Long-term yeast β-glucan reshapes the gut to protect the brain from Alzheimer's like symptoms caused by high-fat-diet in rats

Objective
To determine whether long-term supplementation with yeast β-glucan (BG) mitigates high-fat diet (HFD)–induced Alzheimer’s disease (AD)-like pathologies and cognitive dysfunction, and to define gut–brain mechanisms including roles for short-chain fatty acids (SCFAs) and NLRP3 inflammasome–mediated neuroinflammation. 

Methods

• Female specific-pathogen-free Sprague–Dawley rats were assigned to: (1) aged-control (normal diet), (2) HFD (45% kcal fat), or (3) HFD + BG (HFBG). 
• BG (800 kDa, S. cerevisiae) was given by oral gavage at 100 mg/kg/day for 80 weeks; controls received saline. 
• Behavioral testing included open-field, novel object recognition (NOR), and Morris water maze (MWM). 
• Neuroinflammation markers (hippocampal GFAP, Iba-1; NLRP3, caspase-1, IL-1β, IL-18), AD-like pathology (Aβ deposition; tau AT180 phosphorylation), gut barrier integrity (Muc-2, ZO-1, claudin-1, occludin; serum lipopolysaccharide (LPS), FITC-dextran), and 16S rRNA microbiome profiling were assessed. 
• SCFA levels (acetate, propionate, butyrate) were measured in serum and hippocampus.
• Causality was assessed via fecal microbiota transplantation (FMT) from HFD vs HFBG donors into HFD-fed aged recipients and via SCFA supplementation in drinking water (acetate 67.5 mM, propionate 40 mM, butyrate 25 mM) for 16 weeks. 

Results

• Cognition: BG improved NOR performance and MWM learning/memory (reduced escape latency; increased time/distance in target quadrant) vs HFD; open-field metrics were unchanged. 
• Neuroinflammation: BG reduced hippocampal GFAP and Iba-1 fluorescence and down-regulated NLRP3, caspase-1, IL-1β, IL-18, counteracting HFD-induced activation. 
• AD-like pathology: BG reduced Aβ deposition and tau AT180 phosphorylation without altering total tau (tau-5). 
• Microbiota/SCFAs: BG reversed HFD-associated dysbiosis (normalized Firmicutes/Bacteroidetes ratio; increased SCFA-linked genera such as Akkermansia, Parabacteroides, Ruminococcaceae; decreased LPS-associated taxa), and restored serum and hippocampal SCFAs. 
• Gut barrier: BG increased Muc-2 and tight-junction proteins (ZO-1, claudin-1, occludin) and lowered serum LPS and FITC-dextran, indicating improved barrier integrity. 
• Causality tests: (i) FMT from BG-treated donors transferred higher SCFA levels, improved MWM performance, and reduced NLRP3 activation, Aβ, and tau-P in HFD recipients vs FMT from HFD donors; (ii) SCFA supplementation reproduced improvements in cognition, suppressed NLRP3/caspase-1/IL-1β/IL-18, and reduced Aβ and tau-P. 

Interpretation
Chronic β-glucan (100 mg/kg/day) remodels the gut microbiota to raise SCFAs, repair gut permeability, and dampen hippocampal NLRP3 inflammasome signaling, thereby reducing Aβ/tau pathology and improving cognition under HFD stress. FMT and SCFA supplementation substantiate a microbiota SCFAs-NLRP3 axis mediating BG’s neuroprotective effects. 

Mechanisms & Pathways 

β-Glucan acts as a prebiotic, enriching SCFA-producing bacteria and increasing acetate/propionate/butyrate in serum and hippocampus; SCFAs correlate inversely with NLRP3–caspase-1–IL-1β/IL-18 activation and AD-like pathology. Improved Muc-2/ tight-junction expression limits LPS translocation, reducing upstream inflammatory tone. 

Dosage & Adverse Reactions

• BG dose: 100 mg/kg/day by oral gavage for 80 weeks (800 kDa material). 
• SCFA dose (intervention arm): acetate 67.5 mM, propionate 40 mM, butyrate 25 mM in drinking water for 16 weeks. 
• Adverse events: The paper does not report BG-related adverse effects; the long duration was justified by prior indications of low/no side effects and by chronic exposure models, but explicit adverse events monitoring outcomes are not detailed. 

Quality of Study 

Strengths include very long-term exposure, comprehensive phenotyping (behavioral, histologic, molecular, microbiome, metabolite), and mechanistic confirmation via FMT and SCFA add-back. 

Limitations include female-only rats, single BG dose and may not be translatable to humans, no pharmacokinetics and safety reported, some small assay n’s (e.g., n=3 for imaging/westerns in subsets), and preclinical generalizability constraints. 

Implications
These data support yeast β-glucan as a microbiome-modulating strategy to counter HFD-related neuroinflammation and AD-like pathology via SCFA-linked inhibition of NLRP3 and restoration of gut barrier. Further studies should evaluate dose-response, safety, and translational human trials in at-risk metabolic phenotypes.