Indole-3-propionic Acid Research Articles

Intermittent fasting inhibits platelet activation and thrombosis through the intestinal metabolite indole-3-propionate

Abstract Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting (IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E (ApoE) knockout (ApoE−/−) mice, by enhancing intestinal flora production of indole-3-propionic acid (IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor (PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia-reperfusion injury in ApoE−/− mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathway.

Increase in IAA levels by EPSPS copy number variation relates to fitness advantage in Eleusine indica.

Long-term use of chemical weed control has led to some weedy species evolving herbicide resistance traits with fitness advantage. Our previous studies revealed glyphosate resistance in an Eleusine indica population due to copy number variation of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) comes with fitness advantage under non-competitive conditions. Here, transcriptomics and targeted metabolomics were used to investigate physiological basis associated with the fitness advantage. Relative copy number of EPSPS gene and plant dry weight of the glyphosate-resistant (R) population was 88.3- and 1.2- times, respectively, higher than that in the wild type (WT) plants that were isolated from within the R population. Seven genes were screened to be relevant to fitness growth trait by RNA-seq. The level of aromatic amino acids Tryptophan (Trp), Phenylalanine (Phe) and Tyrosine (Tyr), products in the shikimate pathway catalyzed by EPSPS, was 1.2-times higher in R compared to the WT plants. The metabolites associated with Trp metabolism indole-3-acetic acid (IAA), 3-indolepropionic acid (IPA), indole-3-acetamide (IAM) in the R plants were 2.0-, 1.8- and 1.4- times higher than that in the WT plants, respectively. All the results indicate that fitness advantage in the studied R E. indica population may be caused by higher IAA production due to over-expression of the EPSPS gene and pleiotropically by elevated carbon metabolism. The findings in this research can provide reference information for control strategies to the glyphosate-resistant E. indica. © 2025 Society of Chemical Industry.

P0055 Impact of Indole-3-Propionic Acid on Bacterial Invasion Potential of Klebsiella Strains Isolated from Pediatric Ulcerative Colitis Patients

Abstract Background Indole-3-propionic acid (IPA), a tryptophan metabolite produced by microbes, has demonstrated beneficial effects, including reversing dysbiosis, balancing bacterial populations, and reducing inflammation.1,2,3 However, the mechanisms behind these effects and their impact on pathogenic microbes remain unclear. This study aimed to evaluate the effects of IPA on bacterial invasion in vitro, using potential pathobionts (Klebsiella variicola and Klebsiella quasipneumoniae) isolated from non-inflamed sections of the colon in pediatric ulcerative colitis (UC) patients. We hypothesized that IPA could reduce virulence traits, promoting a more homeostatic environment, which could lower inflammation in pediatric UC patients. Methods Caco-2 cells (colonic epithelial cell line) were infected with Klebsiella strains, with or without 0.5 mM IPA. Bacterial invasion was assessed via gentamicin protection assay, and qPCR measured Interleukin-8, IL-10, and TNF-α expression in infected cells. Transepithelial electrical resistance (TEER) assay evaluated barrier integrity, and qPCR analyzed the expression of bacterial virulence genes, including entB (siderophores), manC (capsule), and hcp1 (type VI secretion) in IPA-treated and untreated cultures. Additionally, siderophore production was quantified using a Chrome-Azurol Sulfonate (CAS) assay, and Anthony’s stain visualized the bacterial capsule. Results IPA-treated Caco-2 cells showed significantly reduced bacterial invasion, with further reductions when bacteria were also exposed to IPA. qPCR revealed a significant decrease in IL-8 expression in IPA-treated cells during infection. IL-10 levels decreased non-significantly, and TNF-α expression showed variable results. A trend toward improved tight junction integrity was observed in the TEER assay with IPA treatment, although no significant differences were detected. IPA treatment increased the expression of entB, manC, and hcp1 genes, except for K. variicola, where manC expression remained unchanged. IPA significantly reduced the capsule thickness of K. variicola and resulted in a significant reduction in K. quasipneumoniae siderophore production. Conclusion IPA reduces bacterial invasion and modulates immune responses in Caco-2 cells infected with Klebsiella pathobiont strains. It reduces the virulence of K. quasipneumoniae by targeting siderophore production and diminishes the virulence of K. variicola by reducing capsule formation, suggesting its potential as an anti-virulence agent against these pathobionts. These findings highlight IPA’s potential as an immunomodulatory agent for managing IBD. However, further research is needed into other Klebsiella virulence pathways and host-microbiota interactions.

P1335 Dietary Carnosic Acid Eases Colitis by Activating NRF2 Signal via Regulating Gut Microbiota and Metabolites

Abstract Background Ulcerative colitis (UC) is a chronic intestinal inflammatory disease, which is closely related to the imbalance of intestinal microbiota and metabolic alterations. We have studied the role of dietary carnosic acid (CA) in alleviating intestinal inflammation through regulating the intestinal microbiota and its metabolites. Methods Mice were fed with a diet supplemented with CA or a normal diet, and the enteritis model was established using dextran sulfate sodium (DSS). The feces of mice fed with different diets were transplanted into germ-free mice to determine the direct role of the CA-regulated microbiota in alleviating colitis. The intestinal microbiota was analyzed by 16S rRNA sequencing, serum metabolites were analyzed by liquid chromatography-mass spectrometry (LC-MS) metabolomics, and downstream targets were analyzed by RNA sequencing. Results Through the analysis of the microbiota based on the 16S rRNA gene, we found for the first time that the addition of CA to the diet improved the imbalance of the intestinal microbiota induced by DSS. The protective mechanism of CA against DSS-induced colitis is to improve the function of the intestinal mucosal barrier by activating the Nrf2 signaling pathway. It is worth noting that the addition of CA to the diet can enrich the microbe-derived 3-indolepropionic acid, thereby activating the Nrf2 signaling in human colonic epithelial cells. In addition, exogenous 3-indolepropionic acid treatment has a similar protective effect on DSS-induced colitis by improving the Nrf2 signaling-dependent mucosal barrier function. Conclusion In conclusion, our research results indicate that the intestinal microbiota - 3-indolepropionic acid - Nrf2 axis plays an important role in maintaining intestinal homeostasis, which may represent a new method for preventing colitis by manipulating the metabolites of the intestinal microbiota.

Gut microbial metabolite indole-3-propionic acid alleviates polycystic ovary syndrome in mice by regulating the AhR-NLRP3 axis.

Polycystic ovary syndrome (PCOS) is a complex disorder that significantly impacts female reproductive health and increases the risk of metabolic and reproductive diseases. Emerging evidence suggests that alterations in gut microbiota and their metabolic activities contribute to PCOS pathogenesis, although the underlying mechanisms remain elusive. In the current study, we found that patients with PCOS had altered metabolic profiles, particularly characterized by reduced levels of indole-3-propionic acid (IPA). Administration of IPA alleviated dehydroepiandrosterone (DHEA)-induced PCOS in mice, as demonstrated by improved estrus cycle, insulin sensitivity, ovarian morphology and hormone levels. Additionally, IPA treatment alleviated DHEA-induced oxidative stress in the ovaries and enhanced thermogenesis in brown adipose tissue. Furthermore, IPA attenuated DHEA-induced inflammation both in vivo and in vitro. Mechanistically, IPA treatment suppressed DHEA-induced inflammatory responses and inhibited NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation by activating the aryl hydrocarbon receptor (AhR). Collectively, our findings indicate that IPA ameliorates DHEA-induced PCOS through modulation of the AhR-NLRP3 pathway in mice, suggesting that regulating gut microbial tryptophan metabolism and AhR activation may represent a promising therapeutic strategy for PCOS prevention.

Bacterial indole-3-propionic acid inhibits macrophage IL-1β production through targeting methionine metabolism.

The gut microbiota plays key roles in host health by shaping the host immune responses through their metabolites, like indole derivatives from tryptophan. However, the direct role of these indole derivatives in macrophage fate decision and the underlying mechanism remains unknown. Here, we found that bacterial indole-3-propionic acid (IPA) downregulates interleukin-1beta (IL-1β) production in M1 macrophages through inhibition of nuclear factor-kappa B (NF-κB) signaling. Mechanistically, IPA binds specifically with methionine adenosyl-transferase 2A (MAT2A) to promote S-adenosylmethionine (SAM) synthesis, which facilitates the DNA methylation of ubiquitin-specific peptidase 16 (USP16, a deubiquitinase), and in turn promotes Toll-like receptor 4 (TLR4) ubiquitination and NF-κB inhibition. Furthermore, IPA administration attenuates sepsis in mouse models induced by lipopolysaccharides (LPS), showcasing its potential as a microbial-derived adjunct in alleviating inflammation. Collectively, our findings reveal a newly found microbial metabolite-immune system regulatory pathway mediated by IPA.

Adiposity-related anthropometric parameters, indoles and atherosclerotic cardiovascular disease in Chinese adults: a prospective cohort study

Objective: To investigate the relationship of several adiposity-related anthropometric parameters, including BMI, waist circumference (WC), waist-to-hip ratio (WHR), body fat percentage (BFP) and indoles in plasma with the incidence of atherosclerotic cardiovascular disease (ASCVD) in adults in China. Methods: In China Kadoorie Biobank (CKB) study, blood samples were collected from 2 183 participants in the first resurvey in 2008 to detect indoles. Participants' body weight, body height, WC, hip circumference, and BFP were measured at baseline survey in 2004 and resurvey in 2008, the BMI and WHR were calculated with standardized methods. The long-term follow-up of all participants started from the completion of the resurvey in 2008 until the occurrence of incident ASCVD, death, loss to follow-up or until December 31, 2018. CKB ascertained outcome status (incident ASCVD) through death and disease registries and national health insurance databases, supplemented by active follow-up. Multivariate linear regression model was used to estimate the associations of anthropometric measurements at baseline survey and the first resurvey, and changes in these measurements with 3 indoles [indole, indole-3-acetic acid (IAA), and indole-3-propionic acid (IPA)]. Cox proportional hazard regression model was used to estimate the associations between indoles and the risk for ASCVD. Results: Anthropometric measurements at baseline survey or the first resurvey were negatively associated with plasma IPA level. The regression coefficient (β) of baseline BMI (per 1.0 kg/m2) with 0.1 standard deviation (SD) IPA was -0.23 (95%CI: -0.36 - -0.10) (false discovery rate=0.004). After adjusting for baseline BMI, the β of baseline WC, WHR and BFP with 0.1 SD IPA were -0.09 (95%CI: -0.18 - -0.01), -0.12 (95%CI: -0.19 - -0.05), and -0.20 (95%CI: -0.32 - -0.08), respectively. The annual change in BMI (difference between BMI in 2008 and 2004 divided by the time interval) was associated with indole and IAA, with β of 1.40 (95%CI: 0.58 - 2.21) and -1.07 (95%CI: -1.91 - -0.23), respectively, at each 0.1 increase of SD. Over a median (Q1, Q3) follow-up of 10.46 (10.36, 10.53) years after 2008 resurvey, 236 cases of ASCVD were recorded. IAA and IPA levels were negatively associated with the risk for ASCVD, with hazard ratios for one SD increase of IAA and IPA of 0.87 (95%CI: 0.76 - 0.99) and 0.84 (95%CI: 0.73 - 0.96), respectively. Conclusions: Our results suggested that anthropometric measurements and their changing trends affect the levels of plasma imicrobial tryptophan metabolite levels, decreased levels of IAA and IPA levels are associated with increased risk of ASCVD and indoles in plasma including IPA and IAA might be the mediating factors for adiposity-induced ASCVD.

The mechanism of action of indole-3-propionic acid on bone metabolism.

Indole-3-propionic acid (IPA), a metabolite produced by gut microbiota through tryptophan metabolism, has recently been identified as playing a pivotal role in bone metabolism. IPA promotes osteoblast differentiation by upregulating mitochondrial transcription factor A (Tfam), contributing to increased bone density and supporting bone repair. Simultaneously, it inhibits the formation and activity of osteoclasts, reducing bone resorption, possibly through modulation of the nuclear factor-κB (NF-κB) pathway and downregulation of osteoclast-associated factors, thereby maintaining bone structural integrity. Additionally, IPA provides indirect protection to bone health by regulating host immune responses and inflammation via activation of receptors such as the Aryl hydrocarbon Receptor (AhR) and the Pregnane X Receptor (PXR). This review summarizes the roles and signaling pathways of IPA in bone metabolism and its impact on various bone metabolic disorders. Furthermore, we discuss the therapeutic potential and limitations of IPA in treating bone metabolic diseases, aiming to offer novel strategies for clinical management.

Indole derivatives and their associated microbial genera are associated with the 1-year changes in cardiometabolic risk markers in Chinese adults

BackgroundAlthough emerging evidence suggests that indole derivatives, microbial metabolites of tryptophan, may improve cardiometabolic health, the effective metabolites remain unclear. Also, the gut microbiota that involved in producing indole derivatives are less studied. We identified microbial taxa that can predict serum concentrations of the key indole metabolite indole-3-propionic acid (IPA) at population level and investigated the associations of indole derivatives and IPA-predicting microbial genera with cardiometabolic risk markers.MethodsIn a cohort of 318 community-dwelling adults, serum indole metabolites and fecal microbiota (16S ribosomal RNA) were measured at baseline. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and fasting blood glucose were repeatedly measured at baseline and again after 1 year. Brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI) were measured after 1 year. The association between indole derivatives and the 1-year changes in blood lipids and glucose, and association of indole derivatives with baPWV and ABI were investigated using linear regression models.ResultsEach 1 µmol/L increase in indole-3-acetic acid (IAA) levels was associated with 5.08% (P = 0.046) decrease in LDL-C. IPA levels were inversely associated with baPWV (percentage difference = -1.32%, P = 0.036). Per 1 µmol/L increase in Indole-3-aldehyde (IAld) levels was associated with 1.91% (P = 0.004) decrease in TC and 0.58% (P = 0.019) increase in ABI, but 1.79% decrease in HDL-C with borderline significance (P = 0.050). We identified 18 bacterial genera whose relative abundance was positively associated with serum IPA concentrations (PFDR < 0.05) and constructed a microbial score to reflect the overall IPA-producing potential. This score was inversely associated with baPWV (percentage difference = -0.48%, P = 0.007).ConclusionsOur results suggest that IAA, IPA, IAld, and IPA-predicting microbial score are favorably associated with several cardiometabolic risk markers, although IAld may decrease HDL-C levels.

The prebiotic potential of dietary onion extracts: shaping gut microbial structures and promoting beneficial metabolites.

Onions are well-known vegetables that offer various health benefits. This study explores the impact of onion extracts on gut microbiome using an in vitro fecal incubation model and metabolome analysis. Fecal samples were collected from 19 healthy donors and incubated in the presence or absence of onion extracts for 24 h. To reduce inter-individual variability in the gut microbiome, we employed enterotyping based on baseline fecal microbiota: 14 subjects with a Bacteroides-dominant type (enterotype B) and 5 subjects with Prevotella-dominant type (enterotype P). Alpha diversity was significantly reduced in the onion-treated group compared to the non-treated control group in both Bacteroides- and Prevotella-dominant types. However, significant structural differences in bacterial communities were observed based on weighted UniFrac distance. Notably, short-chain fatty acid (SCFA)-producing bacteria, such as Bifidobacterium_388775, Feacalibacterium, and Fusicatenibacter, were overrepresented in response to onion extracts in enterotype B. Furthermore, genes related to butyrate production were significantly overrepresented in the onion-treated group within enterotype B. Consistent with the enriched taxa and the predicted metabolic pathways, SCFAs and their related metabolites were significantly enriched in the onion-treated group. Additionally, tryptophan metabolism-derived metabolites, including indolelactate (ILA) and indolepropionate (IPA), were elevated by 4- and 32-fold, respectively, in the onion-treated group compared to the control group. In vitro growth assays showed an increase in lactobacilli strains in the presence of onion extracts. These results provide evidence that onion extracts could serve as promising prebiotics by altering gut microbial structure and promoting the production of beneficiary metabolites, including SCFAs and indole derivatives, and enhancing the growth of probiotics.IMPORTANCEThis study is significant as it provides compelling evidence that onion extracts have the potential to serve as effective prebiotics. Utilizing an in vitro fecal incubation model and enterotyping to reduce inter-individual variability, the research demonstrates how onion extracts can alter gut microbial structure and promote the production of beneficial metabolites, including SCFAs and indole derivatives like ILA and IPA. Additionally, onion extract treatment enhances the growth of beneficial probiotics. The findings underscore the potential of onion extracts to improve gut health by enriching specific beneficial bacteria and metabolic pathways, thereby supporting the development of functional foods aimed at improving gut microbiota composition and metabolic health.

Carrot-Derived Rhamnogalacturonan-I Consistently Increases the Microbial Production of Health-Promoting Indole-3-Propionic Acid Ex Vivo.

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. 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. 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, padjusted = 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. 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.

Fructo-oligosaccharides Alleviated Ulcerative Colitis via Gut Microbiota-Dependent Tryptophan Metabolism in Association with Aromatic Hydrocarbon Receptor Activation in Mice.

Fructo-oligosaccharide (FOS) is a typical prebiotic with intestinal health-promoting effects. Here, we explored the anticolitis activity of FOS and clarified the underlying mechanisms. Dextran sulfate sodium (DSS)-induced mice were gavaged with FOS (400 mg/kg) for 37 days, and administration of FOS alleviated DSS-induced colitis symptoms. Besides, FOS improved gut microbiota dysbiosis and modulated the intestinal microbiota-controlled tryptophan metabolic pathways. Targeted metabolomic results showed that FOS significantly increased the colonic levels of indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) and subsequently increased the expressions of aromatic hydrocarbon receptors (AhR) in the colon and further promoted the expressions of interleukin-22 (IL-22) and intestinal tight junction proteins in the colitis mice. These findings for the first time highlight a novel anticolitis mechanism of FOS by alleviating intestinal microbiota dysbiosis and modulating microbial tryptophan metabolism to promote IAA and IPA production for triggering AhR/IL-22 axis activation.

The gut microbiota-derived metabolite indole-3-propionic acid enhances leptin sensitivity by targeting STAT3 against diet-induced obesity.

Obesity is associated with the gut microbiome. Here, we report that gut commensal Clostridia bacteria regulate host energy balance through the tryptophan-derived metabolite indole-3-propionic acid (IPA). IPA acts as an endogenous leptin sensitiser to counteract obesity. Mechanistically, IPA is secreted from the gut into the circulation, and then targets to the STAT3 in the hypothalamic appetite regulation centre, promoting its phosphorylation and nuclear translocation, which enhances the body's response to leptin, and regulates the balance between appetite and energy metabolism. The in vitro pull-down assays involving site-directed mutagenesis demonstrate that Trp623 in the SH2 domain is the key binding site for STAT3-IPA interaction. High-fat diet (HFD), rather than genetic factors, induces excessive secretion of antimicrobial peptides by Paneth cells, inhibiting the growth of Clostridia in the gut and resulting in decreased production of the beneficial metabolite IPA. IPA or Clostridium sporogenes supplement effectively controls weight gain, improves glucose metabolism, and reduces inflammation in DIO mice. IPA fails to achieve such effects in ob/ob mice, while exogenous leptin administration restores the therapeutic effect of IPA. Our study suggests that the IPA-based gut-brain axis regulates host metabolism, and supplementation with microbiome-derived IPA could be a promising intervention strategy for treating obesity.

A novel cocrystal of indole-3-propionic acid and nicotinamide: Structure design, preparation, characterization and preliminary physiochemical properties evaluation

Indole-3-propionic acid (IPA), an intestinal microbiota produced metabolite, has been supposed as a promising clinical drug candidate to ameliorate progressive neurological and neuropsychiatric disorders associated with gut microbiota dysbiosis due to age-related infirmity. In this study, in order to enhance the aqueous solubility of IPA, nicotinamide (NIC) was selected as a coformer to synthesize a novel cocrystal (IPA-NIC) which was characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), thermal analysis, and Fourier transform infrared spectroscopy (FT-IR). The cocrystal structure was found to be in a 2:1 stoichiometric ratio consisting of four IPA molecules and two NIC molecules linked through heteromolecular hydrogen bonds within an asymmetric unit. The physiochemical properties of solubility, dissolution and permeability were demonstrated to be simultaneously improved. Preliminary forced studies under thermal (60 °C) and humid (92.5 % RH) conditions indicated that the cocrystal remained stable which would be beneficial to the further development as a potential drug candidate.

Tetradecyl 2,3-Dihydroxybenzoate Improves Cognitive Function in AD Mice by Modulating Autophagy and Inflammation Through IPA and Hsc70 Targeting.

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.

Early Metabolomic Profiling as a Predictor of Renal Function Six Months After Kidney Transplantation.

Kidney transplantation is the therapy of choice for patients with advanced chronic kidney disease; however, predicting graft outcomes remains a significant challenge. Early identification of reliable biomarkers could enhance post-transplant management and improve long-term outcomes. This study aimed to identify metabolomic biomarkers within the first week after kidney transplantation that predict renal function at six months. We conducted a prospective study involving 50 adult patients who received deceased donor kidney transplants. Plasma samples collected one week after transplant were analyzed using liquid chromatography-mass spectrometry in a semi-targeted metabolomic approach. A Partial Least Squares-Discriminant Analysis (PLS-DA) model identified metabolites associated with serum creatinine > 1.5 mg/dL at six months. Metabolites were selected based on a Variable Importance in Projection (VIP) score > 1.5, which was used to optimize model performance. The PLS-DA model demonstrated strong predictive performance with an area under the curve (AUC) of 0.958. The metabolites negatively associated with serum creatinine > 1.5 mg/dL were 3-methylindole, guaiacol, histidine, 3-indolepropionic acid, and α-lipoic acid. Conversely, the metabolites positively associated with worse kidney graft outcomes included homocarnosine, 5-methylcytosine, xanthosine, choline, phenylalanine, kynurenic acid, and L-kynurenine. Early metabolomic profiling after transplantation shows promise in predicting renal function. Identifying metabolites with antioxidant and anti-inflammatory properties, as well as those that are harmful and could be targeted therapeutically, underscores their potential clinical significance. The link between several metabolites and the tryptophan pathway suggests that further specific evaluation of this pathway is warranted. These biomarkers can enhance patient management and graft survival.

Indole Propionic Acid (IPA), A Gut Microbiota-Derived Metabolite, in Active Pulmonary Tuberculosis (TB) Infection: A Case Control Study

Introduction: A metabolomics study revealed that the tryptophan (Trp) pathway is upregulated in tuberculosis (TB) infection. Indole propionic acid (IPA) is a gut microbiota-derived tryptophan metabolite with antimycobacterial properties through TrpE inhibition and as ligand for AhR in in vitro and in vivo studies. TB infection is associated with gut dysbiosis. However, plasma IPA levels and related factors in active TB patients have not yet been explored. This study aimed to determine the differences and correlations between plasma IPA levels and patient characteristics (age, gender, BMI and GeneXpert result), IPA-producing gut microbiota (Clostridium sporogenes, Lactobacillus sp., and Peptostreptococcus anaerobius), and IFN-γ concentrations in active TB patients and healthy subjects. Materials and methods: A case-control study was performed in 29 active TB patients and 30 healthy controls (HCs) in Aceh, Indonesia. The plasma IPA and IFN-γ levels were measured by ELISA, and the relative abundance of gut microbiota was determined by quantitative PCR (qPCR). The results and discussion: Increased plasma IPA levels (median (IQR) of 22.2 pmol/L (21.3 - 23.9) vs. 18.9 pmol/L (17 - 22.8), p 0.000) were associated with active TB according to the adjusted model (AOR 1.36 (95 % CI 0.37 - 5.1)). Increase of plasma IPA level in higher mycobacterial load patients was found. Higher plasma IPA was positively associated with female, normo- and overweight status, and higher relative abundance of C. sporogenes. The metabolite could be used to discriminate active TB disease at a cutoff of 21.40 pmol/L (72 % sensitivity, 70 % specificity and AUC 0.77). Dysbiosis in IPA-producing bacteria was showed in active TB patients. Conclusion: Plasma IPA could be considered as TB biomarker, and it may also influence disease progression. Future works are needed to validate plasma IPA as biomarker in LTBI and other respiratory infection, as well as its role as biomarker of treatment monitoring response. HIGHLIGHTS The upregulation of the tryptophan (Trp) pathway in tuberculosis infection. Indole propionic acid (IPA) is a Trp metabolite with antimycobacterial properties Higher plasma IPA levels were found in TB patients than in healthy subjects. Dysbiosis of several IPA-producing gut microbiota was revealed in this study. GRAPHICAL ABSTRACT

Clostridium sporogenes-derived metabolites protect mice against colonic inflammation

ABSTRACT Gut microbiota-derived metabolites play a pivotal role in the maintenance of intestinal immune homeostasis. Here, we demonstrate that the human commensal Clostridium sporogenes possesses a specific metabolic fingerprint, consisting predominantly of the tryptophan catabolite indole-3-propionic acid (IPA), the branched-chain acids (BCFAs) isobutyrate and isovalerate and the short-chain fatty acids (SCFAs) acetate and propionate. Mono-colonization of germ-free mice with C. sporogenes (CS mice) affected colonic mucosal immune cell phenotypes, including up-regulation of Il22 gene expression, and increased abundance of transcriptionally active colonic tuft cells and Foxp3+ regulatory T cells (Tregs). In DSS-induced colitis, conventional mice suffered severe inflammation accompanied by loss of colonic crypts. These symptoms were absent in CS mice. In conventional, but not CS mice, bulk RNAseq analysis of the colon revealed an increase in inflammatory and Th17-related gene signatures. C. sporogenes-derived IPA reduced IL-17A protein expression by suppressing mTOR activity and by altering ribosome-related pathways in Th17 cells. Additionally, BCFAs and SCFAs generated by C. sporogenes enhanced the activity of Tregs and increased the production of IL-22, which led to protection from colitis. Collectively, we identified C. sporogenes as a therapeutically relevant probiotic bacterium that might be employed in patients with inflammatory bowel disease (IBD).

Maternal Diet during Pregnancy Alters the Metabolites in Relation to Metabolic and Neurodegenerative Diseases in Young Adult Offspring

Maternal nutrition during the critical period of pregnancy increases the susceptibility of offspring to the development of diseases later in life. This study aimed to analyze metabolite profiles to investigate the effect of maternal diet during pregnancy on changes in offspring plasma metabolites and to identify correlations with metabolic parameters. Pregnant Sprague-Dawley rats were exposed to under- and overnutrition compared to controls, and their offspring were fed a standard diet after birth. Plasma metabolism was profiled in offspring at 16 weeks of age using liquid chromatography–mass spectrometry (LC-MS/MS) and gas chromatography–tandem mass spectrometry (GC-MS/MS). We analyzed 80 metabolites to identify distinct metabolites and metabolic and neurodegenerative disease-associated metabolites that were sex-differentially altered in each group compared to controls (p &lt; 0.05, VIP score &gt; 1.0). Specifically, changes in 3-indolepropionic acid, anthranilic acid, linoleic acid, and arachidonic acid, which are involved in tryptophan and linoleic acid metabolism, were observed in male offspring and correlated with plasma leptin levels in male offspring. Our results suggest that fatty acids involved in tryptophan and linoleic acid metabolism, which are altered by the maternal diet during pregnancy, may lead to an increased risk of metabolic and neurodegenerative diseases in the early life of male offspring.

Increasing plant protein in the diet induces changes in the plasma metabolome that may be beneficial for metabolic health. A randomized crossover study in males

Background & aimDietary shifts replacing animal protein (AP) with plant protein (PP) sources have been associated with lowering cardiometabolic risk (CMR), but underlying mechanisms are poorly characterized. This nutritional intervention aims to characterize the metabolic changes induced by diets containing different proportions of AP and PP sources in males at CMR. DesignThis study is a 4-week, crossover, randomized, controlled-feeding trial in which 19 males with CMR followed two diets providing either 36% for the control diet (CON-D) or 64% for the flexitarian diet (FLEX-D) of total protein intake from PP sources. Plasma nontargeted metabolomes (LC-MS method) were measured in the fasted state and after a high-fat challenge meal at the end of each intervention arm. Lipogenesis and protein synthesis fluxes, flow-mediated dilatation (FMD) and gluco-lipidic responses were assessed after the challenge meal. Data were analyzed with mixed models, and univariate and multivariate models for metabolomics data. ResultsIn both arms CMR improved with time, with decreased body weight (-0.9%), insulin resistant (-34%, HOMA-IR, Homeostatic Model Assessment for Insulin Resistance) and low-density lipoproteins (LDL)-cholesterol (-11%). Diet had no effect on FMD or metabolic fluxes, but a trend was observed for a stronger decrease in HOMA-IR and lower postprandial glucose after FLEX-D vs CON-D. The abundance of 21 and 37 metabolites differed between diets at fasted and fed states, respectively, including food intake biomarkers of AP (methylhistidine, eicosapentaenoic acid, hydroxyprolines) and PP sources (trigonelline, N-acetyl-ornithine). In fasted or fed states, indole acrylic acid and indole propionic acid, both products of tryptophan catabolism, were higher after FLEX-D vs CON-D, while the indispensable amino acids-related metabolites alpha-aminoadipic acid, hydroxymethylbutyric acids and propionylcarnitine were lower. In the postprandial state only, the ω-oxidation products dodecanedioic, tetradecanedioic and hexadecanedioic acids were higher after FLEX-D vs CON-D. ConclusionsDespite little changes in risk factors after 4 wk, this study evidenced subtle metabolic adaptations in amino acids and lipid metabolism and gut microbiota activity occurring after higher PP source intake that may be beneficial to CMR. ClinicalTrials.gov study identifierNCT04236518 Clinical Trial RegistryNCT04236518 on ClinicalTrials.gov