The role of probiotics, prebiotics, and postbiotics: cellular and molecular pathways activated on glial cells in Alzheimer's disease

Abstract

Supplementation with prebiotics and probiotics can modulate the intestinal microbiota, returning it to a more physiological state; therefore, they can be considered as a possible treatment in many prevalent conditions, including neurodegenerative diseases. Alzheimer's disease (AD) is the most common form of dementia, accounting for 60 to 70% of cases. The neuropathological features of AD include neuritic plaques (extracellular deposits of the beta-amyloid protein, Aβ), neurofibrillary tangles (resulting from hyperphosphorylation of the tau protein), a predominantly cholinergic synaptic decrease, and the presence of inflammatory markers, all these characteristics together trigger the neurodegenerative process and cognitive deterioration. The etiology of AD is multifactorial, however, in recent years evidence has been shown on the significant association between dysbiosis, neuroinflammation, and neurodegeneration. In the present review, we will discuss the role of gut microbiota in the pathogenesis of AD, as well as the underlying mechanisms that trigger the use of probiotics, prebiotics, and postbiotics in neuroinflammation. Our attention will focus on the cellular and molecular mechanisms triggered by astrocytes and microglia, cells involved in mediating neuroinflammation and neurodegeneration in AD.

Keywords: Alzheimer’s disease; glial cells; neuroinflammation; postbiotic; prebiotic; probiotic.

Figure 1

Role of prebiotics, probiotics, and postbiotics in the gut-brain axis. The synergistic interplay between prebiotics, probiotics, and postbiotics fosters intestinal microbiota homeostasis by selectively enhancing the growth of beneficial microbial taxa while suppressing pathogenic populations. This microbial modulation is closely linked to elevated production of neuroactive metabolites, notably butyrate, which has been shown to fortify the integrity of the blood–brain barrier (BBB) and modulate neuronal activity. In parallel, these bioactive compounds enhance intestinal barrier function by upregulating the expression of tight junction proteins, including occludins, claudins, and zonula occludens-1 (ZO-1). Systemically, they activate neuroprotective pathways by modulating immune responses, balancing pro- and anti-inflammatory cytokines, attenuating oxidative stress via upregulation of antioxidant enzymes and regulating the biosynthesis and release of key neurotransmitters such as serotonin, GABA, and dopamine. Collectively, these mechanisms contribute to the attenuation of neuropathological hallmarks associated with Alzheimer’s disease, including β-amyloid plaque accumulation and neurofibrillary tangle formation.

Figure 2

Influence of prebiotics on the microbiota–gut–brain axis. Fructooligosaccharides (FOS) and galactooligosaccharides (GOS) promote the growth of beneficial gut bacteria such as Bifidobacterium and Lactobacillus, enhancing microbial production of neurotransmitters including serotonin and dopamine. Fermentation of FOS and GOS by the gut microbiota and/or probiotics generates short-chain fatty acids (SCFAs)—notably butyrate, lactate, and propionate—that lower colonic pH and shape microbial composition, thereby influencing SCFA output. Most SCFAs are absorbed in the proximal colon via bicarbonate exchange, contributing to pH homeostasis. Cecal pH (~5.5) is consequently lower than rectal pH (~6.5), limiting the proliferation of acid-sensitive pathogens. SCFAs cross the blood–brain barrier (BBB) via monocarboxylate transporters (MCT1 and MCT4), with MCT1—expressed in cortical and hippocampal astrocytes—showing higher substrate specificity for acetate and butyrate. Through BBB- and vagus-mediated pathways, prebiotics modulate glial and microglial activity, suppressing inflammatory cytokines (IL-1β, IL-6, TNF-α) and reducing the accumulation of neurodegenerative markers such as amyloid-β and phosphorylated tau. SCFAs also trigger microglial immune gene expression via Toll-like receptor 4 (TLR4) and NF-κB signaling, contributing to neuroprotection and central immune regulation.

Figure 3

Molecular mechanisms underlying the neuroprotective effects of postbiotics. This figure illustrates the proposed neurobiological actions of postbiotics—such as short-chain fatty acids (SCFAs), postculture supernatants, and bacterial extracellular vesicles (ECVs)—within the microbiota–gut–brain axis in rodent models. Postbiotics have been associated with enhanced cognitive function and reduced anxiety- and depressive-like behaviors. In the central nervous system, they promote neurotrophic support (↑BDNF, ↑NGF), augment antioxidant defenses (↑GSH, ↑SOD), and modulate neurotransmission (↑GABA_Aα1, ↑GABA_Bβ1). They also influence signaling pathways involved in neuroplasticity and inflammation (TrkB, TLR2), potentially attenuating oxidative stress, apoptosis, and neuroinflammatory responses. Moreover, postbiotic interventions are linked to a decrease in pro-inflammatory mediators (↓IL-1β, ↓IL-6, ↓NLRP3, ↓CCL2, ↓IP-10), reduced glial reactivity (↓GFAP, ↓Iba-1), and diminished amyloid-β (Aβ) plaque accumulation, possibly through histone deacetylase (HDAC) modulation and the actions of Vitamin K2, plasmalogens, and bacterial-derived ECVs.