Vagal Afferent Microbial Signal Modulation
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From Analysis:
What are the mechanisms by which gut microbiome dysbiosis influences Parkinson's disease pathogenesis through the gut-brain axis?
Hypotheses from Same Analysis (8)
These hypotheses emerged from the same multi-agent debate that produced this hypothesis.
Description
Molecular Mechanism and Rationale
The vagus nerve represents a critical bidirectional communication highway between the gut microbiome and the central nervous system, with vagal afferent neurons serving as primary transducers of microbial metabolites and inflammatory signals. This hypothesis proposes that targeted modulation of vagal afferent signaling through manipulation of GLP1R (glucagon-like peptide-1 receptor) and BDNF (brain-derived neurotrophic factor) pathways can provide disease-modifying therapy for neurodegenerative conditions.
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✓ Supporting Evidence 10
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related neurodegenerative disorders, affecting several millions of aged people globally. Among these disorders, AD is more severe, affecting about 7% of individuals aged 65 and above. AD is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while PD is primarily a movement disorder illness having three major kinesia or movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. AD is characterized by deposition of extracellular beta-amyloid (Aβ) proteins and intracellular neurofibrillary tangles (NFT), composed of hyperphosphorylated tau proteins in the neurons located particularly in hippocampus and cerebral cortex regions of brain, resulting the neuronal loss, while PD is characterized by deposition of intraneuronal aggregates of mostly composed of alpha-synuclein gene as Lewy bodies (LB) in the striatal region, known as substantia nigra pars compacta (SNpc) of brain, leading to the death of dopaminergic neurons. These are known as pathological hallmarks of these diseases. However, in some overlapping cases, known as Alzheimer with Parkinson disease or vice versa, alpha-synuclein deposition in AD and tau deposition in PD patients are found. Oxidative stress-induced glial cells activation, neuroi
Accumulating evidence suggests that the gut microbiome can modulate brain and behaviour including those relevant to eating behaviours and reward signalling through the dynamic communication pathways of the microbiota-gut-brain-axis. Emerging evidence links altered gut microbial composition to disordered eating patterns, implicating the gut microbiome as a possible mechanism underlying eating disorders, as well as a potential therapeutic target for these conditions. In this review, we synthesise evidence across preclinical and clinical research to propose an integrated framework wherein the gut microbiome, interoception and reward circuits may interact to shape disordered eating behaviours. We firstly explore how microbial signals modulate homeostatic and reward feeding systems via vagal afferents, neurotransmitter modulation and immune-neural pathways, and how these signals converge in brain regions implicated in reward systems and interoception. Particular attention is given to how these interactions may occur in under- and over-eating phenotypes of disordered eating. The therapeutic potential of microbiota-targeted interventions to modulate eating disorder-induced dysregulations in interoception and reward signalling is discussed. Combined evidence suggests a paradigm shift in the etiological considerations of eating disorders is warranted taking into account dysregulations of gut microbiota and its effects on reward processing and interoceptive signalling. Specifically, we
Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative di… MEDIUM▼
Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, inclu
Growth differentiation factor 15, GDF15, and glucagon-like peptide-1 (GLP-1) analogues act through brainstem neurons that co-localise their receptors, GDNF-family receptor α-like (GFRAL) and GLP1R, to reduce food intake and body weight. However, their use as clinical treatments is partially hampered since both can also induce sickness-like behaviours, including aversion, that are mediated through a well-characterised pathway via the exterolateral parabrachial nucleus. Here, in mice, we describe a separate pathway downstream of GFRAL/GLP1R neurons that involves a distinct population of brain-derived neurotrophic factor (BDNF) cells in the medial nucleus of the tractus solitarius. Thus, BDNFmNTS neurons are required for the weight-reducing actions of both GDF15 and the GLP1RA, Exendin-4. Moreover, acute activation of BDNFmNTS neurons is sufficient to reduce food intake and drive fatty acid oxidation and might provide a route for longer-term weight loss.
In Silico Pharmacogenomic Assessment of Glucagon-like Peptide-1 (GLP1) Agonists and the Genetic Addiction Risk… MEDIUM▼
INTRODUCTION: Glucagon-Like Peptide-1 Receptor (GLP1R) agonists have become widespread anti-obesity/diabetes pharmaceuticals in the United States. AIM: This article aimed to provide our current knowledge on the plausible mechanisms linked to the role of Ozempic (Semaglutide), which is generalized as one of the anti-addiction compounds. METHODS: The effects of GLP1R agonists in Alcohol Use Disorder (AUD) and substance use disorder (SUD) are mediated, in part, through the downregulation of dopamine signaling. We posit that while GLP1R agonism could offer therapeutic advantages in hyperdopaminergia, it may be detrimental in patients with hypodopaminergia, potentially leading to long-term induction of Suicidal Ideation (SI). The alleged posit of GLP1 agonists to induce dopamine homeostasis is incorrect. This study refined 31 genes based on the targets of Ozempic, GLP1R, and related enzymes for SI and 10 genes of the Genetic Addiction Risk Score (GARS) test. STRING-MODEL refined 29 genes, and further primary analyses indicated associations of GLP1R with DRD3, BDNF, CREB1, CRH, IL6, and DPP4. RESULTS: In-depth silico enrichment analysis revealed an association between candidate genes and depressive phenotypes linked with dopaminergic signaling. Finally, through primary and in-depth silico analyses, we demonstrated multiple findings supporting that GLP1R agonists can induce depression phenotypes. CONCLUSION: Our findings suggest that associated polymorphisms seem to have overlapping
INTRODUCTION: Progesterone receptor component 1 (PGRMC1) has been identified as a potential target in atypical antipsychotic drug-induced metabolic disturbances as well as neuroprotection in the central nervous system. In our study, we aimed to figure out the essential role of PGRMC1 signaling pathway underlying clozapine-induced cognitive impairment. METHODS: In male SD rats, we utilized recombinant adeno-associated viruses (BBB 2.0) and the specific inhibitor of PGRMC1 (AG205) to regulate the expression of PGRMC1 in the brain, with a special focus on the hippocampus. Treatments of clozapine and AG205 were conducted for 28 days, and subsequent behavioral tests including modified elevated plus maze and Morris water maze were conducted to evaluate the cognitive performance. Hippocampal protein expressions were measured by Western blotting. RESULTS: Our study showed that long-term clozapine administration led to cognitive impairment as confirmed by behavioral tests as well as histopathological examination in the hippocampus. Clozapine inhibited neural survival through the PGRMC1/EGFR/GLP1R-PI3K-Akt signaling pathway, leading to a decrease in the downstream survival factor, brain-derived neurotrophic factor (BDNF), and simultaneously promoted neural apoptosis in the rat hippocampus. Intriguingly, by targeting at the hippocampal PGRMC1, we found that inhibiting PGRMC1 mimics, while its upregulation notably mitigates clozapine-induced cognitive impairment through PGRMC1 and its do
The purpose of the present study was to elucidate the pharmacological effects of Geniposide (GEN) on high diet fed and streptozotocin (STZ)-caused diabetic cognitive impairment. The mice were fed with high fat diet (HFD) for 4 weeks and intraperitoneally injected with 60 mg/kg STZ for three times within 72 h. The mice with glucose level over 15 mmol/l were regarded as diabetic and selected for further studies. The animals were intragastrically treated with metformin or GEN once daily for 4 weeks. Afterwards, the animals were applied for Y maze, novel object recognition (NOR) test, step-through passive avoidance test, and Morris water maze (MWM) test. The blood glucose and body weight were examined. The SH-SY5Y cells were treated with GEN in the presence or absence of ibrutinib and stimulated with high-glucose culture medium. The tumor necrosis factor-a (TNF-α) and interleukin (IL)-6 in serum, hippocampus, and supernatant were measured using ELISA method. The protein expressions of Bruton's tyrosine kinase (BTK), Toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), nuclear factor kappa-B (NF-κB), p-NF-κB, brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB), p-CREB, and glucagon-like peptide-1 receptor (GLP-1R) were detected by western blot analyses. As a result, the GEN treatment notably attenuated the body weight, blood glucose, and cognitive decline. GEN also inhibited the generations of inflammatory cytokines. Furthermor
The potential role of Tirzepatide as adjuvant therapy in countering colistin-induced nephro and neurotoxicity … MEDIUM▼
Although colistin has a crucial antibacterial activity in treating multidrug-resistant gram-negative bacteria strains; it exhibited renal and neuronal toxicities rendering its use a challenge. Previous studies investigated the incretin hormones either glucose-dependent insulinotropic polypeptide (GIP) or glucagonlike peptide-1 (GLP-1) for their neuroprotective and nephroprotective effectiveness. The present study focused on investigating Tirzepatide (Tirze), a dual GLP-1/GIP agonist, as an adjuvant therapy in the colistin treatment protocol for attenuating its renal and neuronal complications. Rats were divided into; The normal control group, the colistin-treated group received colistin (300,000 IU/kg/day for 7 days; i.p.). The Tirze-treated group received Tirze (1.35 mg/kg on the 1,4,7thdays; s.c.) and daily colistin. Tirze effectively enhanced histopathological alterations, renal function parameters, and locomotor activity in rats. Tirze mechanistically acted via modulating various signaling axes evolved under the insult of phosphatidylinositol 3-kinases (PI3K)/phosphorylated protein kinase-B (p-Akt)/ glycogen synthase kinase (GSK)3-β hub causing mitigation of nuclear factor (NF)-κB (NF-κB) / tumor necrosis factor-α (TNF-α), increment of nuclear factor erythroid 2-related factor 2 (Nrf2)/ glutathione (GSH), downregulation of ER stress-related biomarkers (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)), antiapoptotic effects coupling with reduct
Vagal afferent signaling via GLP1R activation enhances BDNF expression in the dorsal motor nucleus of the vagu… STRONG▼
Chronic NP-1 administration reduces body weight and hepatic steatosis despite induction of tolerance in adiponectin gene transcription with respect to the acute actions of this drug. This study explored the hypothesis that NP-1 could exert these effects through mechanisms independent of adiponectin. To this aim, we took advantage of the Zucker (fa/fa) rat model, which exhibits obesity, fatty liver and elevated leptin and adiponectin levels. Body weight and food intake were reduced after chronic NP-1 treatment. Plasma TNFα concentrations were elevated but no increase in adiponectin was found. Even so, NP-1 ameliorated fatty liver and corrected dyslipidemia by mechanisms probably associated with reduced feeding, transcription of Cpt1 and down-regulation of Hmgcr-CoA expression. In brown fat tissue NP-1 increased Dnmt1 (inhibitor of Adipoq) while it reduced Ucp1 expression and heat production, which excludes thermogenesis as a mechanism of the NP-1 slimming effect. The anti-obesity action of chronic NP-1 administration might be mediated by TNFα, which is known to have anorectic actions in the hypothalamus and to regulate both Dmnt1 and Ucp1 expression in adipose tissues. This finding opens up the possibility of using NP-1-mediated TNFα-induced weight loss as an innovative treatment of complicated obesity under strict pharmacologic control.
Short-chain fatty acid butyrate produced by commensal microbiota potentiates vagal afferent neuron excitabilit… STRONG▼
The pneumococcal enzyme-linked immunosorbent assay (ELISA) reference standard serum, lot 89SF, has been in use since 1990 and was replaced in 2013 with a new reference standard, 007sp, that is projected to be available for the next 25 years. 007sp was generated under an FDA-approved clinical protocol; 278 adult volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine Pneumovax II, and a unit of blood was obtained twice from each immunized subject within 120 days following immunization. Pooled serum was prepared from the plasma of 262 subjects, filled at 6 ml per vial, and lyophilized. Five independent laboratories participated in bridging the serotype-specific IgG assignments for 89SF to the new reference standard, 007sp, to establish equivalent reference values for 13 pneumococcal capsular serotypes (1,3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) by using the WHO reference ELISA. In a second study involving three laboratories, a similar protocol was used to assign weight-based IgG concentrations in micrograms per ml to 007sp of seven serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) also present in the 23-valent pneumococcal unconjugated polysaccharide vaccine. In addition, the IgG assignments for a 12-member WHO quality control (QC) serum panel were also extended to cover these seven serotypes. Agreement was excellent, with a concordance correlation coefficient (r(c)) of >0.996 when each laboratory was compared to the assigned values for the 12
✗ Opposing Evidence 9
The neuroprotective effects of glucagon-like peptide 1 in Alzheimer's and Parkinson's disease: An in-depth rev… MEDIUM▼
Currently, there is no disease-modifying treatment available for Alzheimer's and Parkinson's disease (AD and PD) and that includes the highly controversial approval of the Aβ-targeting antibody aducanumab for the treatment of AD. Hence, there is still an unmet need for a neuroprotective drug treatment in both AD and PD. Type 2 diabetes is a risk factor for both AD and PD. Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor that has shown neuroprotective effects in preclinical studies, and the success of GLP-1 mimetics in phase II clinical trials in AD and PD has raised new hope. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. GLP-1 analogs are safe, well tolerated, resistant to desensitization and well characterized in the clinic. Herein, we review the existing evidence and illustrate the neuroprotective pathways that are induced following GLP-1R activation in neurons, microglia and astrocytes. The latter include synaptic protection, improvements in cognition, learning and motor function, amyloid pathology-ameliorating properties (Aβ, Tau, and α-synuclein), the suppression of Ca2+ deregulation and ER stress, potent anti-inflammatory effects, the blockage of oxidative stress, mitochondrial dysfunction and apoptosis pathways, enhancements in the neuronal insulin sensitivity and energy metabolism, functional improvements in autophagy and mitophagy, elevated BDNF and glial cell line-derived neurotrophic factor (GDNF) synthesis as w
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related neurodegenerative disorders, affecting several millions of aged people globally. Among these disorders, AD is more severe, affecting about 7% of individuals aged 65 and above. AD is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while PD is primarily a movement disorder illness having three major kinesia or movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. AD is characterized by deposition of extracellular beta-amyloid (Aβ) proteins and intracellular neurofibrillary tangles (NFT), composed of hyperphosphorylated tau proteins in the neurons located particularly in hippocampus and cerebral cortex regions of brain, resulting the neuronal loss, while PD is characterized by deposition of intraneuronal aggregates of mostly composed of alpha-synuclein gene as Lewy bodies (LB) in the striatal region, known as substantia nigra pars compacta (SNpc) of brain, leading to the death of dopaminergic neurons. These are known as pathological hallmarks of these diseases. However, in some overlapping cases, known as Alzheimer with Parkinson disease or vice versa, alpha-synuclein deposition in AD and tau deposition in PD patients are found. Oxidative stress-induced glial cells activation, neuroi
The effects of Fc fusion protein glucagon-like peptide-1 and glucagon dual receptor agonist with different rec… MEDIUM▼
BACKGROUND: Glucagon-like peptide-1 (GLP-1)/glucagon (GCG) dual receptor agonists with different receptor selectivity are under investigation and have shown significant improvement in both weight loss and glycemic control, but the optimal potency ratio between the two receptors to balance efficacy and safety remains unclear. EXPERIMENTAL APPROACH: We designed and constructed several dual receptor agonists with different receptor potency ratios using Fc fusion protein technology. The long-term effects of the candidates on body weight and metabolic dysfunction-associated steatotic liver disease (MASLD) were evaluated in diet-induced obese (DIO) model mice, high-fat diet (HFD)-ob/ob mice and AMLN diet-induced MASLD mice. Repeat dose toxicity assays were performed to investigate the safety profile of the candidate (HEC-C070) in Sprague Dawley (SD) rats. KEY RESULTS: The high GCG receptor (GCGR) selectivity of HEC-C046 makes it more prominent than other compounds for weight loss and most MASLD parameters but may lead to safety concerns. The weight change of HEC-C052 with the lowest GCG agonism was inferior to that of selective GLP-1 receptor agonist (GLP-1RA) semaglutide in DIO model mice. The GLP-1R selectivity of HEC-C070 with moderate GCG agonism has a significant effect on weight loss and liver function in obese mice, and its lowest observed adverse effect level (LOAEL) was 30 nmol/kg in the repeat dose toxicity study. CONCLUSION: We compared the potential of the Fc fusion pro
Vagal afferent signaling blockade through vagotomy or selective afferent denervation does not impair GLP-1R-me… MODERATE▼
BDNF signaling enhancement through direct central administration shows superior neuroprotective outcomes compa… MODERATE▼
Accumulation of amyloid-beta (Abeta) into senile plaques in Alzheimer's disease (AD) is a hallmark neuropathological feature of the disorder, which likely contributes to alterations in neuronal structure and function. Recent work has revealed changes in neurite architecture associated with plaques and functional changes in cortical signaling in amyloid precursor protein (APP) expressing mouse models of AD. Here we developed a method using gene transfer techniques to introduce green fluorescent protein (GFP) into neurons, allowing the investigation of neuronal processes in the vicinity of plaques. Multiphoton imaging of GFP-labeled neurons in living Tg2576 APP mice revealed disrupted neurite trajectories and reductions in dendritic spine density compared with age-matched control mice. A profound deficit in spine density (approximately 50%) extends approximately 20 mum from plaque edges. Importantly, a robust decrement (approximately 25%) also occurs on dendrites not associated with plaques, suggesting widespread loss of postsynaptic apparatus. Plaques and dendrites remained stable over the course of weeks of imaging. Postmortem analysis of axonal immunostaining and colocalization of synaptophysin and postsynaptic density 95 protein staining around plaques indicate a parallel loss of presynaptic and postsynaptic partners. These results show considerable changes in dendrites and dendritic spines in APP transgenic mice, demonstrating a dramatic synaptotoxic effect of dense-cored
Liraglutide Attenuates Atorvastatin-Induced Hepatotoxicity by Restoring GLP-1R Expression and Activating Nrf2 … MEDIUM▼
HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GL
Management of Diabetes Mellitus in Normal Renal Function, Renal Dysfunction and Renal Transplant Recipients, F… MEDIUM▼
Diabetes Mellitus (DM) is a leading cause of both Cardiovascular Disease (CVD) and End-stage Renal Disease (ESRD). After 2008, there has been much evidence presented, and recently the guidelines for sugar control have changed to focus on being more disease orientated. GLP-1 Receptor Agonists (GLP-1R) and sodium glucose cotransporter-2 inhibitors are suggested as the first line towards fighting all DM, CVD and ESRD. However, the benefits of GLP-1R in organ transplantation recipients remain very limited. No clinical trials have been designed for this particular population. GLP-1R, a gastrointestinal hormone of the incretin family, possesses antidiabetic, antihypertensive, anti-inflammatory, anti-apoptotic and immunomodulatory actions. There are few drug-drug interactions, with delayed gastric emptying being the major concern. The trough level of tacrolimus may not be significant but should still be closely monitored. There are some reasons which support GLP-1R in recipients seeking glycemic control. Post-transplant DM is due to an impaired β-cell function and glucose-induced glucagon suppression during hyperglycemia, which can be reversed by GLP-1R. GLP-1R infusion tends to relieve immunosuppressant related toxicity. Until now, in some cases, glycemic control and body weight reduction can be anticipated with GLP-1R. Additional renal benefits have also been reported. Side effects of hypoglycemia and gastrointestinal discomfort were rarely reported. In conclusion, GLP-1R could be
Geniposide Ameliorated Dexamethasone-Induced Cholesterol Accumulation in Osteoblasts by Mediating the GLP-1R/A… MEDIUM▼
BACKGROUND: Overexposure to glucocorticoid (GC) produces various clinical complications, including osteoporosis (OP), dyslipidemia, and hypercholesterolemia. Geniposide (GEN) is a natural iridoid compound isolated from Eucommia ulmoides. Our previous study found that GEN could alleviate dexamethasone (DEX)-induced differentiation inhibition of MC3T3-E1 cells. However, whether GEN protected against Dex-induced cholesterol accumulation in osteoblasts was still unclear. METHODS: DEX was used to induce rat OP. Micro-CT data was obtained. The ALP activity and mineralization were determined by the staining assays, and the total intracellular cholesterol was determined by the ELISA kits. The protein expression was detected by western blot. RESULTS: GEN ameliorated Dex-induced micro-structure damages and cell differentiation inhibition in the bone trabecula in rats. In MC3T3-E1 cells, Dex enhanced the total intracellular cholesterol, which reduced the activity of cell proliferation and differentiation. Effectively, GEN decreased DEX-induced cholesterol accumulation, enhanced cell differentiation, and upregulated the expression of the GLP-1R/ABCA1 axis. In addition, inhibition of ABAC1 expression reversed the actions of GEN. Treatment with Exendin9-39, a GLP-1R inhibitor, could abrogate the protective activity of GEN. CONCLUSIONS: GEN ameliorated Dex-induced accumulation of cholesterol and inhibition of cell differentiation by mediating the GLP-1R/ABCA1 axis in MC3T3-E1 cells.
Comparative effects of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitor… MEDIUM▼
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common in type 2 diabetes mellitus (T2D), leading to high morbidity and mortality. Managing HFpEF in diabetic patients is challenging with limited treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown potential cardiovascular benefits. This meta-analysis compares the effects of GLP1-RA and SGLT2 inhibitors on HFpEF in T2D patients. METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating GLP1-RA and SGLT2 inhibitors' impact on HFpEF in T2D patients. Databases searched included PubMed, MEDLINE, and Cochrane Library up to July 2024. Primary outcomes were changes in left ventricular ejection fraction (LVEF), myocardial fibrosis (extracellular volume fraction, ECV), and functional capacity (6-minute walk test, 6MWT). Secondary outcomes included HbA1c, body weight, and systolic blood pressure (SBP). RESULTS: Twelve studies with 3,428 patients (GLP1-RA: 1,654; SGLT2 inhibitors: 1,774) were included. Both GLP1-RA and SGLT2 inhibitors significantly improved LVEF compared to placebo (GLP1-RA: mean difference [MD] 2.8%, 95% confidence interval [CI] 1.5 to 4.1, p < 0.001; SGLT2 inhibitors: MD 3.2%, 95% CI 2.0 to 4.4, p < 0.001). SGLT2 inhibitors significantly reduced myocardial fibrosis (MD -3.5%, 95% CI -4.2 to -2.8, p < 0.001) more than GLP1-RA (MD -2.3%, 95% CI -3.0 to -1.6, p < 0.00
🧬 Theorist Proposes novel mechanisms and generates creative hypotheses ▼
Novel Therapeutic Hypotheses for Gut-Brain Axis in Parkinson's Disease
Hypothesis 1: Bacterial Curli Amyloid Mimicry Pathway
Title: Targeting Bacterial Curli Fibrils to Prevent α-Synuclein Cross-SeedingDescription: Gut bacteria produce curli amyloid fibrils that structurally mimic α-synuclein and act as nucleation seeds, promoting pathological α-synuclein aggregation through molecular mimicry. Therapeutic intervention with curli synthesis inhibitors (like Congo Red derivatives) could prevent this cross-kingdom amyloid seeding and halt early PD pathogenesis.
Target: CsgA (c
🔍 Skeptic Identifies weaknesses, alternative explanations, and methodological concerns ▼
Critical Evaluation of Gut-Brain Axis Hypotheses in Parkinson's Disease
Hypothesis 1: Bacterial Curli Amyloid Mimicry Pathway
Weaknesses in Evidence:
- Cross-seeding specificity: The supporting studies primarily used C. elegans models, which lack the complex human blood-brain barrier and immune system (PMID:26751493). Cross-kingdom amyloid interactions may not translate to mammalian systems.
- Causation vs. correlation: The presence of bacterial amyloids in PD patients doesn't establish causation - they could be a consequence rather than cause of gut dysbiosis.
- **Selectivi
🎯 Domain Expert Assesses practical feasibility, druggability, and clinical translation ▼
Practical Feasibility Assessment: Gut-Brain Axis PD Hypotheses
HYPOTHESIS 1: Bacterial Curli Amyloid Inhibition
Druggability: MODERATEChemical Matter & Tool Compounds:
- Congo Red derivatives: FN-1501 (developed by Funxional Therapeutics) - synthetic Congo Red analog with improved pharmacokinetics
- Curcumin analogs: EF24, Difluorinated curcumin (showed anti-amyloid activity in preclinical studies)
- Small molecule amyloid inhibitors: Epigallocatechin gallate (EGCG), Quercetin, Resveratrol
Existing Clinical Candidates:
- **None specifically targeting bacterial
⚖ Synthesizer Integrates perspectives and produces final ranked assessments ▼
Price History
| Event | Price | Change | Source | Time | |
|---|---|---|---|---|---|
| ⚖ | Recalibrated | $0.521 | ▼ 0.4% | 2026-04-12 10:15 | |
| ⚖ | Recalibrated | $0.523 | ▼ 0.5% | 2026-04-10 15:58 | |
| ⚖ | Recalibrated | $0.526 | ▲ 0.6% | 2026-04-10 15:53 | |
| ⚖ | Recalibrated | $0.522 | ▼ 3.8% | 2026-04-08 18:39 | |
| ⚖ | Recalibrated | $0.543 | ▼ 11.5% | 2026-04-06 04:04 | |
| ⚖ | Recalibrated | $0.614 | ▼ 0.5% | 2026-04-04 16:38 | |
| ⚖ | Recalibrated | $0.617 | ▲ 0.9% | 2026-04-04 16:02 | |
| 📄 | New Evidence | $0.612 | ▼ 0.7% | evidence_batch_update | 2026-04-04 09:08 |
| ⚖ | Recalibrated | $0.616 | ▼ 1.5% | 2026-04-03 23:46 | |
| ⚖ | Recalibrated | $0.625 | ▲ 7.4% | market_dynamics | 2026-04-03 01:06 |
| ⚖ | Recalibrated | $0.582 | ▼ 9.3% | market_dynamics | 2026-04-03 01:06 |
| ⚖ | Recalibrated | $0.642 | ▲ 25.9% | 2026-04-02 21:55 | |
| ⚖ | Recalibrated | $0.510 | ▼ 10.5% | market_recalibrate | 2026-04-02 19:14 |
| 📄 | New Evidence | $0.570 | ▼ 9.9% | market_dynamics | 2026-04-02 17:18 |
| 💬 | Debate Round | $0.633 | ▲ 4.6% | debate_engine | 2026-04-02 14:04 |
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Mechanism Pathway for GLP1R, BDNF
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
h_ee1df336["h-ee1df336"] -->|targets| GLP1R__BDNF["GLP1R, BDNF"]
GLP1R__BDNF_1["GLP1R, BDNF"] -->|associated with| neurodegeneration["neurodegeneration"]
GLP1R__BDNF_2["GLP1R, BDNF"] -->|implicated in| neurodegeneration_3["neurodegeneration"]
CLDN1__OCLN__ZO1__MLCK["CLDN1, OCLN, ZO1, MLCK"] -->|co associated with| GLP1R__BDNF_4["GLP1R, BDNF"]
AHR__IL10__TGFB1["AHR, IL10, TGFB1"] -->|co associated with| GLP1R__BDNF_5["GLP1R, BDNF"]
GLP1R__BDNF_6["GLP1R, BDNF"] -->|co associated with| NLRP3__CASP1__IL1B__PYCAR["NLRP3, CASP1, IL1B, PYCARD"]
GLP1R__BDNF_7["GLP1R, BDNF"] -->|co associated with| SNCA__HSPA1A__DNMT1["SNCA, HSPA1A, DNMT1"]
GLP1R__BDNF_8["GLP1R, BDNF"] -->|co associated with| TH__AADC["TH, AADC"]
GLP1R__BDNF_9["GLP1R, BDNF"] -->|co associated with| TLR4__SNCA["TLR4, SNCA"]
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style GLP1R__BDNF fill:#ce93d8,stroke:#333,color:#000
style GLP1R__BDNF_1 fill:#ce93d8,stroke:#333,color:#000
style neurodegeneration fill:#ef5350,stroke:#333,color:#000
style GLP1R__BDNF_2 fill:#ce93d8,stroke:#333,color:#000
style neurodegeneration_3 fill:#ef5350,stroke:#333,color:#000
style CLDN1__OCLN__ZO1__MLCK fill:#ce93d8,stroke:#333,color:#000
style GLP1R__BDNF_4 fill:#ce93d8,stroke:#333,color:#000
style AHR__IL10__TGFB1 fill:#ce93d8,stroke:#333,color:#000
style GLP1R__BDNF_5 fill:#ce93d8,stroke:#333,color:#000
style GLP1R__BDNF_6 fill:#ce93d8,stroke:#333,color:#000
style NLRP3__CASP1__IL1B__PYCAR fill:#ce93d8,stroke:#333,color:#000
style GLP1R__BDNF_7 fill:#ce93d8,stroke:#333,color:#000
style SNCA__HSPA1A__DNMT1 fill:#ce93d8,stroke:#333,color:#000
style GLP1R__BDNF_8 fill:#ce93d8,stroke:#333,color:#000
style TH__AADC fill:#ce93d8,stroke:#333,color:#000
style GLP1R__BDNF_9 fill:#ce93d8,stroke:#333,color:#000
style TLR4__SNCA fill:#ce93d8,stroke:#333,color:#000
3D Protein Structure
🧬 GLP1R — PDB 6X18 Click to expand 3D viewer
Source Analysis
What are the mechanisms by which gut microbiome dysbiosis influences Parkinson's disease pathogenesis through the gut-brain axis?
neurodegeneration | 2026-04-01 | completed