neuroinflammation, neurotransmitter production (e.g., serotonin, GABA), and cognitive function.  For instance, microbial metabolites like SCFAs, indoles, or bacterial products (e.g. LPS) can activate vagal afferents either directly or indirectly via enteroendocrine cells. Activated vagal afferents transmit via the nucleus tractus solitarius (NTS) in the medulla to central autonomic and limbic networks, modulating inflammation, mood and behavior. Meanwhile, vagal efferents release acetylcholine in the gut to modulate motility, secretion and immune tolerance ^[12]. Thus, the vagus nerve provides a bidirectional neural highway: gut signals ascend rapidly to influence brain regions, while descending vagal tone regulates gut homeostasis. In Alzheimer’s disease (AD), vagus nerve dysfunction contributes to neurodegeneration bypromoting neuroinflammation (via cytokines like IL-1β and TNF-α), facilitating the spread of amyloid-β (Aβ) and tau pathology, and exacerbating cholinergic deficiency. Studies suggest that vagotomy may reduce AD risk, while vagus nerve stimulation (VNS)—both invasive and transcutaneous—shows promise in improving cognition by reducing inflammation and enhancing acetylcholine release. Additionally, gut microbiota modulation (probiotics, prebiotics) and α7nAChR agonists may help restore vagal signalling and slow AD progression. Emerging therapies targeting the vagus nerve highlight its potential as a novel therapeutic avenue for Alzheimer’s disease ^{[15, 16, 17]}.

1.4 The Immune System:

The gut immune system (gut-associated lymphoid tissue, GALT) is integral to the GBA. The gut microbiota modulates the immune system through interactions with gut-associated lymphoid tissue (GALT). The intestinal mucosa is protected by physical barriers (mucus, tight junctions) and immune defenses. Beneath the epithelium lies a dense network of immune cells (macrophages, dendritic cells, T and B lymphocytes) that survey the microbiota. Specialized epithelial cells secrete antimicrobial peptides (AMPs) and IgA into the lumen to neutralize pathogens. In a healthy state (eubiosis), this mucosal immune system maintains tolerance: dendritic cells sample commensal microbes and promote regulatory T-cell (Treg) responses via anti-inflammatory cytokines (e.g. TGFβ, IL-10), preserving barrier integrity. However, when homeostasis is disrupted (dysbiosis or injury), pathogen-associated molecular patterns (PAMPs) like LPS and toxins can breach the epithelium. For example, enterotoxin-induced tight junction damage (“leaky gut”) allows LPS to enter the circulation ^[18]. Inflammatory cytokines (TNF-α, IL-6, IL-1β, etc.) from activated gut immune cells then circulate systemically ^{[12, 18]}. These cytokines can signal the brain via a compromised blood–brain barrier or by activating endothelial and vagal afferents, thereby linking peripheral immune state to CNS inflammation. In summary, the gut immune system both senses microbial activity and relays immune signals (cytokines, chemokines, PAMPs) that can influence brain function ^[18]. The release of cytokines and other immune mediators influences systemic and central immune responses ^[19]. These interactions influence systemic immunity through cytokine release (e.g., IL-6, IL-10, TNF-α) and alter blood-brain barrier (BBB) permeability, facilitating neuroinflammatory cascades ^{[20, 21]}. Dysbiosis-driven chronic inflammation exacerbates Aβ aggregation and tau phosphorylation, whereas probiotic or fecal microbiota transplant (FMT) interventions may mitigate these effects ^{[20, 22, 23]}. Chronic gut inflammation has been implicated in neurodegenerative diseases such as Parkinson's and Alzheimer's disease ^[19].

1.5 Microbial Metabolites

Microbiota produce myriad metabolites that act as messengers in the GBA. Short-chain fatty acids (SCFAs) (e.g., acetate, propionate, butyrate) are generated by anaerobic fermentation of dietary fibers ^[24]. SCFAs are crucial for colonocyte nourishment and influence genetic activity, intestinal movement, and mucosal barrier integrity by modulating epigenetic processes like histone deacetylation. Importantly, they also affect the brain: SCFAs can cross into the blood and are transported into the CNS via monocarboxylate transporters, influencing neuroinflammation and neuroplasticity ^{[18, 24]}. For example, butyrate has neuroprotective roles in animal models, while low SCFA levels have been associated with neurodegenerative disease states. SCFAs also stimulate microglia and enhance blood–brain barrier integrity ^[18], indicating a direct metabolic route for gut microbes to modulate CNS immune cells. Microbes also produce neurotransmitters or their precursors. Certain bacteria and enteroendocrine cells synthesize GABA, serotonin (5-HT), dopamine, and other neuromodulators ^{[12, 25]}. For instance, 90% of body serotonin is produced by enterochromaffin cells in the gut – regulated by microbial metabolites ^[24]. Commensals like Bifidobacterium and Lactobacillus produce GABA, and others generate precursors to dopamine and acetylcholine ^{[12, 25]}. These molecules may enter circulation or stimulate vagal afferents (via enteroendocrine or “neuropod” cells), ultimately influencing brain neurotransmitter pools ^[25]. Lastly, the gut microbiota modulates bile acid metabolism: gut bacteria convert primary bile acids into signalling secondary bile acids. These bile acids can act on neural receptors (FXR, TGR5) in the brain, affecting neuroinflammation and neurotransmitter synthesis ^[26]. Dysregulation of bile acid signalling has been linked to cognitive impairment. In sum, microbial metabolites – SCFAs, microbial-derived neurotransmitters, bile acids, and others (indoles, tryptophan metabolites) – form a key chemical pathway connecting gut microbes to brain physiology ^{[18, 26]}.

2. Bidirectional Communication in the Gut-Brain Axis

The GBA facilitates bidirectional communication between the gut and the brain through multiple interconnected pathways. The gut-brain axis (GBA) is a complex, bidirectional communication system that links the enteric and central nervous systems. It encompasses neural, endocrine, immune, and microbial signalling pathways that enable the gastrointestinal tract to interact dynamically with the central nervous system, specifically the brain. This communication plays a critical role in maintaining homeostasis and influencing behavior, emotion, and cognition. Recent research underscores the gut microbiota's vital role in modulating these pathways, highlighting its impact on various neurological and psychiatric disorders.

Fig. 2 Schematic diagram showing the communication between the gut and brain. This is a bidirectional relationship that is strongly influenced by multiple pathways, including the autonomic nervous system (ANS), enteric nervous system (ENS), hypothalamic–pituitary–adrenal (HPA), immune pathways, endocrine pathways, and neural pathways."

The vagus nerve comprises approximately 80% afferent fibers that transmit information from the gut to the brain. About 80% of the vagus nerve fibers are sensory (afferent), transmitting gut-derived signals to the brain. This neural traffic is influenced by gut microbiota and their by-products, including SCFAs and neurotransmitters like serotonin, which modulate vagal tone and thereby affect central functions. This modulation influences brain functions, including mood and cognition, and may impact neurodegenerative processes associated with AD ^[27]. The vagus nerve is the principal neural highway of the gut–brain axis. Its afferent fibers carry mechanosensory and chemosensory information from the gut lumen and mucosa directly to the brainstem ^[12]. Signals from enteroendocrine cells (e.g., CCK, GLP-1, PYY release) or microbial products (SCFAs, LPS) activate vagal afferents, which then project to the nucleus of the solitary tract (NTS) and higher centers. Animal studies show that vagotomy abolishes many microbiota-driven effects on brain function, underscoring the vagus’s role ^{[12, 28]}. In the brainstem and hypothalamus, vagal input modulates autonomic tone and neuroendocrine outputs (e.g., stress response via HPA axis). Conversely, descending autonomic (vagal and sympathetic) fibers enable the CNS to regulate gut motility, secretion and blood flow. Thus, the neural branch of the GBA provides rapid, direct gut-to-brain signalling: gut stimuli (stretch, nutrients, microbial metabolites) elicit reflex changes in brain states (satiety, mood, neuroinflammation) ^[12].

2.2 Endocrine (Gut Hormones)

Gut-derived hormones are another endocrine arm of the GBA. After a meal or microbial stimulation, enteroendocrine cells secrete peptides (e.g. ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY, CCK) that enter the bloodstream ^[29]. These hormones convey information about energy intake and gut status to the brain. For example, the “hunger hormone” ghrelin (from stomach) rises before meals, signalling the hypothalamus and cortex to stimulate appetite. In contrast, satiety peptides (CCK, GLP-1, PYY) reduce food intake and modulate mood. These gut hormones can act directly in brain regions (especially the hypothalamic arcuate nucleus) – either by crossing the blood–brain barrier or by acting on circumventricular organs – or indirectly by activating vagal afferents ^{[29, 30]}. Adipose-derived leptin, while not a gut peptide, plays a related endocrine role: it signals long-term energy stores to the brain (leptin crosses the BBB to inhibit hunger) ^[30]. Notably, the gut microbiota influences these endocrine signals: microbial metabolites can stimulate enteroendocrine cells (e.g. SCFAs trigger GLP-1 release) and can affect circulating levels of ghrelin and leptin ^{[25, 30]}. In sum, endocrine mediators (gut peptides, hormones like ghrelin/leptin, and even microbial metabolites acting as signalling molecules) carry gut-derived information via the blood to brain centers controlling appetite, stress and cognition.

2.3 Immune (LPS, Cytokines)

Immune signalling provides another gut–brain communication route. When gut barrier function is compromised (due to dysbiosis, diet, stress, aging), microbial components and inflammatory mediators spill into the circulation. A prime example is LPS (endotoxin) from Gram-negative bacterial walls ^[18]. Elevated blood LPS (metabolic endotoxemia) triggers systemic inflammation by activating TLR4 on immune cells, leading to release of cytokines (IL-6, TNF-α, IL-1β) ^[18]. Such cytokines may infiltrate the brain by breaching the blood–brain barrier or via interactions with endothelial cells and the vagus nerve, subsequently activating microglia and disrupting normal neurotransmitter dynamics. ^{[12, 18]}. Indeed, LPS itself can activate vagal afferents via TLRs on nodose ganglia ^[18]. In neurodegenerative contexts, systemic inflammation primes microglia toward a pro-inflammatory state. In Alzheimer’s models, for instance, peripheral LPS administration has been shown to increase cerebral amyloid deposition and neuroinflammation ^[14]. In humans, patients with AD have higher plasma levels of LPS and inflammatory markers than healthy elderly ^[31]. Thus, immune signalling (circulating LPS and cytokines) forms a bidirectional bridge: gut inflammation can fuel brain inflammation, and conversely stress-induced brain cytokines (e.g. via HPA axis) can affect gut immunity ^{[12, 18]}.

2.4 Metabolic (SCFAs, Tryptophan Derivatives)

Metabolites serve as a metabolic communication channel. SCFAs (discussed above) exemplify this: once absorbed, SCFAs bind receptors on vagal afferents and modulate neuroactive factors (BDNF, catecholamines) in the brain. Similarly, gut metabolism of tryptophan links to neuroactive kynurenines. The microbiome influences host tryptophan pathways: some gut bacteria convert tryptophan into indoles (e.g. indole-3-propionic acid) or produce neurotransmitter-like amines (tryptamine). Host cells convert tryptophan to 5-HT or down the kynurenine pathway. Importantly, kynurenine metabolites (e.g. kynurenic acid, quinolinic acid) can cross the BBB; their balance affects glutamatergic signalling in the brain. An imbalance favouring neurotoxic quinolinic acid is implicated in neurodegeneration ^[32]. In sum, gut microbes modulate metabolic precursors (amino acids, vitamins) and produce neuroactive metabolites (SCFAs, tryptophan derivatives) that reach the brain via the bloodstream, altering neuronal and glial function ^{[18, 32]}.

3. Gut Microbiota and Alzheimer’s Disease

3.1 Dysbiosis and Altered Microbial Composition

Numerous studies report that Alzheimer’s patients exhibit gut dysbiosis – shifts in microbiota composition compared to cognitively healthy elderly. Meta-analyses and sequencing studies have found reduced diversity and characteristic taxonomic changes in AD or prodromal stages ^{[33, 34]}. Common findings include an increase in pro-inflammatory taxa (e.g. Proteobacteria, Bifidobacterium, Escherichia/Shigella) and a decrease in beneficial commensals (e.g. Firmicutes families like Clostridiaceae, Lachnospiraceae; and Bacteroides species) ^{[33, 34]}. For instance, one meta-analysis showed higher Proteobacteria and Phascolarctobacterium in AD, whereas Firmicutes and Rikenellaceae were depleted ^[33]. A Chinese cohort found AD-spectrum patients had more Escherichia/Shigella and less Bacteroides fragilis than controls ^[34]. These shifts may be driven by aging, diet and comorbidities: aging itself increases gut permeability and exposure to microbial products ^[34], potentially fostering inflammatory-prone communities. Overall, AD-related dysbiosis reflects a move toward a more inflammatory, less homeostatic gut ecosystem – a state linked to metabolic endotoxemia and immune activation.

Fig.3 The Gut-Brain Axis: Mechanisms Linking Gut Dysbiosis to Neuroinflammation and Brain Function

3.2 Intestinal Permeability and LPS-related Inflammation

Dysbiosis often accompanies “leaky gut” in AD. Increased intestinal permeability has been observed with aging and in AD models ^{[18, 34]}, allowing gut-derived toxins like LPS to enter circulation. LPS is a potent innate immune stimulant ^[18]. In AD patients, elevated serum LPS levels have been detected, and LPS has been found deposited in the brains of AD patients (co-localizing with Aβ plaques) ^{[14, 31]}. Experimentally, peripheral LPS exposure in animals exacerbates AD-like pathology: systemic LPS injections drive prolonged increases in hippocampal Aβ and tau pathology and impair cognition. Thus, an impaired gut barrier and endotoxemia can provoke systemic inflammation and potentiate AD neuroinflammation ^{[14, 31]}. Cytokines released by gut-triggered immune cells (e.g. IL-1β, IL-6, TNF-α) can cross the blood–brain barrier and activate microglia ^{[12, 14]}. This creates a vicious cycle: gut-derived inflammation primes brain innate immunity, promoting neurodegeneration.

3.3 Microbiota Influence on Amyloid?β (Aβ) Metabolism

Emerging evidence suggests gut microbes directly affect Aβ homeostasis. Some intestinal bacteria produce amyloid-like proteins (e.g. curli from E. coli). Bacterial amyloids are structurally similar (β-sheet rich) to human Aβ and may “cross-seed” aggregation: in animal models, oral exposure to curli-producing bacteria enhanced central amyloid deposition and induced microglial activation ^[14]. In addition, systemic inflammation (LPS, cytokines) promotes Aβ production and impairs its clearance ^{[14, 31]}. Germ-free transgenic AD mouse models develop far fewer amyloid plaques than conventionally-raised counterparts, and microbiota recolonization rescues plaque formation, implicating microbiome in Aβ pathology ^[34]. Consistent with this, the “endotoxin hypothesis” of AD posits that gut-derived LPS and inflammation drive amyloidogenesis ^{[14, 31]}. In sum, dysbiotic microbiota may accelerate Aβ deposition by supplying amyloidogenic molecules and by triggering inflammatory cascades that upregulate Aβ production in the brain.

3.4 Neuroinflammation and Microglial Activation

Gut dysbiosis in AD is linked to heightened brain inflammation Immune cells in the brain, particularly microglia, can be activated by microbial components such as LPS and cytokines that enter the bloodstream during gut dysbiosis. Chronic microglial activation is a hallmark of AD ^{[14, 31]}. In models, exposure to gut-derived amyloids or endotoxins leads to microgliosis and astrogliosis in the CNS ^[14]. The end products of tryptophan metabolism (quinolinic acid) and other neurotoxic metabolites can further stimulate microglia. Clinically, AD patients exhibit increased pro-inflammatory cytokines in cerebrospinal fluid. Thus, gut-driven systemic inflammation likely primes microglia to a pro-inflammatory state, exacerbating neuronal injury. Conversely, a healthy microbiome (with adequate SCFAs) supports anti-inflammatory microglial phenotypes ^[18]. In AD, reduced beneficial metabolites (like butyrate) and increased inflammatory signals tilt the balance toward neuroinflammation.

3.5 Microbial Neurotransmitter Production

Gut microbes modulate levels of neuroactive molecules that may be altered in AD. Dysbiosis in AD is often associated with decreased populations of bacteria that produce GABA (e.g. Bifidobacterium, Lactobacillus) ^[12] and altered modulation of serotonin. Since the gut produces most body serotonin, microbial changes can impact circulating 5-HT levels and downstream brain serotonin synthesis ^{[24, 25]}. Altered tryptophan metabolism (shunted toward inflammatory kynurenines) in AD may also diminish serotonin production. Similarly, microbial effects on choline metabolism can influence acetylcholine (lost in AD). In germ-free mouse studies, absence of microbiota lowers peripheral GABA and dopamine levels ^[35]. Human studies show that probiotic supplementation can raise GABA and improve cognition. Thus, dysregulated microbial neurotransmitter synthesis (reduced GABA, imbalanced serotonin precursors) may disturb brain neurotransmission in AD, contributing to cognitive and mood symptoms ^{[12, 25]}. Restoring a healthy microbiota may help rebalance these signalling molecules.

Current Research (2020–2025)

Human Studies of Gut Microbiota in AD

Recent human studies (2020–2025) have expanded on early findings of altered gut profiles in AD. Many use 16S rRNA sequencing or metagenomics. Consistent themes include reduced microbial diversity in AD, with depletion of beneficial Firmicutes (e.g. Lachnospiraceae, Ruminococcaceae producers of butyrate) and enrichment of pro-inflammatory taxa (e.g. Proteobacteria) ^[6]. For example, a 2024 meta-analysis of RCTs reported that probiotics (Lactobacilli, Bifidobacteria) modestly improved cognitive test scores in AD/MCI patients, though results were variable ^[37,38]. Some studies have identified gut microbiota metabolites (e.g. certain bile acids, phenolic compounds) as potential biomarkers of AD progression. However, findings are not always uniform: geographic and dietary differences affect results (e.g. one study found Bacteroidetes increased in Western AD patients but decreased in Chinese AD patients ^[6]).

Animal Models and Mechanistic Research

Animal models have provided mechanistic evidence. Transgenic mice expressing human AD mutations (e.g., APP/PS1, 5xFAD, 3xTg) show distinct gut microbiota compared to wild-type, often with reduced diversity and specific phylum shifts ^[6]. Importantly, microbiome manipulations can modulate AD-like pathology in these models:

• Fecal Microbiota Transplant (FMT): Transferring gut microbiota from healthy (wild-type) mice into AD-model mice ameliorates pathology. Zhang et al. (2019) showed that FMT in APP/PS1 mice improved cognition, reduced brain Aβ burden and tau phosphorylation, and increased synaptic proteins, alongside normalization of gut metabolites ^[40]. Conversely, transplanting AD-associated microbiota into normal mice can induce cognitive deficits.
• Antibiotic or Germ-Free Models: Broad-spectrum antibiotics or germ-free rearing reduce neuroinflammation and Aβ in some AD models, implying gut bacteria drive pathology. For example, AD mice treated with antibiotics show lower microglial activation ^[41].
• Probiotics/Prebiotics: Numerous animal studies test single strains. Probiotics (notably Lactobacillus and Bifidobacterium species) often reverse gut dysbiosis and reduce brain inflammation in AD rodents. A 2024 meta-analysis of 21 animal studies found probiotic supplementation significantly decreased pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and reduced amyloid plaque deposition, while improving spatial and working memory ^[37]. Prebiotic fibers (e.g. inulin, fructooligosaccharides) likewise promote SCFA production and have shown cognitive benefits in AD models ^[42].
• Dietary Interventions: Nutritional strategies high in dietary fiber, omega-3s, or polyphenols—like the Mediterranean diet—are shown to enhance gut microbial balance and cognitive performance in Alzheimer's models. For instance, polyphenol supplements from berries increased butyrate levels and attenuated tauopathy in transgenic mice.

Ongoing Clinical Trials and Trends

While preclinical findings are strong, human clinical trials are still in early stages. A few small RCTs have tested probiotic supplements in AD patients with mixed results: one trial (12 weeks) showed slight improvement in Mini-Mental State Exam (MMSE) scores, whereas others found no significant cognitive change ^{[37, 38]}. Trials with sodium oligomannate (a marine-derived oligosaccharide that modulates gut metabolites) in China reported slowed cognitive decline, leading to conditional approval for mild AD (mechanism involves gut microbiota modulation) ^[6]. Other approaches under study include prebiotic fibers, synbiotics, and even engineered probiotic strains designed to secrete neuroprotective compounds. Clinical research is also beginning to track gut microbiota as a biomarker: longitudinal studies measure microbiome composition and metabolite changes concerning cognitive decline.

Therapeutic Strategies Targeting the Gut–Brain Axis

Given mechanistic links, several gut-targeted therapies are being pursued (Table 1). These include microbial therapies (probiotics, prebiotics, FMT), dietary approaches, and pharmacological agents that modify gut–brain signalling.