Synbiotics in Alzheimer’s disease: mechanisms, clinical evidence, and therapeutic prospects

Abstract

Background

Growing evidence implicates gut microbiota (GM) dysbiosis in Alzheimer’s disease (AD) pathogenesis via the gut-brain axis. Dysbiosis contributes to neuroinflammation, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier disruption, and cognitive decline. Synbiotics (combinations of probiotics and prebiotics) offer a promising strategy to modulate GM, potentially ameliorating these AD hallmarks through multiple mechanisms including enhanced production of neuroprotective short-chain fatty acids (SCFAs), reduced inflammation, improved gut barrier integrity, and immunomodulation.

Objective

This review critically evaluates the current evidence on the therapeutic potential of synbiotics for AD. It aims to synthesize findings from preclinical and clinical studies regarding the efficacy of synbiotics in improving cognitive function and AD pathology, elucidate the underlying biological mechanisms including GM modulation, SCFA production, immune regulation, and gut-brain signaling, and identify key challenges and future research directions for translating GM-targeted interventions into effective AD therapies.

Conclusion

Synbiotics demonstrate significant potential, particularly in early AD, by improving cognitive domains, reducing neuroinflammation and AD biomarkers, and modulating beneficial microbial metabolites. However, challenges include confounding factors, unresolved questions about causality, inconsistent results in advanced disease, and insufficient large-scale human trials. Future success hinges on rigorous longitudinal randomized controlled trials integrating multi-omics approaches, advanced in vitro models, and personalized strategies considering baseline microbiota and host genetics. While not a standalone cure, synbiotics represent a valuable component within multi-target therapeutic approaches aimed at modulating the gut-brain axis to slow AD progression.

Key Points

• Gut microbiota dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis via the gut-brain axis. Synbiotics (probiotic-prebiotic combinations) show promise in ameliorating AD hallmarks by enhancing neuroprotective short-chain fatty acid production, reducing inflammation, and improving gut barrier integrity.

• Preclinical and clinical studies indicate synbiotics improve cognitive function, reduce neuroinflammation and AD biomarkers, and modulate beneficial metabolites, especially in early AD. However, challenges include confounding factors (diet, genetics, disease stage), unresolved causality, inconsistent results in advanced AD, and insufficient large-scale human trials.

• Future success requires rigorous longitudinal randomized controlled trials integrating multi-omics approaches and personalized strategies. Synbiotics are not a standalone cure but a valuable component of multi-target therapies to slow AD progression.

Introduction

Recent research highlights gut microbiota’s (GM) critical roles in host physiology, including immune regulation, pathogen suppression, neural development, blood-brain barrier (BBB) integrity, nutritional transformation, and more [1–13]. Stool microbes broadly reflect GM diversity despite differences from gut inhabitants [14, 15]. Crucially, GM dysbiosis, characterized by reduced diversity, is linked via the gut-brain axis to neurodegenerative disorders like Alzheimer’s disease (AD) [16, 17]. AD, accounting for up to 70% of dementia cases [18], involves amyloid-β accumulation and hyperphosphorylated tau proteins, causing synaptic dysfunction, inflammation, and metabolic disruption [19, 20]. GM dysbiosis can increase intestinal permeability and systemic inflammation, exacerbating AD pathology; microbial metabolites may cross a compromised BBB, triggering neuroinflammation [21]. Molecular AD mechanisms include neuronal loss, cytotoxicity, and protein aggregates [22, 23]. Consequently, synbiotics (probiotic-prebiotic combinations) targeting GM are emerging as promising AD interventions. Bacterial toxins can influence neurotransmitters via vagal afferents [24], while innate immune responses via Toll-like receptors (TLRs) contribute to inflammation; TLR dysregulation in microglia is implicated in AD [25–27]. Modulating TLRs through GM interventions offers novel therapeutic potential [25]. Combining GM modulation with anti-inflammatory agents such as dietary advanced glycation end products (d-AGEs), butyrate, vitamin D3) shows promise [28]. However, key questions about synbiotics’ efficacy in reversing AD symptoms remain. This review evaluates evidence, challenges, and mechanistic pathways of specific synbiotics for AD, synthesizing findings to clarify their therapeutic potential.

Synbiotics modulating gut microbiota

In recent years, compelling evidence has established a strong association between GM and human health and disease. GM diversity is influenced by dietary factors, such as fiber-rich and fermented foods, whereas artificial sweeteners and processed foods may promote dysbiosis [29, 30]. Dietary supplements, including prebiotics and probiotics, have demonstrated clinical significance. However, questions remain regarding their combined effects. Some theories attribute these effects to the direct action of individual components in the combination, though their impact may differ from that of empirical formulations [31]. Moreover, the scientific rationale behind synbiotics in regulating GM is well-supported when combining selected bacterial taxa at the genus, species, and strain levels. One example is acute rotavirus infection, which causes gastroenteritis in children. Oral administration of synbiotics containing Bifidobacterium lactis B94 and prebiotic inulin shortened the duration of the infection and controlled watery diarrhea [32]. Additionally, serum levels of aspartate aminotransferase (AST) were significantly reduced by consuming a Leuconostoc holzapfelii-enriched synbiotic beverage [33].

Beyond enhancing intestinal immunity, GM is linked to various diseases, including neurological and psychiatric disorders [34, 35]. GM influences brain microstructure, functional connectivity, cognitive function, mood, and intrinsic brain activity [36]. Studies in mouse models have revealed microbial effects on blood-brain barrier (BBB) integrity. GM also modulates neurogenesis and neurotransmitter production [19]. While alpha diversity (within-sample microbial diversity) varies, consistent beta diversity (between-sample microbial diversity) patterns are observed in both AD and Parkinson’s disease (PD) patients, reinforcing the association between neurodegenerative diseases (NDDs) and specific microbial taxa [37]. Notably, consuming fermented foods and beverages has been shown to slow cognitive decline and exert neuroprotective effects in older adults [38]. Reduced alpha diversity is associated with chronic pain, though findings on beta diversity remain inconsistent, along with decreased abundance of Roseburia and Faecalibacterium. Additionally, a decline in Odoribacter splanchnicus and Faecalibacterium prausnitzii, alongside an increase in Eggerthella spp., serves as a GM biomarker for chronic pain [39]. Common taxonomic changes in dementia etiology include reductions in Firmicutes and Bifidobacteria, while Proteobacteria levels rise [40]. Figure 1; Table 1.

Fig. 1.

Gut-brain axis and the role of synbiotics in Alzheimer’s disease

Table 1.

Clinical evidence of various synbiotics on clinical trials with respect to dose concentrations

Characterization of subjects	Synbiotic	Dosage	Main outcome	Ref
Obesity
20 overweight/obese subjects (BMI: 33.5 kg/m2)	L. acidophilus DDS-1, B. lactis UABla-12, B. longum UABl-14, and B. bifidum UABb-10 + trans-GOS	Total 7.5 × 109 CFU/d + 5.5 g/d for 3 m	Increased the abundance of gut bacteria associated with positive health effects, especially Bifidobacterium and Lactobacillus, and increased the gut microbiota richness	[41]
134 overweight/obese subjects (BMI:28.0–34.9 kg/m2)	B. animalis subsp. lactis 420 + Litesse® Ultra™ (LU)	1010 CFU/d + 12 g/d for 6 m	Plasma bile acids glycocholic acid, glycoursodeoxycholic acid, and taurohyodeoxycholic acid and tauroursodeoxycholic acid were reduced Christensenellaceae was consistently increased and correlated negatively to waist-hip ratio	[42]
60 subjects with (BMI ≥ 25 kg/m2	Sanprobi Super Formula®	2–4 capsules/d for 12w	Improved the condition of the microbiota and intestinal barrier	[43]
60 subjects (age: 20–50 y; BMI:25–35 kg/m2)	L. acidophilus, L. casei and B. bifidum + inulin	each 109 CFU /d + 0.8 g/d for 8 w	Improvements in TG, TC, LDL-C, body weight, stress, anxiety, and depression	[44]
32 adult women (BMI: 30–34.9 kg/m2)	B. lactis + FOS	109 CFU/d + 5 g/d for 8 w	Increase in pyruvate and alanine and decrease in citrate and BCAA Negative correlations between arginine and glutamine with fat mass	[45]
70 participants (age: 6–18 years old; BMI:≥80%)	L. casei, L. rhamnosus, S. thermophilus, B. breve, L. acidophilus, B. longum and L. bulgaricus + FOS	Total 2 × 10 8 CFU /d + 5 g/d for 8 w	Decrease in BMI Z-score, waist circumference, TG and TC, and increase in waist-to-hip	[46]
NAFLD
53 patients with NAFLD (ALT: ≥1.5 times the upper limit of the normal range; controlled attenuation parameter (CAP) :> 270 dB/m)	B. animalis subspecies lactis BB-12 + FOS	10 9 CFU/d + 0.4 g/d for 8 w	Decreased serum AST, γ-GT, TNF-α,NF-κB activity and hepatic steatosis	[47]
102 patients with NAFLD (mean age: 40 y; BMI: 31.2 ± 4.9 kg/m2)	B. animalis and inulin	108 CFU/d + 1.5 g/d for 24 w	Improved hepatic steatosis AST, ALT, ALP and γ-GT reduced	[48]
138 NAFLD patients (ages:18 and 60 y; BMI: 25–29.9 kg/m2; FBG: 100–125 mg/dL; impaired oral glucose tolerance test: 140–199 mg/dL)	Familakt (total 109 CFU of 7 strains of bacteria: L. casei, L. rhamnosus, L. acidophilus, L. bulgaricus, B. breve, B. longum, S. thermophilus + 0.4 g FOS)	One capsule/d for 16 w	Sitagliptin-Familakt produced greater improvement in FBS, AST, Chol, and LDL compared to sitagliptin alone	[49]
50 patients with nonalcoholic steatohepatitis	L. reuteri + Fiber Mais Flora ® (4 g of dietary fiber)	2 × 10 8 CFU/d + 10 g/d for 3 m	A reduction in steatosis, lost weight, diminished BMI and waist circumference measurement Permeability or LPS levels showed no change	[50]
IRS
38 patients with IRS (age:≥18 y)	Protexin®(total 2 × 10 8CFU:L. casei , L. rhamnosus , S. thermophilus , B. breve , L. acidophilus , B. longitude and L. bulgaricus + 0.4gFOS)	2 capsules /d for 28 w	The levels of fasting blood sugar and insulin resistance improved significantly	[51]
Diabetes
60 subjects with gestational diabetic GDM who were not on oral hypoglycemic agents	L. acidophilus strain T16, L. casei strain T2, and B.bifidum strain T1 +  inulin	2 × 109 each /d + 800 mg/d for 6 w	Decrease in serum high-sensitivity C-reactive protein (hs-CRP) plasma malondialdehyde (MDA), total antioxidant capacity (TAC), total glutathione (GSH) levels, cesarean section rate, incidence of hyperbilirubinemic newborns, and newborns’ hospitalization	[52]
81 patients with diabetes (Age:35–70 y)	L. sporogenes and inulin	1.2 × 1010CFU/d + 8.4 g/d for 8 w	A significant rise in plasma nitric oxide A significant reduction in MDA levels	[53]
78 patients with diabetes (Age:35–70 y)	L. sporogenes + inulin	1.2 × 1010 CFU + 8.4 g/d for 8 w	A significant decrease in serum TAG, VLDL-C, TC/HDL-C and a significant increase in serum HDL-C levels	[54]
88 obese patients with T2D (Age 30–80 y; HbA1c: 6.0%- 9.0%; BMI: ≥ 25.0 kg/m2)	L. paracasei strain Shirota and B.breve strain Yakult + GOS	3 × 108 CFU each/d + 7.5 g/d for 24 w	No significant changes in inflammatory markers were found in the synbiotic group compared to the control group	[55]
62 patients with T2D	L. sporogenes + inulin	2.7 × 108CFU/d + 1.08 g/d for 8 w	A significant increase in plasma total GSH Reduced FPG, serum TG and HDL-cholesterol levels	[56]
81 patients with T2D (Age: 35–70 ye)	L. sporogenes + inulin	1.2 × 1010 CFU/d + 8.4 g/d for 8 w	A significant reduction in serum insulin levels, homeostatic model assessment for insulin resistance scores and homeostatic model assessment-β-cell function	[57]
RTI
925 pregnant mothers carrying infants at high risk for allergy	L. rhamnosus GG and LC705, B. breve Bb99, and P. freudenreichii ssp. shermanii JS + GOS	Total 1.6–1.8 × 1010 CFU/d + 1.6 g/d for 6 m	Increase resistance to RTI during the first 2 years of life in infants	[58]
78 children younger (Age: ≥ 5 y)	L. acidophilus Rosell-52, B. infantis Rosell-33, B. bifidum Rosell-71 + GOS	5 × 10⁹CFU/d + 0.75 g/d for 9 m	Provide effective control of the frequency of respiratory infections was three months, and six months were required to establish control of the frequency of wheezing	[59]
181 healthy children, (Age: 12–48 m)	L. bulgaricus and B. animalis subspecies lactis 12 + inulin	5 × 10⁹CFU each /d + 1 g/d for 9 m	Significantly fewer days of reported fever, significant improvement in social functioning, and school functioning increased frequency of bowel movements	[60]
721 healthy subjects	L, plantarum, L, rhamnosus and B, lactis and FOS	10 × 10 9 CFU each/d + 3 g/d for 90 d	Reducing the incidence and severity of respiratory diseases during the cold season	[61]
Allergy
800 Pregnant women at 24–32 w of gestation	B.bifidum OLB6378 + FOS	7 × 109 CFU/d + 1 g/d for 6 m	NO effect	[62]
29 patients with asthma and house dust mite allergy	B. breve M-16 V + Immunofortis®(scGOS/lcFOS,9:1)	1010CFU/d + 8 g/d for 4 w	Significant reduction in systemic production of Th2-cytokines after allergen challenge and improved peak expiratory flowPEF	[63]
90 children with atopic dermatitis (Age: ≥ 7 m)	B. breve M-16 V + Immunofortis®(scGOS/lcFOS,9:1)	1.3 × 109 CFU /d + 0.8 g/d for 4 w	This synbiotic prevents asthma-like symptoms in infants with AD	[64]
IBD
41 patients with mild to moderate UC	B. breve strain Yakult + GOS	3 × 109 CFU/d + 5.5 g/d for one year	The clinical status of the UC patients as assessed by colonoscopy, significantly improved the amount of myeloperoxidase in the lavage also decreased	[65]
18 patients with active UC	B.longum + Synergy 1 (FOS and inulin)	4 × 10 11 CFU/d + 12 g/d for 4 w	Sigmoidoscopy scores (scale 0–6) were reduced mRNA levels for human beta defensins 2, 3, and 4, which are strongly upregulated in active UC, were significantly reduced TNF-α IL-1β reduced	[66]
120 patients with UC	B.longum + psyllium	2 × 109 CFU/d + 8 g/d for 4 w	C-reactive protein decreased significantly Inflammatory Bowel Disease Questionnaires scores improved	[67]
10 active CD outpatients without history of operation for CD were enrolled	B. breve, B.longum and L. casei + psyllium	Total 7.5 × 1011 CFU/d + 9.9 g/d for 17 m	CD activity index (CDAI), International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score reduced Two patients were able to discontinue their prednisolone therapy, while four patients decreased their intake	[68]
35 active CD with Crohn’s disease activity indices CDAI score between 150 and 450	B. longum + Synergy I	4 × 1011 CFU/d + 12 g/d for 6 m	Significant reductions occurred in TNF-alpha expression in synbiotic patients at 3 months, although not at 6 months Significant improvements in clinical outcomes occurred with synbiotic consumption, with reductions in both CDAI and histological scores	[69]
Cancer
73 patients with colorectal cancer	Simbioflora (total 10 9CFU: L.acidophilus NCFM, L. rhamnosus HN001, L. casei LPC-37, and B.lactis HN019 + 6 g FOS)	1 capsule/d for 16 w	Reduce in CRP and IL-6	[70]
37 colon cancer patients	B. lactis Bb12 and L. delbreuckii rhamnosus GG + SYN1 (FOS-enriched inulin)	108 CFU each /d + 12 g/d for 6 m	Bifidobacterium and Lactobacillus increased and Clostridium perfringens decreased Reduced colorectal proliferation and the capacity of fecal water to induce necrosis in colonic cells Increased the production of interferon gamma in the cancer patients	[71]
61 patients with advanced esophageal cancer who were scheduled to receive neoadjuvant chemotherapy	B. breve strain Yakult and L. casei strain Shirota + FOS	2 × 108 CFU each/d + 45 g/d for 10 d	The concentrations of acetic acid and propionic acid were significantly higher The frequencies of severe lymphopenia and diarrhea were significantly less and febrile neutropenia occurred less	[72]
76 overweight or obese postmenopausal women with a history of hormone-receptor-positive breast cancer BC. (Age: 50–75; BMI 25–40 kg/m2)	L.casei, L.acidophilus, L. rhamnosus, L. bulgaricus, B.breve, B. longum, and S. thermophiles + GOS	Total 109 CFU /d + 35 mg/d for 8 w	Increased adiponectin reduction in TNF-α levels and hs-CRP levels	[73]
54 patients with biliary cancer before hepatectomy	B. breve strain Yakult and L. casei strain Shirota + GOS	1 × 108 CFU each/d + 12 g/d for 2 w	Combined with early enteral nutrition, this symbiotic can reduce postoperative infections in biliary cancer	[74]
91 patients with colorectal cancer before hepatectomy	Lacidophilus, L. rhamnosus, L.casei, B.lactis + FOS	Total 10 8–109 CFU /d + 6 g/d for 19 d	The perioperative administration of symbiotics significantly reduced postoperative infection rates in patients with colorectal cancer	[75]

Clinical evidence on synbiotics and Alzheimer’s disease

Synbiotic interventions targeting the gut-brain-microbiota axis show promise for AD. In APP/PS1 mice, synbiotics with xylo-oligosaccharides activated the peroxisome proliferator-activated receptor (PPAR) pathway, reduced neuroinflammation, reversed cognitive decline, and alleviated psychological burden [76]. This 12-week period equates to three months and involves human AD patients. By modulating GM via PPAR activation, synbiotics inhibit AD progression and may delay onset [77]. Combinations like β-nicotinamide mononucleotide (NMN) reduce amyloid plaques [78], while Clostridium sporogenes with xylan increases neuroprotective indole-3-propionic acid [79]. Clinical studies report that 12-week co-supplementation with probiotics (Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium spp.) and selenium improves cognitive function and metabolic profiles in AD patients [80, 81]. Synbiotics may positively influence mood, cognition, memory, and reduce hospitalization [82], with Lactobacillus and Bifidobacterium strains increasing SCFAs, improving cognition, and reducing inflammation [83]. Specific Lactobacillus psychobiotics enhance cognition via the gut-brain axis [84].

Synbiotics mitigate AD pathology by reducing oxidative stress, tau hyperphosphorylation, and amyloid-β toxicity [85]. They elevate neuroprotective peptide hormones, improve insulin homeostasis, boost antioxidant activity, and may delay amyloid-β deposition [86]. Benefits include improved plasma triglycerides, insulin resistance, VLDL cholesterol, and reduced malondialdehyde [87]. However, research remains inconclusive: synbiotics may restore gut health and improve cognition [88], potentially offering novel therapeutic strategies [89, 90], but efficacy may be compromised during antibiotic use or contribute to cognitive impairment [91]. Supplementation duration significantly influences outcomes [92], with greater efficacy in early cognitive dysfunction than advanced disease. Negative trends were observed with Lactobacillus plantarum [93].

Biological mechanisms of synbiotic action: insights from clinical evidence

Synbiotics consistently increase the abundance of beneficial bacteria, particularly Bifidobacterium and Lactobacillus, and enhance overall microbial diversity (richness) [41]. These bacteria are primary producers of health-promoting metabolites. A core mechanism is the fermentation of prebiotics (FOS, GOS, inulin) by probiotics into SCFAs like acetate, propionate, and butyrate. Elevated SCFAs, such as acetic and propionic acid [72], provide energy for colonocytes and influence host metabolism. They stimulate glucagon-like peptide-1 (GLP-1) release, improving insulin sensitivity [51, 57] and reducing fasting blood sugar [51, 56]. Butyrate enhances mitochondrial function and energy expenditure. Crucially, butyrate acts as a potent histone deacetylase (HDAC) inhibitor, promoting an anti-inflammatory environment in the gut and systemically by suppressing pro-inflammatory cytokines like TNF-α, IL-1β, and NF-κB activity [47, 69, 73].

SCFAs, especially butyrate, are the primary energy source for colonocytes, promoting epithelial cell proliferation, strengthening tight junctions, and increasing mucus production [43], thereby enhancing the gut barrier. Synbiotics significantly alter bile acid profiles, reducing specific plasma bile acids like glycocholic acid [42]. They influence bile acid deconjugation and recycling, impacting lipid metabolism, glucose homeostasis, and FXR/TGR5 receptor signaling, with systemic metabolic and anti-inflammatory consequences. Increased Christensenellaceae [42], often linked to leanness, suggests modulation of host lipid metabolism. Synbiotics also alter amino acid profiles, such as increasing pyruvate and alanine while decreasing citrate and branched-chain amino acids (BCAAs) [45]; high BCAA levels are linked to insulin resistance. Negative correlations between arginine/glutamine and fat mass [45] suggest influences on muscle metabolism and adiposity.

A primary target of synbiotics is strengthening the intestinal barrier [50]. Probiotics enhance mucus production, compete with pathogens for adhesion sites, and produce antimicrobial peptides, while prebiotics fuel beneficial bacteria. Improved barrier function [43] reduces translocation of bacterial endotoxins like lipopolysaccharide (LPS), a key driver of systemic inflammation implicated in metabolic diseases (Obesity, T2D, NAFLD) and neuroinflammation [47]. Synbiotics consistently reduce systemic inflammatory markers, including pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, NF-κB [47, 69, 73]) and acute-phase proteins (CRP, hs-CRP [52, 73]). They influence immunity by potentially reducing neutrophil infiltration (lower myeloperoxidase [65]), modulating macrophage polarization towards an anti-inflammatory (M2) phenotype, enhancing anti-inflammatory cytokine production (IL-10), and regulating T-cell responses (reducing Th2 cytokines in allergy [63]). Synbiotics combat oxidative stress by increasing total antioxidant capacity (TAC), glutathione (GSH) levels [52, 56], and reducing markers like malondialdehyde (MDA) [52, 53]. They suppress pathogenic bacteria (reduction in Clostridium perfringens [71]) by competing for nutrients/adhesion sites, producing bacteriocins, and lowering luminal pH.

Synbiotics improve metabolic health through reduced hepatic steatosis [47, 48, 50], improved lipid profiles (decreased TG, TC, LDL-C; increased HDL-C [44, 54]), reduced insulin resistance [51, 57], and modulation of adipokines (increased adiponectin [73]). Gut microbiota changes (increased Christensenellaceae [42], Bifidobacterium) drive SCFA production, bile acid modification, and reduced endotoxemia. Key mechanisms include improved insulin sensitivity/secretion (increased HOMA-β [57]), reduced hyperglycemia [51, 56], amelioration of oxidative stress [52, 53], and reduced inflammation [52]; SCFAs (acetate, propionate) regulate glucose via GLP-1 and PYY. Synbiotics enhance mucosal immunity, promoting IgA production, modulating dendritic cells, and stimulating regulatory T cells (Tregs), leading to reduced respiratory tract infections (RTIs) [58–61] and modulated allergic responses (reduced Th2 cytokines [63], prevention of asthma-like symptoms [64]).

Synbiotics reduce intestinal inflammation by downregulating pro-inflammatory cytokines (TNF-α, IL-1β [66, 69]), reducing neutrophil activity (MPO [65]), enhancing barrier function [43], increasing defensin production [66], and promoting epithelial repair, helping restore microbial balance in IBD. Effects in other contexts include reduced systemic inflammation (CRP, IL-6 [70]), modulated microbiota composition (increasing beneficial, decreasing harmful bacteria [71]), reduced procarcinogenic factors (e.g., fecal water genotoxicity [71]), potential immune surveillance enhancement (increased IFN-γ [71]), reduced chemotherapy side effects (febrile neutropenia, diarrhea [72]), and reduced perioperative infection rates [74, 75]. Synbiotics modulate the gut-brain axis via neural (vagus), endocrine (HPA axis), immune (cytokines), and metabolic (SCFAs, tryptophan metabolites) pathways. The vagus nerve is acknowledged as a key neural pathway within the gut-brain axis through which gut microbes and bacterial toxins can influence central neurotransmission and neuroinflammation, notably via vagal afferents (24). The review further identifies synbiotics as modulators of the gut-brain axis via neural (vagus), endocrine, immune, and metabolic pathways. However, a dedicated mechanistic exploration of how synbiotics specifically target or modulate vagus nerve signaling, particularly its roles in dampening systemic inflammation, regulating neuroimmune activity such as microglial function, and facilitating neuroprotection, is not comprehensively understood.

Probiotics can produce neurotransmitter precursors (GABA, serotonin). Synbiotics increase serum Brain-Derived Neurotrophic Factor (BDNF) levels, crucial for neuronal survival, plasticity, and cognition [94]. By decreasing systemic inflammation and endotoxemia, they reduce neuroinflammation. Probiotic/synbiotic supplementation improves cognitive function: enhancing mental flexibility and reducing stress [95], improving cognition and sleep in MCI [96], improving specific domains (memory, visuospatial skills, attention) in healthy elderly [97], and preventing decline/suppressing atrophy in MCI [98]. Mechanisms involve BDNF increase, anti-inflammatory effects, reduced oxidative stress, and microbial modulation of neural signaling [99]. The APOE genotype (Alzheimer’s risk factor) associates with distinct microbiome profiles (differences in Prevotellaceae, Ruminococcaceae, butyrate producers [96]), suggesting the microbiome-gut-brain (MGB) axis mediates genetic risk. Fecal Microbiota Transplantation (FMT) maintained/improved cognition in MCI and prevented worsening, coinciding with microbiota changes [100], supporting a causal role for gut microbes in cognitive health. Synbiotics show significant cognitive benefits in MCI and early-stage AD by reducing neuroinflammation and improving metabolism [76, 97, 98], but efficacy diminishes in moderate-to-late stages due to irreversible neuronal loss and advanced pathology [101]. This responsiveness gradient, evidenced by superior outcomes in MCI versus advanced AD [102, 103], highlights a critical window for early intervention [76, 97]. Stage-specific dysbiosis (e.g., Phascolarctobacterium increases in MCI [102]) underscores the need for stratified trials to optimize timing in AD [104, 105]. Figure 2; Table 2.

Fig. 2.

Biological mechanisms of synbiotic action: insights from clinical evidence

Table 2.

Clinical trials synbiotics reversing AD

Study objective	Study design	Main findings	Conclusion	Ref
Evaluate probiotic + selenium co-supplementation in AD patients	Randomized, double-blind, controlled trial (12 weeks)	Improved cognitive function and metabolic profiles	Co-supplementation may benefit clinical and metabolic status in AD	[82]
Assess probiotic effects on cognitive function/mood in older adults	Randomized, double-blind, placebo-controlled trial	Enhanced mental flexibility, reduced stress; gut microbiota changes observed	Probiotics improve cognition and mood in community-dwelling older adults	[94]
Examine probiotic intervention in mild cognitive impairment (MCI)	Clinical trial	Improved cognition and sleep quality	Probiotics benefit multiple neural behaviors in MCI patients	[97]
Test Bifidobacterium breve effects on cognition/brain atrophy in suspected MCI	24-week randomized, double-blind, placebo-controlled trial	Improved cognitive function and suppressed brain atrophy	Probiotics may prevent cognitive decline and structural brain changes in MCI	[98]
Investigate Bifidobacterium longum BB68S in healthy elderly cognition	Randomized, double-blind, placebo-controlled trial	Enhanced memory, visuospatial skills, and attention	Probiotics improve specific cognitive domains in healthy older adults	[99]
Explore fecal microbiota transplantation (FMT) for age-related cognitive impairment	Clinical trial (preliminary)	Maintained/improved cognition in MCI; microbiota changes correlated with outcomes	FMT shows potential as a treatment for cognitive impairments by modulating gut microbiota	[100]

Challenges in reversing Alzheimer’s disease symptoms with synbiotics

Lifestyle factors, particularly long-term dietary patterns, are potent modulators of the GM, as diet directly supplies substrates for microbial metabolism, shaping community structure and metabolite production. Polypharmacy, common in elderly populations and chronic conditions like AD, introduces complexity. Many drugs, including antibiotics, proton pump inhibitors, metformin, and psychotropics, exhibit unintended off-target effects on gut bacteria, potentially disrupting the community targeted for therapeutic modulation by synbiotics [101]. Furthermore, GM composition exhibits striking variations linked to disease stage and geography. The Phascolarctobacterium genus demonstrates a specific increase during the mild cognitive impairment (MCI) stage, a prodromal phase of AD, suggesting stage-specific dysbiosis [102]. Conversely, the abundance of the Bacteroidetes phylum differs significantly between AD cohorts in the U.S. compared to China, highlighting how regional factors (diet, environment, genetics) dramatically influence the baseline and disease-associated microbiome [103]. This geographical variation extends to specific taxa; the effects and abundance of genera like Phascolarctobacterium and families like Clostridiaceae vary considerably among AD patients across different global regions, indicating their role is moderated by an interplay between disease progression and geographical/environmental context [104]. Host genetics also significantly shape the GM landscape in AD. The presence of the apolipoprotein E (APOE) ε4 allele (rs429358), the strongest genetic risk factor for late-onset AD, is associated with distinct alterations in gut microbial composition compared to non-carriers, even before clinical symptoms manifest [105], suggesting genetic predisposition can create a permissive or resistant gut environment for neurodegeneration-linked dysbiosis.

Insights from other neurodegenerative conditions, like multiple sclerosis (MS), reveal shared themes of dysbiosis, though specific microbial signatures differ. MS research documents increased Akkermansia, Ruminococcus, Blautia, and Bacteroidetes, coupled with reductions in beneficial SCFAs like butyrate. These changes correlate with decreases in genera/species such as Bifidobacterium, Coprococcus, Lachnospira, and Prevotella, and phyla/families like Firmicutes and Lachnospiraceae [106]. While consistent GM patterns emerge across cognitive disorders and neurodegeneration, a critical limitation persists: a profound insufficiency in mechanistic studies. The observation of overlapping microbial taxonomic changes in conditions like PD and AD raises fundamental, unresolved questions about causality. Are these microbial shifts primary drivers of neuropathology, contributing to disease onset and progression? Or are they merely secondary consequences biomarkers of underlying neurodegenerative processes, neuronal death, inflammation, and physiological stress [107]? Disentangling cause from effect is paramount for targeted interventions. This leads to a fundamental unresolved question: Do specific microbial changes precede and potentially contribute to AD pathology, or do they arise as a result of the disease state itself? AD patients exhibit systemic low-grade inflammation, impaired immunity, and increased infection susceptibility. While antimicrobial interventions might seem logical, the specific operational taxonomic units (OTUs) most relevant to AD remain poorly defined [108, 109]. It is critically unknown whether the predominant microbes identified in AD dysbiosis actively drive disease progression or are merely early contributors. Consequently, exploring a combined pathogenic therapy approach incorporating antibacterial, antifungal, and potentially antiviral agents’ warrants investigation as a strategy to modulate a potentially pathogenic microbiome in AD, although this carries significant risks of further disrupting microbial balance [110, 111].

Non-pharmacological strategies aimed at modulating chronic inflammation through the gut-brain axis include dietary modifications (Mediterranean and MIND diets), probiotics, prebiotics, synbiotics, and fecal FMT. While appealing due to perceived safety, their efficacy in consistently and significantly improving core neuropsychiatric functioning and cognitive outcomes in AD patients remains largely unproven in large, rigorous trials. Current mechanistic research explores their potential to influence fundamental brain processes like synaptic pruning and neural connection optimization. While microbiota-immune system crosstalk is well-documented, the specific mechanisms by which the microbiota influences microglial function and subsequently, microglial-mediated synaptic pruning a process critically dysregulated in AD, remain elusive [112]. How synbiotics might precisely modulate this intricate pathway is unknown. Crucially, research specifically examining synbiotic formulations designed to mitigate AD pathology and robustly comparing their effects against both placebo and healthy controls is currently insufficient [113]. This paucity of high-quality, targeted clinical trials prevents establishing standardized synbiotic protocols, reliable dosing regimens, or definitive medical recommendations for therapeutic gut-brain axis interventions in AD management [114]. This evidence gap extends to nutraceuticals. Curcumin, a natural polyphenol with demonstrated neuroprotective, anti-amyloidogenic, and anti-inflammatory properties in vitro and in animal models, shows considerable promise for managing NDDs due to these pleiotropic effects [115]. However, its clinical translation is hampered by poor oral bioavailability and complex pharmacokinetics. Curcumin is metabolized by gut bacteria into potentially more active compounds (tetrahydrocurcumin), but the extent of conversion, systemic levels of metabolites, their BBB permeability, and ultimate contribution to therapeutic effects versus limitations in humans are poorly understood [116]. Similarly, other dietary polyphenols like anthocyanins possess antioxidant and anti-inflammatory activities suggesting clinical potential for NDD therapy [117], but remain significantly underexplored in AD concerning GM interactions, bioavailability, optimal dosing, and human efficacy.

Emerging therapeutic dietary strategies like ketogenic diets present a confusing picture, with studies reporting conflicting physiological responses and cognitive outcomes [118], underscoring patient heterogeneity and the need to identify beneficiaries and optimal protocols. At the molecular level, emerging research strongly implicates dysregulation of the kynurenine pathway (KP), a major route of tryptophan metabolism and its neuroactive metabolites in driving neuroinflammation, excitotoxicity, and oxidative stress, positioning it as a key pathophysiological feature of AD [23]. However, elucidating the precise role of the GM in modulating the KP within AD-associated dysbiosis, and its contribution to neurotoxicity, requires deeper mechanistic insight. Future GM research must explicitly address whether and how different APOE genotypes modulate dysbiosis outcomes, given APOE’s central role in AD risk, lipid metabolism, and potentially neuroinflammation.

Advancing AD pathogenesis understanding necessitates moving beyond bacterial census-taking. Comprehensive analysis of the entire synbiotic microbiota, including the virome (viruses) and mycobiome (fungi), through integrated translational approaches (bench to bedside and back), is essential, as these components likely play significant but understudied roles. A particularly promising yet underexplored area involves establishing the mechanistic links between changes in adipokines (hormones like leptin and adiponectin secreted by adipose tissue) and alterations in the GM. Adipokines are central to body weight regulation, energy metabolism, inflammation, and synaptic function. Their dysregulation in obesity and metabolic syndrome, known AD risk factors, suggests interconnected pathways linking adipose tissue, gut microbiome, inflammation, and brain health in AD progression. Understanding these connections could reveal novel therapeutic targets spanning metabolism, immunity, and the microbiome.

Prospects of synbiotics and therapeutic strategies in Alzheimer’s disease

The search for effective AD interventions increasingly focuses on sophisticated multi-target strategies, exploring gene therapy and combination approaches to simultaneously address core pathologies, amyloid-β plaques, neurofibrillary tau tangles, alongside impaired synaptic plasticity, compromised neurovascular function, dysregulated epigenetics, metabolic disturbances (insulin resistance, cholesterol homeostasis), and the GM role in blood-brain barrier integrity [119]. Insights from prion diseases suggest microglial inflammation’s potential link to amyloid fibril formation, warranting exploration in AD [27, 120]. The limited efficacy of current FDA-approved symptomatic treatments (acetylcholinesterase inhibitors, NMDA receptor antagonists) underscores the need for holistic paradigms beyond symptom management, incorporating potential infectious or microbiome-mediated etiological components. While advanced AD stages involve irreversible neuronal loss [121], gut-brain axis modulation offers promise: most studies demonstrate measurable cognitive improvement with targeted probiotics [122], particularly enhancing immediate memory and overall cognitive function [123].

Robust randomized controlled trials and longitudinal cohort studies remain essential to validate novel interventions [124]. Integrating metagenomic sequencing (GM taxonomy/function), host genomics, and neurological metabolomics is pivotal for precision medicine, facilitating early AD diagnosis via microbial/host-derived inflammation biomarkers before significant cognitive decline [125]. Advanced in vitro models, like 3D brain organoids coupled with microfluidic “gut-on-a-chip” or “brain-on-a-chip” systems, will help model dynamic GM-brain axis interactions [38]. Emerging frontiers include investigating GM-derived volatile organic compounds (volatilome) in AD pathogenesis, as these can cross the blood-brain barrier [126]. Merging genome-scale metabolic models (GEMs) with longitudinal disease studies could enable personalized anti-inflammatory diets optimized for neuroprotective GM reshaping [127]. State-of-the-art meta-omics, deep metagenomics (strain-level resolution), meta-transcriptomics (active gene expression), microbial proteomics/metabolomics (microbial proteins/metabolites in stool/serum/CSF), are indispensable [128]. Computational mapping of microbial signaling pathways (SCFAs, bile acids, neurotransmitters, immune modulators) is key to elucidating host-microbe-environment interactions [129].

Dietary supplementation with Litsea cubeba essential oil (LCO, 250–500 mg/kg) enhanced synbiotic-like mechanisms in pigs: improving nutrient digestibility (crude protein, ash, calcium, ether extract), modulating fecal microbiota (altering SMB53, L7A_E11 abundance), and increasing serum catalase levels (systemic antioxidant boost) [130–133]. Genetically modified probiotics engineered to deliver neuroprotective factors (BDNF, anti-inflammatory cytokines, Aβ-degrading enzymes) directly within the gut represent a promising frontier [124]. A critical gap is the influence of sex on GM composition, neuroinflammation, and AD susceptibility [96, 105, 106]. Females exhibit higher AD incidence and distinct GM profiles (reduced Bacteroidetes diversity) versus males, potentially altering therapeutic responses [105, 106]. Hormonal differences (e.g., postmenopausal estrogen decline) modulate gut permeability and neuroinflammation [27], while genetic factors like APOE ε4 confer greater female AD risk [105]. Future trials must stratify by sex to optimize personalized synbiotic regimens [124, 125]. Figure 3.

Fig. 3.

Challenges and prospects of synbiotics therapeutic strategies in Alzheimer’s disease

Conclusion

This review establishes the GM critical role in AD pathogenesis via the gut-brain axis. Synbiotics show significant promise as non-drug interventions. Evidence indicates they can reduce key AD hallmarks like neuroinflammation, amyloid-beta deposits, and tau pathology, while improving gut barrier function, increasing beneficial short-chain fatty acids, modulating immune responses, enhancing metabolism, and crucially, improving cognitive function and mood, especially in early-stage disease. These benefits arise through multiple mechanisms, including microbial shifts, metabolic changes, immunomodulation, and neurotrophic support. However, major challenges hinder progress towards reversing established AD symptoms. These include the complexity of establishing a stable neuroprotective GM, influenced by diet, medications, genetics, geography, and disease stage.

Fundamental questions about causality remain. Limitations also involve insufficient large-scale human trials, variable synbiotic formulations and results, potential negative interactions, and a lack of understanding regarding non-bacterial microbes and micronutrient roles. The relative efficacy versus probiotics alone and precise links to microglial function need further study. Despite hurdles, GM-focused therapies, including synbiotics, hold bright prospects. Future success requires rigorous longitudinal trials using multi-omics approaches integrated with genomics and neuroimaging for personalized biomarkers. Advanced models, dietary personalization, and engineered probiotics represent key research avenues. Synbiotics are unlikely to reverse late-stage damage alone but hold significant potential as part of an early, holistic strategy targeting the gut-brain axis to delay onset, slow progression, improve quality of life, and synergize with other interventions, demanding interdisciplinary research.

Abbreviations

AD

Alzheimer disease

AST

Aspartate aminotransferase

ASD

Autism spectrum disorder

BBB

Blood-brain barrier

BCAAs

Branch chain amino acids

BCP

Bovine colostrum product

BDI

Beck depression inventory

CNS

Central nervous system

FMT

Fecal microbiota transplantation

GM

Gut microbiota

MCI

Mild cognitive impairment

MDD

Major depressive disorder

MS

Multiple sclerosis

NDDs

Neurodegenerative disease

OUT

Operational taxonomic unit

PCBs

Polychlorinated biphenyls

PD

Parkinson’s disease

PrP C

Cellular prion protein

RCTs

Randomized control trials

SCFAs

Short chain fatty acids

TLRs

Toll-like receptors

Authors’ contributions

All authors contributed equally.

Funding

Fujian Provincial Natural Science Foundation Co-Sponsored Program (No. 2024J08328). National Natural Science Foundation of China (Youth) Program (No. 82405349). National Natural Science Foundation of China (No. 82305141). Fujian Provincial Health Commission Youth Research Project (No. 2024QNB021). Xiamen Health Commission High-Quality Development Science and Technology Plan Project (No. 2024GZL-GG49).

Data availability

The data and materials used in this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interest.