Search Results (70)

Background: Gut barrier dysfunction and altered gut microbial metabolism are emerging signatures of chronic gut disorders. Considering growing interest in combining structurally and mechanistically distinct bioactives, we investigated the individual and combined effects of serum-derived bovine immunoglobulin (SBI) and N-acetylglucosamine (NAG) on the gut microbiome and barrier integrity. Methods: The validated ex vivo SIFR^® (Systemic Intestinal Fermentation Research) technology, using microbiota from healthy adults (n = 6), was combined with a co-culture of epithelial/immune (Caco-2/THP-1) cells. Results: While SBI and NAG already significantly improved gut barrier integrity (TEER, transepithelial electrical resistance, +21% and +29%, respectively), the strongest effect was observed for SBI_NAG (+36%). This potent combined effect related to the observation that SBI and NAG each induced distinct, complementary shifts in microbial composition and metabolite output. SBI most selectively increased propionate (~Bacteroidota families) and health-associated indole derivatives (e.g., indole-3-propionic acid), while NAG most specifically boosted acetate and butyrate (~Bifidobacteriaceae, Ruminococcaceae, and Lachnospiraceae). The combination of SBI_NAG displayed effects of the individual ingredients, thus, for instance, enhancing all three short-chain fatty acids (SCFA) and elevating microbial diversity (CMS, community modulation score). Conclusions: Overall, SBI and NAG exert complementary, metabolically balanced effects on the gut microbiota, supporting combined use, particularly in individuals with gut barrier impairment or dysbiosis linked to lifestyle or early-stage gastrointestinal disorders. Full article

Background/Objectives: Sepsis-associated liver injury (SALI) is a critical and often early complication of sepsis, defined by distinct hyper-inflammatory and immunosuppressive phases that shape patient phenotypes. Methods: Characterizing these phases establishes a foundation for immunomodulation strategies tailored to individual immune responses, as discussed subsequently. Results: The initial inflammatory response activates pathways such as NF-κB and the NLRP3 inflammasome, leading to a cytokine storm that damages hepatocytes and is frequently associated with higher SOFA scores and a higher risk of 28-day mortality. Kupffer cells and infiltrating neutrophils exacerbate hepatic injury by releasing proinflammatory cytokines and reactive oxygen species, thereby causing cellular damage and prolonging ICU stays. During the subsequent immunosuppressive phase, impaired infection control and tissue repair can result in recurrent hospital-acquired infections and a poorer prognosis. Concurrently, hepatocytes undergo significant metabolic disturbances, notably impaired fatty acid oxidation due to downregulation of transcription factors such as PPARα and HNF4α. This metabolic alteration corresponds with worsening liver function tests, which may reflect the severity of liver failure in clinical practice. Mitochondrial dysfunction, driven by oxidative stress and defective autophagic quality control, impairs cellular energy production and induces hepatocyte death, which is closely linked to declining liver function and increased mortality. The gut-liver axis plays a central role in SALI pathogenesis, as sepsis-induced gut dysbiosis and increased intestinal permeability allow bacterial products, including lipopolysaccharides, to enter the portal circulation and further inflame the liver. This process is associated with sepsis-related liver failure and greater reliance on vasopressor support. Protective microbial metabolites, such as indole-3-propionic acid (IPA), decrease significantly during sepsis, removing key anti-inflammatory signals and potentially prolonging recovery. Clinically, SALI most commonly presents as septic cholestasis with elevated bilirubin and mild transaminase changes, although conventional liver function tests are insufficiently sensitive for early detection. Novel biomarkers, including protein panels and non-coding RNAs, as well as dynamic liver function tests such as LiMAx (currently in phase II diagnostics) and ICG-PDR, offer promise for improved diagnosis and prognostication. Specifying the developmental stage of these biomarkers, such as identifying LiMAx as phase II, informs investment priorities and translational readiness. Current management is primarily supportive, emphasizing infection control and organ support. Investigational therapies include immunomodulation tailored to immune phenotypes, metabolic and mitochondrial-targeted agents such as pemafibrate and dichloroacetate, and interventions to restore gut microbiota balance, including probiotics and fecal microbiota transplantation. However, translational challenges remain due to limitations of animal models and patient heterogeneity. Conclusion: Future research should focus on developing representative models, validating biomarkers, and conducting clinical trials to enable personalized therapies that modulate inflammation, restore metabolism, and repair the gut-liver axis, with the goal of improving outcomes in SALI. Full article

In recent years, gut–brain axis signaling has been recognized as an essential factor modifying behavior, mood, cognition, and cellular viability under physiological and pathological conditions. Consequently, the intestinal microbiome has become a potential therapeutic target in neurological and psychiatric disorders. The microbiota-derived metabolite of tryptophan (Trp), indole-3-propionic acid (IPA), was discovered to target a number of molecular processes and to impact brain function. In this review, we outline the key mechanisms by which IPA may affect neuronal activity and survival and provide an update on the evidence supporting the neuroprotective action of the compound in various experimental paradigms. Accumulating data indicates that IPA is a free radical scavenger, a ligand of aryl hydrocarbon receptors (AhR) and pregnane X receptors (PXR), and an anti-inflammatory molecule. IPA decreases the synthesis of the proinflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and other cytokines, reduces the generation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, and enhances the synthesis of neurotrophic factors. Furthermore, produced in the gut, or administered orally, IPA boosts the central levels of kynurenic acid (KYNA), a neuroprotective metabolite of Trp. IPA reduces the release of proinflammatory molecules in the gut, breaking the gut–inflammation–brain vicious cycle, which otherwise leads to neuronal loss. Moreover, as a molecule that easily enters central compartment, IPA may directly impact brain function and cellular survival. Overall, the gathered data confirms neuroprotective features of IPA, and supports its potential use in high-risk populations, in order to delay the onset and ameliorate the course of neurodegenerative disorders and cognitive impairment. Clinical trials evaluating IPA as a promising therapeutic add-on, able to slow down the progress of neurodegenerative disorders such as Alzheimer’s or Parkinson’s disease and to limit the morphological and behavioral consequences of ischemic stroke, are urgently needed. Full article

The human gut microbiota is a complex ecosystem that influences host metabolism, immune function, and cardiovascular health. Dysbiosis, defined as an imbalance in microbial composition or function, has been linked to the development and progression of atherosclerosis. This connection is mediated by microbial metabolites that enter the systemic circulation and interact with vascular and immune pathways. Among these, trimethylamine N-oxide (TMAO) has been most extensively studied and is consistently associated with cardiovascular events. Other metabolites, including lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), and secondary bile acids, also contribute by modulating inflammation, endothelial function, and lipid metabolism. Recent research has expanded to emerging metabolites such as indoxyl sulfate, indole-3-propionic acid, and polyamines, which may provide additional mechanistic insights. These microbial products are increasingly explored as biomarkers of cardiovascular risk. TMAO has shown predictive value in large human cohorts, while microbiota composition and diversity measures remain less consistent across studies. However, interpretation of these biomarkers is limited by methodological variability, interindividual differences, and lack of standardization. Therapeutic interventions targeting the gut–heart axis are under investigation. Dietary strategies such as the Mediterranean diet and fiber-rich nutrition, probiotics and prebiotics, and fecal microbiota transplantation (FMT) show promise, while pharmacological approaches targeting TMAO or bile acid pathways are in early stages. This review summarizes current knowledge on the mechanistic, diagnostic, and therapeutic links between the gut microbiota and atherosclerosis, highlighting both established findings and emerging directions for future research. Full article

Background: Secondary (nosocomial) bacterial meningitis remains a serious problem in patients with severe brain damage. The aim of this study was to assess the differences in the aromatic metabolites of tryptophan, phenylalanine, and tyrosine, in serum and cerebrospinal fluid (CSF) samples collected simultaneously from patients with long-term sequelae of severe brain damage with suspected secondary bacterial meningitis. Methods: Group I included 16 paired serum and CSF samples from patients (N = 11) without secondary bacterial meningitis; group II included 13 paired serum and CSF samples from patients (N = 4) with secondary bacterial meningitis. Results: The median concentrations of serum 5-hydroxyindole-3-acetic, CSF 4-hydroxyphenyllactic (p-HPhLA), CSF 4-hydroxyphenylacetic, CSF phenyllactic, and indole-3-lactic acids in serum and CSF were statistically higher in group II compared to group I (p-value ≤ 0.03), while 4-hydroxyphenylpropionic and indole-3-acetic in serum were lower in group II compared to group I (p-value = 0.04). In group I, p-HPhLA serum concentrations were greater than or equal to its CSF concentrations in 14 paired samples; in group II, p-HPhLA concentrations in serum were lower than in CSF in all paired samples. Conclusions: The obtained results demonstrate the differences in the profile of aromatic metabolites in serum and CSF and may confirm the hypothesis of the p-HPhLA microbial origin in the CSF of patients with secondary bacterial meningitis. Full article

Background/Objectives: Gut-derived tryptophan (Trp) metabolites play important roles in metabolic and cardiovascular regulation. Although animal studies suggest their protective effects against metabolic dysfunction, data in adolescents, particularly those with obesity, remain limited. The objective of this study was to evaluate associations between circulating gut-derived Trp metabolites and markers of cardiometabolic, vascular, and platelet health in adolescents with obesity. Methods: Data were analyzed from 28 adolescents (ages 13–18; mean BMI = 36 ± 6.4 kg/m²). Fasting blood was collected to assess lipid profiles using a clinical analyzer and insulin resistance using the homeostatic model assessment for insulin resistance (HOMA-IR). Gut-derived Trp metabolites were measured by UPLC–mass spectrometry, peak oxygen uptake (VO_{2 peak}) by gas exchange during an incremental cycle ergometer test, and body composition by dual-energy X-ray absorptiometry. Platelet spare respiratory capacity (SRC), endothelial function, and liver fat were measured using high-resolution respirometry, flow-mediated dilation (FMD) of the brachial artery, and magnetic resonance imaging respectively. Results: Indole-3-propionic acid was inversely associated with diastolic blood pressure (rho = −0.39, p = 0.047), total cholesterol (rho = −0.55, p = 0.002), and LDL-C (rho = −0.57, p = 0.0014), independent of sex and obesity severity. Indoxyl sulfate was positively correlated with fasting glucose (rho = 0.47, p = 0.012), and adolescents with impaired fasting glucose had 1.6-fold higher IS levels. Indole-3-acetaldehyde declined with age (rho = −0.50, p = 0.007), and Indole-3-acetic acid and indole were higher in Hispanics vs. non-Hispanics. No significant associations were observed between Trp metabolites and FMD, VO₂ peak, or SRC. Conclusions: Gut-derived Trp metabolites, particularly indole-3-propionic and indoxyl sulfate, are associated with markers of cardiometabolic risk in adolescents with obesity. These findings support their potential relevance in early-onset cardiovascular disease risk. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver condition linked to obesity and metabolic imbalance. Alterations in the gut microbiota are increasingly recognized as contributors to its progression. Alistipes putredinis, a core member of the human gut microbiota, has been linked with metabolic health, but its functional role in MASLD remains unclear. Methods: This study evaluated the potential of A. putredinis strain Ap77, isolated from the stool of a healthy adult, to mitigate MASLD-related alterations in a high-fat diet (HFD)-induced rat model. Animals were divided into normal chow (NC), HFD, and HFD plus Ap77 groups and received daily oral gavage of Ap77 or PBS for 8 weeks. Results: Ap77 supplementation attenuated the body weight increase associated with high-fat diet consumption. It also reduced hepatic triglyceride levels and fat mass and improved liver histology. Transcriptomic analysis revealed suppression of inflammation-associated pathways. Correspondingly, the concentrations of IL-1β, IL-6, and TNF-α in both the liver and serum were reduced. Ap77 supplementation was associated with an increased abundance of health-associated bacterial genera, such as Lachnospiraceae UCG_010, Akkermansia, and Flavonifractor, as well as elevated serum levels of butyrate, indole-3-propionic acid, and indoleacrylic acid. Notably, correlation analysis revealed that Lachnospiraceae UCG_010 was positively associated with these metabolites. Conclusions: A. putredinis Ap77 alleviates hepatic steatosis and inflammation in MASLD, potentially by reshaping gut microbiota and suppressing inflammation-related signaling pathways. Full article

This study aimed to evaluate the effects of yeast culture (YC) supplementation on growth performance, dietary nutrient digestibility, ruminal fermentation characteristics, methane (CH₄) synthesis potential, ruminal bacterial composition, antioxidant and immune capacities in beef cattle. Thirty-six finishing Simmental beef cattle were employed for this experiment. The experiment included three dietary treatments: the basal diet (CON), the basal diet supplemented with Diamon V XP (XP; 50 g/day per cattle), and the basal diet supplemented with Keliben (KLB; 50 g/day per cattle). Various metabolites, such as acetophenone (12.7%), ascorbic acid (10.3%), citric acid (7.25%), D-(+)-proline (6.42%), succinic acid (5.70%), betaine (5.65%) and DL-malic acid (2.62%) were abundant in XP; and ascorbic acid (14.0%), oleamide (9.23%), citric acid (6.03%), betaine (5.88%), succinic acid (4.42%), indole-3-acrylic acid (2.85%) and DL-malic acid (1.73%) were abundant in KLB. Supplementing YC to the cattle increased the apparent total-tract digestibility of DM, OM, NDF and ADF, and tended to increase average daily gain. The supplementation of YC to the cattle had no effect on the rumen fermentation pathway as reflected by the unaltered molar percentage of acetate or propionate. The supplementation of XP decreased the concentration of rumen dissolved CH₄, although no effect on the concentration of dissolved hydrogen was observed. The supplementation of KLB to the cattle increased Paraprevotella relative abundance, while the supplementation of XP decreased Euryarchaeota relative abundance in the rumen. Supplementing XP to the cattle increased serum GSH-Px, catalase and T-AOC concentrations, and was accompanied by decreased MAD concentration, indicating improved antioxidant capacity. Supplementing XP to the cattle increased the concentrations of serum IgA, IgG, IL-2, IL-10, IFN-γ and C4, compared with the CON group, and the KLB group had higher concentrations of serum IgA, IgG, IgM, IL-10, IFN-γ, C3 and C4 compared with the CON and XP groups, which revealed that both XP and KLB can improve the immune function, and that KLB showed a stronger effect. Overall, the supplementation of YC is beneficial to the nutrient digestibility, growth performance and health of beef cattle. Furthermore, XP was more effective than KLB in improving antioxidant capacity and reducing CH₄ production, while KLB was more effective in improving the immune capacity of beef cattle than XP. Full article

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disorder globally. Probiotic supplementation has shown promise in its prevention and treatment. Although Weissella viridescens, a lactic acid bacterium with immunomodulatory effects, has antibacterial and anti-inflammatory activities, there is a lack of direct evidence for its role in alleviating MASLD. This study aimed to investigate the protective effects of W. viridescens strain Wv2365, isolated from healthy human feces, in a high-fat diet (HFD)-induced rat model of MASLD. Methods: Rats were randomly assigned to a normal chow diet (NC), high-fat diet (HFD), and HFD supplemented with W. viridescens Wv2365 (Wv2365) groups. All groups were fed their respective diets for 8 weeks. During this period, the NC and HFD groups received a daily oral gavage of PBS, while the Wv2365 group received a daily oral gavage of Wv2365. Results: Wv2365 supplementation significantly reduced HFD-induced body weight gain, improved NAFLD activity scores, alleviated hepatic injury, and restored lipid metabolism. A liver transcriptomic analysis revealed the downregulation of inflammation-related pathways, along with decreased serum levels of TNF-α, IL-1β, IL-6, MCP-1, and LPS. Wv2365 also activated the Nrf2/HO-1 antioxidant pathway, enhanced hepatic antioxidant enzyme activities and reduced malondialdehyde levels. A gut microbiota analysis showed the enrichment of beneficial genera, including Butyricicoccus, Akkermansia, and Blautia. Serum metabolomic profiling revealed increased levels of metabolites including indole-3-propionic acid, indoleacrylic acid, and glycolithocholic acid. Conclusions: Wv2365 attenuates hepatic injury, oxidative stress, and inflammation in a rat model of high-fat-diet-induced MASLD, supporting its potential as a probiotic candidate for the modulation of MASLD. Full article

The development of the human immune system starts during the fetal period in a largely, but probably not completely, sterile environment. During and after birth, the immune system is exposed to an increasingly complex microbiota. The first microbiota encountered during passage through the birth canal colonize the infant gut and induce the tolerance of the immune system. Transplacentally derived maternal IgG as well as IgA from breast milk protect the infant from infections during the first 100 days, during which the immune system further develops and immunological memory is formed. The Weaning and introduction of solid food expose the immune system to novel (food) antigens and allow for other microbiota to colonize. The cells and molecules involved in the mutual and intricate interactions between microbiota and the developing immune system are now beginning to be recognized. These include bacterial components such as polysaccharide A from Bacteroides fragilis, as well as bacterial metabolites such as the short-chain fatty acid butyrate, indole-3-aldehyde, and indole-3-propionic acid. All these, and probably more, bacterial metabolites have specific immunoregulatory functions which shape the development of the human immune system during the first 1000 days of life. Full article

The effect of the gut microbiota extends beyond their habitant place from the gastrointestinal tract to distant organs, including the cardiovascular system. Research interest in the relationship between the heart and the gut microbiota has recently been emerging. The gut microbiota secretes metabolites, including Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids (BAs), indole propionic acid (IPA), hydrogen sulfide (H₂S), and phenylacetylglutamine (PAGln). In this review, we explore the accumulating evidence on the role of these secreted microbiota metabolites in the pathophysiology of ischemic and non-ischemic heart failure (HF) by summarizing current knowledge from clinical studies and experimental models. Elevated TMAO contributes to non-ischemic HF through TGF-ß/Smad signaling-mediated myocardial hypertrophy and fibrosis, impairments of mitochondrial energy production, DNA methylation pattern change, and intracellular calcium transport. Also, high-level TMAO can promote ischemic HF via inflammation, histone methylation-mediated vascular fibrosis, platelet hyperactivity, and thrombosis, as well as cholesterol accumulation and the activation of MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell myocardial infiltration, and HDAC 5 and 6 activities, leading to non-ischemic HF, while reactive oxygen species production and the hyperactivation of caveolin-ACE axis result in ischemic HF. An altered BAs level worsens contractility, opens mitochondrial permeability transition pores inducing apoptosis, and enhances cholesterol accumulation, eventually exacerbating ischemic and non-ischemic HF. IPA, through the inhibition of nicotinamide N-methyl transferase expression and increased nicotinamide, NAD+/NADH, and SIRT3 levels, can ameliorate non-ischemic HF; meanwhile, H₂S by suppressing Nox4 expression and mitochondrial ROS production by stimulating the PI3K/AKT pathway can also protect against non-ischemic HF. Furthermore, PAGln can affect sarcomere shortening ability and myocyte contraction. This emerging field of research opens new avenues for HF therapies by restoring gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation and as such normalizing circulating levels of TMAO, SCFA, BAs, IPA, H₂S, and PAGln. Full article

Background: Using dietary interventions to steer the metabolic output of the gut microbiota towards specific health-promoting metabolites is often challenging due to interpersonal variation in treatment responses. Methods: In this study, we combined the ex vivo SIFR^® (Systemic Intestinal Fermentation Research) technology with untargeted metabolite profiling to investigate the impact of carrot-derived rhamnogalacturonan-I (cRG-I) on ex vivo metabolite production by the gut microbiota of 24 human adults. Results: The findings reveal that at a dose equivalent to 1.5 g/d, cRG-I consistently promoted indole-3-propionic acid (IPA) production (+45.8% increase) across all subjects. At a dose equivalent to 0.3 g/d, increased IPA production was also observed (+14.6%), which was comparable to the effect seen for 1.5 g/d inulin (10.6%). IPA has been shown to provide protection against diseases affecting the gut and multiple organs. The Pearson correlation analysis revealed a strong correlation (R = 0.65, p_adjusted = 6.1 × 10⁻¹⁶) between the increases in IPA levels and the absolute levels of Bifidobacterium longum, a producer of indole-3-lactic acid (ILA), an intermediate in IPA production. Finally, the community modulation score, a novel diversity index, demonstrated that cRG-I maintained a high α-diversity which has previously been linked to elevated IPA production. Conclusions: The results from the ex vivo SIFR^® experiment mirrored clinical outcomes and provided novel insights into the impact of cRG-I on the gut microbiome function. Importantly, we demonstrated that cRG-I promotes tryptophan conversion into IPA via gut microbiome modulation, thus conferring benefits via amino acid derived metabolites extending beyond those previously reported for short chain fatty acids (SCFA) resulting from carbohydrate fermentation. Full article

Fresh raspberries are highly perishable, but lactic acid bacteria fermentation offers a favourable method for developing healthy products. This study investigated the effects of Lacticaseibacillus paracasei fermentation on the nutrients and phytochemicals of red raspberry nectar using widely targeted metabolomics, as well as its antioxidant activity. The fermentation notably disrupted the raspberry tissue structure, reshaped its non-volatile composition, and increased its DPPH and hydroxyl free radical scavenging abilities. A total of 261 compounds showed significant differences, with 198 upregulated and 63 downregulated. Among these, certain flavonoid glucosides (e.g., pelargonid-in-3-O-rutinoside, delphinidin-3-O-rutinoside-7-O-glucoside, and kaempferol-3-O-glucoside) were significantly downregulated, while some bioactive phenolic acids (e.g., 3-(4-Hydroxyphenyl)-propionic acid and DL-3-phenyllactic acid), alkaloids (e.g., deoxymutaaspergillic acid and indole-3-lactic acid), amino acids (e.g., L-phenylalanine and L-glutamine), and B vitamins (e.g., VB6, VB7, and VB3) were substantially upregulated. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation and enrichment analysis revealed that metabolic pathways and the biosynthesis of secondary metabolites contributed significantly to the new profile of fermented red raspberry nectar. These findings provide valuable insights for developing fermented raspberry products using Lacticaseibacillus paracasei, which can help minimise fresh raspberry loss and enhance their valorisation. Full article

The aim of this study was to investigate the levels of various tryptophan metabolites in patients with alcoholic liver disease (ALD) and metabolic-associated fatty liver disease (MAFLD) at different stages of the disease. The present study included 44 patients diagnosed with MAFLD, 40 patients diagnosed with ALD, and 14 healthy individuals in the control group. The levels of tryptophan and its 16 metabolites (3-OH anthranilic acid, 5-hydroxytryptophan, 5-methoxytryptamine, 6-hydroxymelatonin, indole-3-acetic acid, indole-3-butyric, indole-3-carboxaldehyde, indole-3-lactic acid, indole-3-propionic acid, kynurenic acid, kynurenine, melatonin, quinolinic acid, serotonin, tryptamine, and xanthurenic acid) in the serum were determined via high-performance liquid chromatography and tandem mass spectrometry. In patients with cirrhosis resulting from MAFLD and ALD, there are significant divergent changes in the serotonin and kynurenine pathways of tryptophan catabolism as the disease progresses. All patients with cirrhosis showed a decrease in serotonin levels (^MAFLDp = 0.038; ^ALDp < 0.001) and an increase in kynurenine levels (^MAFLDp = 0.032; ^ALDp = 0.010). A negative correlation has been established between serotonin levels and the FIB-4 index (p < 0.001). The decrease in serotonin pathway metabolites was associated with manifestations of portal hypertension (p = 0.026), the development of hepatocellular insufficiency (p = 0.008) (hypoalbuminemia; hypocoagulation), and jaundice (p < 0.001), while changes in the kynurenine pathway metabolite xanthurenic acid were associated with the development of hepatic encephalopathy (p = 0.044). Depending on the etiological factors of cirrhosis, disturbances in the metabolic profile may be involved in various pathogenetic pathways. Full article

Drug development for Alzheimer’s disease (AD) treatment is challenging due to its complex pathogenesis. Tetradecyl 2,3-dihydroxybenzoate (ABG-001), a leading compound identified in our prior research, has shown promising NGF-mimicking activity and anti-aging properties. In the present study, both high-fat diet (HFD)-induced AD mice and naturally aging AD mice were used to evaluate anti-AD effects. Meanwhile, RNA-sequences, Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), drug affinity-responsive target stability (DARTS) assay, construction of expression plasmid and protein purification, surface plasmon resonance (SPR) analysis, and 16S rRNA sequence analysis were used to identify the target protein of ABG-001 and clarify the mechanism of action for this molecule. ABG-001 effectively mitigates the memory dysfunction in both HFD-induced AD mice and naturally aging AD mice. The therapeutic effect of ABG-001 is attributed to its ability to promote neurogenesis, activate chaperone-mediated autophagy (CMA), and reduce neuronal inflammation. Additionally, ABG-001 positively influenced the gut microbiota, enhancing the production of indole-3-propionic acid (IPA), which is capable of crossing the blood–brain barrier (BBB) and contributes to neuronal regeneration. Furthermore, our research revealed that IPA, linked to the anti-AD properties of ABG-001, targets the heat shock cognate 70 kDa protein (Hsc70) and regulates the Hsc70/PKM2/HK2/LC3 and FOXO3a/SIRT1 signaling pathways. ABG-001 improves the memory dysfunction of AD mice by modulating autophagy and inflammation through IPA and Hsc70 targeting. These findings offer a novel approach for treating neurodegenerative diseases, focusing on the modification of the gut microbiota and metabolites coupled with anti-aging strategies. Full article