The gut microbiota-derived metabolite indole-3-propionic acid (IPA) plays an important role in maintaining intestinal mucosal homeostasis, while the molecular mechanisms underlying IPA regulation on mucosal CD4+ T cell functions in inflammatory bowel disease (IBD) remain elusive. Here we investigated the roles of IPA in modulating mucosal CD4+ T cells and its therapeutic potential in treatment of human IBD. Leveraging metabolomics and microbial community analyses, we observed that the levels of IPA-producing microbiota (e.g. Peptostreptococcus, Clostridium, and Fournierella) and IPA were decreased, while the IPA-consuming microbiota (e.g. Parabacteroides, Erysipelatoclostridium, and Lachnoclostridium) were increased in the feces of IBD patients than those in healthy donors. Dextran sulfate sodium (DSS)-induced acute colitis and CD45RBhighCD4+ T cell transfer-induced chronic colitis models were then established in mice and treated orally with IPA to study its role in intestinal mucosal inflammation in vivo. We found that oral administration of IPA attenuated mucosal inflammation in both acute and chronic colitis models in mice, as characterized by increased body weight, and reduced levels of pro-inflammatory cytokines (e.g. TNF-α, IFN-γ, and IL-17A) and histological scores in the colon. We further utilized RNA sequencing, molecular docking simulations, and surface plasmon resonance analyses and identified that IPA exerts its biological effects by interacting with heat shock protein 70 (HSP70), leading to inducing Th1/Th17 cell apoptosis. Consistently, ectopic expression of HSP70 in CD4+ T cells conferred resistance to IPA-induced Th1/Th17 cell apoptosis. Therefore, these findings identify a previously unrecognized pathway by which IPA modulates intestinal inflammation and provide a promising avenue for the treatment of IBD.

Inflammatory bowel disease (IBD) is a chronic autoimmune condition whose pathogenesis has not been fully elucidated, and current treatments are not definitive and often carry several side effects. The Complementary and Alternative Medicine (CAM) offers a new approach to conventional medicine. However, their clinical application and mechanisms remain limited.Objective: The aim of this review is to evaluate the anti-inflammatory, impact on microbiota and antioxidant efficacy of currently available CAM for IBD.Methods: The literature collection was obtained from Google Scholar, MEDLINE, PubMed and Web of Science (WOS). Studies in both human and animal models, published in English language between 2018 and 2024, were selected. Sixty-seven studies were included in the current review after inclusion and exclusion screening processes.Results: Mostly, studies showed significant anti-inflammatory, gut microbiota restoring, antioxidant effects of polyphenols, polysaccharides, emodin, short-chain fatty acids (SCFA; including butyrate, propionate and acetate), and probiotics although some contrasting results were noted. Current evidence shows that polyphenols exhibit the most consistent result in alleviating IBD pathophysiology, primarily due to their significant SCFA-elevating effect.Discussion: Future studies may focus on human studies, narrowing down on individual factors which may change natural product's metabolism. Further research studies are also essential to obtain therapeutic recommendations.

Excessive intake of dietary fats is strongly associated with an increased risk of various chronic diseases, such as obesity, diabetes, hepatic metabolic disorders, cardiovascular disease, chronic intestinal inflammation, and certain cancers. A significant portion of the adverse effects of high-fat diet on disease risk is mediated through modifications in the gut microbiota. Specifically, high-fat diets are linked to reduced microbial diversity, an overgrowth of gram-negative bacteria, an elevated Firmicutes-to-Bacteroidetes ratio, and alterations at various taxonomic levels. These microbial alterations influence the intestinal metabolism of small molecules, which subsequently increases intestinal permeability, exacerbates inflammatory responses, disrupts metabolic functions, and impairs signal transduction pathways in the host. Consequently, diet-induced changes in the gut microbiota play a crucial role in the initiation and progression of chronic diseases. This review explores the relationship between high-fat diets and gut microbiota, highlighting their roles and underlying mechanisms in the development of chronic metabolic diseases. Additionally, we propose probiotic interventions may serve as a promising adjunctive therapy to counteract the negative effects of high-fat diet-induced alterations in gut microbiota composition.

The metabolic profiling of biological fluids is important in understanding the various biochemical processes in the human body. The content of aromatic metabolites, including microbial ones, in the blood and cerebrospinal fluid, can provide essential information reflecting infectious processes, both systemic and in the central nervous system. A sensitive method with protein precipitation and sample concentration using ultra-high-pressure liquid chromatography-tandem mass spectrometry was proposed and subsequently validated to determine the number of aromatic metabolites of phenylalanine, tyrosine, and tryptophan in the blood serum and cerebrospinal fluid at 2.0-3.7 × 103 nmol/L. Reference values of 4-hydroxybenzoic, 3-(4-hydroxyphenyl)propionic, and indole-3-carboxylic acids were measured in the blood serum of healthy donors (n = 48). Profile of eleven phenyl- and indole-containing acids was revealed in the serum samples (n = 29) of the patients with long-term sequelae of severe brain damage and in the cerebrospinal fluid samples (n = 29) of the post-neurosurgical patients using different sample preparation methods to measure analytes in a wide (nmol/L and μmol/L) concentration range. Statistically significant differences in concentrations of most analytes were detected in serum samples of patients compared to healthy donors (p ≤ 0.03) and in concentrations of 3-phenyllactic, 3-(4-hydroxyphenyl)lactic, indole-3-lactic, and indole-3-carboxylic acids in cerebrospinal fluid samples of patients with signs of secondary bacterial meningitis compared to those without signs of secondary bacterial meningitis (p ≤ 0.027).

Cholestatic liver disease(CLD) is caused by impaired bile flow due to obstruction of the biliary tract, and long-term exposure to bile acids in the liver triggers inflammation, eventually leading to liver toxicity and liver fibrosis. Emodin-8-O-β-D-glucopyranoside(EG) is anthraquinone compound that is widely found in traditional Chinese medicine. It possessed antioxidative and anti-inflammatory activities. However, the effect of EG on cholestatic liver injury(CLI) has not been explored. In this study, Alpha-naphthyl isothiocyanate(ANIT)-induced CLI mice were used to investigate the anti-cholestasis and hepatoprotective effects of EG through serum biochemical index detection, non-targeted metabolomics, lipidomics, and intestinal flora 16S rRNA sequencing. The results suggested that EG restores homeostasis of the gut microbiome while regulating bile acids metabolism and lipid-related metabolic pathways to reduce liver damage in ANIT-induced cholestasis. This study provides a new perspective on the mechanism of EG, and help offer a more natural approach to managing liver damage.

Gallstone disease, arising from the interplay between host metabolism and gut microbiota, represents a significant health concern. Dysbiosis of the gut microbiome and disruptions in circadian rhythm contribute to the pathogenesis of gallstones. This study conducted a comprehensive analysis of gut microbiota and metabolites derived from stool and serum samples of 28 patients with cholesterol gallstones (CGS) and 19 healthy controls, employing methodologies such as 16S rRNA sequencing, metaproteomics, metabolomics, and host genetic analysis. Additionally, a retrospective cohort study was utilized to assess the efficacy of probiotics or ursodeoxycholic acid (UDCA) in preventing CGS formation post-bariatric surgery.

In CGS patients, gut microbiota diversity shifted, with harmful bacteria rising and beneficial ones declining. The altered microbiota primarily affected amino acid, lipid, nucleotide, and carbohydrate metabolism. Metabolic abnormalities were noted in amino acids, glucose, lipids, and bile acids with decreased levels of ursodeoxycholic, glycosodeoxycholic, and glycolithocholic acids, and increased glycohyodeoxycholic and allocholic acids. Glutamine and alanine levels dropped, while phenylalanine and tyrosine rosed. Animal studies confirmed gene changes in gallbladder tissues related to bile acid, energy, glucose, and lipid metabolism. Importantly, UDCA and probiotics effectively reduced CGS risk post-bariatric surgery, especially when combined.

Multi-omics can clarify CGS pathology, by focusing on the gut-metabolism-gene axis, paving the way for future studies on CGS prevention and treatment through gut microbiota or metabolic interventions.

This letter addresses the recently published manuscript by Darnindro et al, which investigates the diversity and composition of colonic mucosal microbiota in Indonesian patients with and without colorectal cancer (CRC). Although the analysis revealed no statistically significant differences in alpha diversity between the CRC and non-CRC groups, the authors identified notable distinctions in the composition and diversity of colonic mucosal microbiota among patients with CRC compared to those without. At the genus level, a statistically significant difference in microbiota composition was documented between the two cohorts. Specifically, the genera Bacteroides, Campylobacter, Peptostreptococcus, and Parvimonas were found to be elevated in individuals with CRC, while Faecalibacterium, Haemophilus, and Phocaeicola were more prevalent in the non- CRC group.

Probiotics emerges as a promising option for ulcerative colitis (UC) treatment, but its application remains challenging due to insufficient colon-targeted delivery efficiency and survival against the inflammation-associated intestinal oxidative stress. To address these issues, here we report a supramolecular liposome-microgel complex (SLMC) incorporated with Bacillus subtilis spores (BSSs) and dexamethasone (DEX) for orally-deliverable probiotic UC therapy. Specifically, BSSs and cholesterols were conjugated with gelatin via diselenide ligation to prepare microgels, followed by supramolecular complexation with UC-targeted DEX-loaded liposome via microfluidic engineering. The orally-administered SLMC efficiently accumulated in UC-affected colonic sites to release BSSs and DEX. DEX elicited rapid anti-inflammatory effect to reduce ROS generation, which cooperated with the ROS consumption by spore germination and diselenide cleavage to orchestrate an anaerobic intestinal microenvironment, thus promoting Bacillus subtilis colonization to restore gut homeostasis and initiate anti-inflammatory microbiota-macrophage metabolic crosstalk. Indeed, in vivo analysis showed that the SLMC treatment markedly inhibited pro-inflammatory TLR4-NF-κB signaling activities in mucosal macrophages through localized DEX delivery and boosting tryptophan metabolite production, leading to robust and durable UC abolishment. This study offers a practical approach for improving UC treatment in the clinic.

Type 2 diabetes (T2D) is a complex disease shaped by genetic and environmental factors, including the gut microbiome. Recent research revealed pathophysiological heterogeneity and distinct subgroups in both T2D and prediabetes, prompting exploration of personalized risk factors. Using metabolomics in two Swedish cohorts (n = 1,167), we identified over 500 blood metabolites associated with impaired glucose control, with approximately one-third linked to an altered gut microbiome. Our findings identified metabolic disruptions in microbiome-metabolome dynamics as potential mediators of compromised glucose homeostasis, as illustrated by the potential interactions between Hominifimenecus microfluidus and Blautia wexlerae via hippurate. Short-term lifestyle changes, for example, diet and exercise, modulated microbiome-associated metabolites in a lifestyle-specific manner. This study suggests that the microbiome-metabolome axis is a modifiable target for T2D management, with optimal health benefits achievable through a combination of lifestyle modifications.

Hepatocellular carcinoma (HCC) is closely linked to alterations in the gut microbiota. This dysbiosis is characterized by significant changes in the microbial population, which correlate with the progression of HCC. Gut dysbiosis ultimately promotes HCC development in several ways: it damages the integrity of the gut-vascular barrier (GVB), alters the tumor microenvironment (TME), and even affects the intratumoral microbiota. Subsequently, intratumoral microbiota present a characteristic profile and play an essential role in HCC progression mainly by causing DNA damage, mediating tumor-related signaling pathways, altering the TME, promoting HCC metastasis, or through other mechanisms. Both gut microbiota and intratumoral microbiota have dual effects on HCC progression; a comprehensive understanding of their complex biological roles will provide a theoretical foundation for potential clinical applications in HCC treatment.

Heart failure with preserved ejection fraction (HFpEF) represents a significant and growing clinical challenge. Initially, for an extended period, HFpEF was simply considered as a subset of heart failure, manifesting as haemodynamic disorders such as hypertension, myocardial hypertrophy, and diastolic dysfunction. However, the rising prevalence of obesity and diabetes has reshaped the HFpEF phenotype, with nearly 45% of cases coexisting with diabetes. Currently, it is recognized as a multi-system disorder that involves the heart, liver, kidneys, skeletal muscle, adipose tissue, along with immune and inflammatory signaling pathways. In this review, we summarize the landscape of metabolic rewiring and the crosstalk between the heart and other organs/systems (e.g., adipose, gut, liver and hematopoiesis system) in diabetic HFpEF for the first instance. A diverse array of metabolites and cytokines play pivotal roles in this intricate crosstalk process, with metabolic rewiring, chronic inflammatory responses, immune dysregulation, endothelial dysfunction, and myocardial fibrosis identified as the central mechanisms at the heart of this complex interplay. The liver-heart axis links nonalcoholic steatohepatitis and HFpEF through shared lipid accumulation, inflammation, and fibrosis pathways, while the gut-heart axis involves dysbiosis-driven metabolites (e.g., trimethylamine N-oxide, indole-3-propionic acid and short-chain fatty acids) impacting cardiac function and inflammation. Adipose-heart crosstalk highlights epicardial adipose tissue as a source of local inflammation and mechanical stress, whereas the hematopoietic system contributes via immune cell activation and cytokine release. We contend that, based on the viewpoints expounded in this review, breaking this inter-organ/system vicious cycle is the linchpin of treating diabetic HFpEF.

Current treatment of inflammatory bowel disease (IBD) relies on anti-inflammatory and immunosuppressive agents. However, this concept is considered outdated due to its restricted efficacy and unavoidable side effects. Herein, a polynorepinephrine-coated programmable probiotic expressing α-aminoadipate aminotransferase (NE-EcN-pA) was constructed to improve the levels of kynurenic acid and xanthurenic acid in the intestine by modulating the endogenous tryptophan metabolism. The NE layer could protect EcN-pA against the harsh environment of the gastrointestinal tract, enhancing its survival and colonization. In UC mice, oral administration of NE-EcN-pA effectively alleviated intestinal inflammation and restored the intestinal epithelial barrier owing to the activation of the aryl hydrocarbon receptor pathway. Furthermore, NE-EcN-pA promoted the diversity of intestinal flora, improved the imbalance of flora, and enhanced the content of short-chain fatty acids in the colon. Overall, NE-EcN-pA can regulate endogenous tryptophan metabolism and gut microbiota, showing promise in the treatment of gastrointestinal disorders.

Fucoidan, a water-soluble polysaccharide derived from marine organisms, has garnered significant attention for its ability to regulate gut microbiota and its anti-tumor properties. However, the existence of a correlation between the anti-tumor effect of fucoidan and its regulation of the gut microbiota remains unknown. In pursuit of this objective, we culled the gut microbiota of mice with broad-spectrum antibiotics to generate pseudo-sterile tumor-bearing mice. Subsequently, fecal microbial transplants were introduced into the pseudo-sterile tumor-bearing mice. The antitumor effects of fucoidan were found to be dependent on the gut microbiota. Fucoidan promoted the proliferation of Akkermansia, Bifidobacterium and Lactobacillus, which have immunomodulatory effects. Furthermore, through regulation of gut microbiota, fucoidan influenced the metabolic process of tryptophan and facilitated its conversion to indole-3-acetic acid. In addition, fucoidan decreased the kynurenine/tryptophan ratio in serum, increased the proportion of CD8+ T cells, and suppressed the expression level of IDO1 in tumor tissues. Our results confirm that fucoidan enhances anti-tumor immune responses and subsequently exhibits anti-tumor effects by modulating the gut microbiota. Our research contributes to the comprehension of the mechanism of anti-tumor effects of fucoidan and facilitates the development of fucoidan as a dietary supplement for cancer patients.

In recent years, we have witnessed a rapidly growing interest in the intricate communications between intestinal microorganisms and the host immune system. Research on the human microbiome is evolving from merely descriptive and correlative studies to a deeper mechanistic understanding of the bidirectional interactions between gut microbiota and the mucosal immune system. Despite numerous challenges, it has become increasingly evident that an imbalance in gut microbiota composition, known as dysbiosis, is associated with the development and progression of various metabolic, immune, cancer, and neurodegenerative disorders. A growing body of evidence highlights the importance of small molecules produced by intestinal commensal bacteria, collectively referred to as gut microbial metabolites. These metabolites serve as crucial diffusible messengers, translating the microbial language to host cells. This review aims to explore the complex and not yet fully understood molecular mechanisms through which microbiota-derived metabolites influence the activity of the immune cells and shape immune reactions in the gut and other organs. Specifically, we will discuss recent research that reveals the close relationship between microbial indole-3-propionic acid (IPA) and mucosal immunity. Furthermore, we will emphasize the beneficial effects of IPA on intestinal inflammation and discuss its potential clinical implications.

Despite the increasing recognition of the interplay between depression and cardiovascular disease (CVD), the precise mechanisms by which depression contributes to the pathogenesis of cardiovascular disease remain inadequately understood. The involvement of gut microbiota and their metabolites to health and disease susceptibility has been gaining increasing attention. In this study, it was found that depression exacerbated cardiac injury, impaired cardiac function (EF%: P < 0.01; FS%: P < 0.05), hindered long-term survival (P < 0.01), and intensified adverse cardiac remodeling (WGA: P < 0.01; MASSON: P < 0.0001) after myocardial ischemia/reperfusion (MI/R) in mice. Then we found that mice receiving microbiota transplants from chronic social defeat stress (CSDS) mice exhibited worse cardiac function (EF%: P < 0.01; FS%: P < 0.01) than those receiving microbiota transplants from non-CSDS mice after MI/R injury. Moreover, impaired tryptophan metabolism due to alterations in gut microbiota composition and structure was observed in the CSDS mice. Mechanistically, we analyzed the metabolomics of fecal and serum samples from CSDS mice and identified indole-3-propionic acid (IPA) as a protective agent for cardiomyocytes against ferroptosis after MI/R via NRF2/System xc-/GPX4 axis, played a role in mediating the detrimental influence of depression on MI/R. Our findings provide new insights into the role of the gut microbiota and IPA in depression and CVD, forming the basis of intervention strategies aimed at mitigating the deterioration of cardiac function following MI/R in patients experiencing depression.

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 pathways.

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.

The human gut microbiota is diverse and abundant and plays important roles in regulating health by participating in metabolism and controlling physiological activities. The gut microbiota and its metabolites have been shown to affect the functioning of the gut and central nervous system through the microbiota-gut-brain axis. It is well established that microbiota play significant roles in the pathogenesis and progression of Parkinson's disease (PD). Disorders of the intestinal microbiota and altered metabolite levels are closely associated with PD. Here, the changes in intestinal microbiota and effects of metabolites in patients with PD are reviewed. Potential mechanisms underlying intestinal microbiota disorders in the pathogenesis of PD are briefly discussed. Additionally, we outline the current strategies for the treatment of PD that target the gut microbiota, emphasizing the development of promising novel strategies.

Fermented foods have been consumed for millennia, valued for their extended shelf life, distinctive sensory properties, and potential health benefits. Emerging research suggests that fermented food consumption may contribute to gut microbiome diversity, immune modulation, and metabolic regulation; however, mechanistic insights and clinical validation remain limited. This review synthesizes current scientific evidence on the microbial and metabolite composition of fermented foods, their proposed health effects, and safety considerations for vulnerable populations. Additionally, we highlight the need for standardized definitions, serving sizes, and regulatory frameworks to enhance consumer transparency and research reproducibility. By providing a structured overview of existing data and knowledge gaps, this review establishes a foundation for integrating fermented foods into dietary recommendations and guiding future research directions.

The gut microbiota is closely associated with the onset and development of type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and chronic low-grade inflammation. However, despite the widespread use of first-line antidiabetic drugs, IR in diabetes and its complications continue to rise. The gut microbiota and its metabolic products may promote the development of T2DM by exacerbating IR. Therefore, regulating the gut microbiota has become a promising therapeutic strategy, with particular attention given to probiotics, prebiotics, synbiotics, and fecal microbiota transplantation. This review first examines the relationship between gut microbiota and IR in T2DM, summarizing the research progress of microbiota-based therapies in modulating IR. We then delve into how gut microbiota-related metabolic products contribute to IR. Finally, we summarize the research findings on the role of traditional Chinese medicine in regulating the gut microbiota and its metabolic products to improve IR. In conclusion, the gut microbiota and its metabolic products play a crucial role in the pathophysiological process of T2DM by modulating IR, offering new insights into potential therapeutic strategies for T2DM.

Sensorineural hearing loss (SNHL) poses a significant global health challenge with substantial socioeconomic and medical implications. The pathophysiology involves excessive reactive oxygen species (ROS) in the cochlea, inflammation, cellular apoptosis, etc. Tryptophan metabolite indole-3-propionic Acid (IPA), produced by gut microbiota, may offer therapeutic benefits by modulating inflammation, oxidative stress, and immune responses. However, the roles of IPA in protecting from treatment hearing loss in adult mice remain to be investigated. We previously validated that exposure to pesticide metabolite 3, 5, 6-Trichloro-2-pyridinol (TCP) caused hearing loss in mice. Herein, continuous administration of 40 mg/kg IPA for 21 days significantly attenuated the hearing threshold elevation in C57BL/6 mice exposed to 50 mg/kg TCP. IPA treatment reduced the loss of hair cells (HCs) and spiral ganglion neurons (SGNs), preserved nerve fibers, and reversed the damage to spiral ligaments (SL) and stria vascularis (SV). Similarly, IPA cotreatment decreased ROS accumulation in the cochlea and inhibited HC and SGN apoptosis. Transcriptomic analysis showed that IPA enhanced immune responses, particularly through neutrophil recruitment and the activation of regenerative signals like IFNγ. These findings underscore IPA's protective effects against TCP-induced hearing loss, highlighting the role of immune mechanisms in cochlear protection.

Acute myocarditis, characterized by inflammatory myocardial injury, significantly risks heart failure and sudden death. Despite its severity, specific biomarkers are lacking. This study applied metabolomic analysis to urine samples from 21 acute myocarditis patients and 21 controls using UPLC-MS/MS, revealing 728 increased and 820 decreased metabolites in patients. The affected pathways were predominantly related to the amino acid metabolism, lipid metabolism, carbohydrate metabolism, nucleotide metabolism, and others. We have validated 19 metabolites with an area under the receiver operating characteristic curve (AUC-ROC) greater than 0.7 and a high level of identification confidence. Potential biomarkers upregulated in acute myocarditis patients included phytosphingosine, N-acetylneuraminic acid, indolelactic acid, L-glutamic acid, 4-pyridoxic acid, N1-methyl-2-pyridone-5-carboxamide, palmitic acid, hydroxyphenyllactic acid, riboflavin, nicotinic acid, choline, N-formylkynurenine, guanine, and hypoxanthine. Conversely, sebacic acid, 4-vinylphenol sulfate, capryloylglycine, 4-ethylphenylsulfate, and azelaic acid were found to be decreased. Collectively, the metabolomic profiling has uncovered distinct metabolic signatures in patients with acute myocarditis. The amino acid metabolism appears to play a pivotal role in the pathogenesis of acute myocarditis, offering potential avenues for diagnostic and therapeutic development.

Obesity affects millions of people in the world. The gut microbiome influences body fat accumulation, but the mechanisms remain to be investigated. Here, we show an association between microbial aromatic amino acid metabolites in serum and body fat accumulation in a large Chinese longitudinal cohort. We next identify that 4-hydroxyphenylacetic acid (4HPAA) and its analogues effectively protect male mice from high-fat-diet-induced obesity. These metabolites act on intestinal mucosa to regulate the immune response and control lipid uptake, which protects against obesity. We further demonstrate that T cells and B cells are not vital for 4HPAA-mediated obesity prevention, and innate lymphoid cells have antagonistic roles. Together, these findings reveal specific microbial metabolites as pivotal molecules to prohibit obesity through immune control, establishing mechanisms of host modulation by gut microbial metabolites.

The gastrointestinal tract is inhabited by trillions of micro-organisms that form the gut microbiome, which serves various functions that can influence neurological pathways. It can release metabolites that could affect the nervous system. The bidirectional communication between the intestine and the central nervous system is known as the gut-brain axis. This communication can be impacted by the microbiota in various direct and indirect ways. There has been a suggested connection between the microbiome and many neurological disorders, including epilepsy, Alzheimer's disease, Parkinson's disease and multiple sclerosis. This has been explored in human and animal studies. While no microbial biomarkers have been identified yet, alterations in several taxa have been suggested to be associated with disease states. The potential of the microbiome to modulate neurological function has sparked multiple clinical trials using gut-altering treatments, some with positive preliminary results.

The intestinal epithelium represents a critical interface between the host and external environment, serving as the second largest surface area in the human body after the lungs. This dynamic barrier is sustained by specialized epithelial cell types and their complex interactions with the gut microbiota. This review comprehensively examines the recent advances in understanding the bidirectional communication between intestinal epithelial cells and the microbiome. We briefly highlight the role of various intestinal epithelial cell types, such as Paneth cells, goblet cells, and enteroendocrine cells, in maintaining intestinal homeostasis and barrier function. Gut microbiota-derived metabolites, particularly short-chain fatty acids and bile acids, influence epithelial cell function and intestinal barrier integrity. Additionally, we highlight emerging evidence of the sophisticated cooperation between different epithelial cell types, with special emphasis on the interaction between tuft cells and Paneth cells in maintaining microbial balance. Understanding these complex interactions has important implications for developing targeted therapeutic strategies for various gastrointestinal disorders, including inflammatory bowel disease, metabolic disorders, and colorectal cancer.

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.

Chronic low back pain (LBP) is a significant global health concern, often linked to vertebral bone marrow lesions (BML), particularly fatty replacement (FR). This study aims to explore the relationship between the gut microbiome, serum metabolome, and FR in chronic LBP patients.

Serum metabolomic profiling and gut microbiome analysis were conducted in chronic LBP patients with and without FR (LBP + FR, n = 40; LBP, n = 40) and Healthy Controls (HC, n = 31). The study investigates alterations in branched-chain amino acids (BCAAs) levels and identifies key microbial species associated with BCAA metabolism. In vitro experiments elucidate the role of BCAAs in adipogenesis of bone marrow mesenchymal stem cells (BM-MSCs) via the SIRT4 pathway.

Chronic LBP patients with FR exhibit depleted BCAA levels in their serum metabolome, along with alterations in the gut microbiome. Specific microbial species, including Ruminococcus gnavus, Roseburia hominis, and Lachnospiraceae bacterium 8 1 57FAA, are identified as influential in BCAA metabolism and BM-MSCs metabolism. In vitro experiments demonstrate the ability of BCAAs to induce BM-MSCs adipogenesis through SIRT4 pathway activation.

This study sheds light on the intricate relationship between the disturbed gut ecosystem, serum metabolites, and FR in chronic LBP. Dysbiosis in the gut microbiome may contribute to altered BCAA degradation, subsequently promoting BM-MSCs adipogenesis and FR. Understanding these interactions provides insights for targeted therapeutic strategies to mitigate chronic LBP associated with FR by restoring gut microbial balance and modulating serum metabolite profiles.

The complex interactions between host genetics and the gut microbiome are well documented. However, the specific impacts of gene expression patterns and microbial composition on each other remain to be further explored.

Here, we investigated this complex interplay in a sizable population of 705 hens, employing integrative analyses to examine the relationships among the host genome, mucosal gene expression, and gut microbiota. Specific microbial taxa, such as the cecal family Christensenellaceae, which showed a heritability of 0.365, were strongly correlated with host genomic variants. We proposed a novel concept of regulatability ( r b 2 ), which was derived from h2, to quantify the cumulative effects of gene expression on the given phenotypes. The duodenal mucosal transcriptome emerged as a potent influencer of duodenal microbial taxa, with much higher r b 2 values (0.17 ± 0.01, mean ± SE) than h2 values (0.02 ± 0.00). A comparative analysis of chickens and humans revealed similar average microbiability values of genes (0.18 vs. 0.20) and significant differences in average r b 2 values of microbes (0.17 vs. 0.04). Besides, cis ( h cis 2 ) and trans heritability ( h trans 2 ) were estimated to assess the effects of genetic variations inside and outside the cis window of the gene on its expression. Higher h trans 2 values than h cis 2 values and a greater prevalence of trans-regulated genes than cis-regulated genes underscored the significant role of loci outside the cis window in shaping gene expression levels. Furthermore, our exploration of the regulatory effects of duodenal mucosal genes and the microbiota on 18 complex traits enhanced our understanding of the regulatory mechanisms, in which the CHST14 gene and its regulatory relationships with Lactobacillus salivarius jointly facilitated the deposition of abdominal fat by modulating the concentration of bile salt hydrolase, and further triglycerides, total cholesterol, and free fatty acids absorption and metabolism.

Our findings highlighted a novel concept of r b 2 to quantify the phenotypic variance attributed to gene expression and emphasize the superior role of intestinal mucosal gene expressions over host genomic variations in elucidating host‒microbe interactions for complex traits. This understanding could assist in devising strategies to modulate host-microbe interactions, ultimately improving economic traits in chickens.

Indole-3-propionic acid (IPA), a tryptophan catabolite derived from gut bacterial metabolism, has been identified as a functional link between the gut microbiome and tuberculosis.

IPA has gained ample attention over the past two decades on account of its multiple physiological roles, besides being both detectable and quantifiable. IPA is well studied across different health conditions, including cardiovascular and neurological conditions. IPA blocks tryptophan synthesis in Mycobacterium by binding to the allosteric tryptophan-binding site of TrpE, thereby threatening Mycobacterium survival due to tryptophan deficit.

Characterizing IPA would enable its use as a tool to investigate the pathophysiology of tuberculosis. Integrating 'OMICS' techniques (through next-generation sequencing) along with targeted microbial metabolomics may help explore the possible association of serum IPA levels with TB in patients. This will aid in identifying IPA-producing gut microbes and selecting probiotic strains as a microbiome-targeting adjunct therapy, eventually enhancing our understanding of the molecular dynamics of the pathophysiology of tuberculosis in the context of the microbiome.

Aging is associated with the decline of tissue and cellular functions, which can promote the development of age-related diseases like cancer, cardiovascular disease, neurodegeneration, and disorders of the musculoskeletal and immune systems. Healthspan is the length of time an individual is in good health and free from chronic diseases and disabilities associated with aging. Two modifiable factors that can influence healthspan, promote healthy aging, and prevent the development of age-related diseases, are diet and microbiota in the gastrointestinal tract (gut microbiota). This review will discuss how dietary phytochemicals and gut microbiota can work in concert to promote a healthy gut and healthy aging. First, an overview is provided of how the gut microbiota influences healthy aging through its impact on gut barrier integrity, immune function, mitochondria function, and oxidative stress. Next, the mechanisms by which phytochemicals effect gut health, inflammation, and nurture a diverse and healthy microbial composition are discussed. Lastly, we discuss how the gut microbiota can directly influence health by producing bioactive metabolites from phytochemicals in food like urolithin A, equol, hesperetin, and sulforaphane. These and other phytochemical-derived microbial metabolites that may promote healthspan are discussed. Importantly, an individual's capacity to produce health-promoting microbial metabolites from cruciferous vegetables, berries, nuts, citrus, and soy products will be dependent on the specific bacteria present in the individual's gut.

This research explored the protective impact of bamboo leaf flavonoids (BLF) in diquat (DQ) stressed broilers; providing insight of antioxidant, immune response and intestinal barrier function. This experiment consisted of two parts. In the first, 240 chicks were allotted to 2 groups with 8 replicates and 15 chicks per replicate. Treatments consisted of a basic feed (control group, CON) and the basic feed plus 1000 mg/kg BLF (BLF group, BLF) for 28 d, respectively. Then, following the conclusion of the first part, 16 healthy broilers were selected from the CON group and the BLF group. They formed the second part of the experiment, and were allotted to 4 treatments with 8 broilers each: CON-no stress (CON-NS) group, CON-DQ group, BLF-NS group and the BLF-DQ group. Broilers were separately injected intraperitoneally with DQ solution at 40 mg/kg body weight or the same dose of phosphate buffer saline. The results revealed adding BLF to diet reduced the ratio of feed to weight gain of broilers compared to the basic feed group (P = 0.021). In comparison to the CON-NS group, BLF improved the levels of serum and jejunal mucosa total antioxidant capacity, immunoglobulin M, serum catalase, immunoglobulin A, interleukin 10, jejunal mucosa interleukin 4, cecal butyric acid, valeric acid, isobutyric acid, isovaleric acid, upregulated zonula occludens-1 (ZO-1), occludin (OCLN) and claudin-1 (CLDN1) expressions, and reduced the levels of jejunal mucosa malondialdehyde (MDA), interleukin 1β, interleukin 6 and serum diamine oxidase (P < 0.05). Diquat stress elevated the contents of serum MDA, D-lactate, jejunal mucosa tumor necrosis factor α, reactive oxygen species and unclassified_f_Lachnospiraceae relative abundance, downregulated ZO-1, OCLN and CLDN1 expressions, and reduced Sobs, Chao and Ace indices (P < 0.05). Compared with CON-NS group, the concentration of isovaleric acid in the BLF-DQ group was higher (P < 0.05). In conclusion, by establishing a DQ stress injury model, it was elucidated that BLF may enhance antioxidant capacity, strengthen immunity, regulate volatile fatty acid contents, improve intestinal morphology, microbiota and other intestinal barrier functions, so as to mitigate the injury induced by oxidative stress in broilers.

We have previously reported that the serum levels of gut-derived tryptophan metabolite indole-3-propionic acid (IPA) are lower in individuals with liver fibrosis. Now, we explored the transcriptome and DNA methylome associated with serum IPA levels in human liver from obese individuals together with IPA effects on shifting the hepatic stellate cell (HSC) phenotype to inactivation in vitro.

A total of 116 obese individuals without type 2 diabetes (T2D) (age 46.8 ± 9.3 years; BMI: 42.7 ± 5.0 kg/m2) from the Kuopio OBesity Surgery (KOBS) study undergoing bariatric surgery were included. Circulating IPA levels were measured using LC-MS, liver transcriptomics with total RNA-sequencing and DNA methylation with Infinium HumanMethylation450 BeadChip. Human hepatic stellate cells (LX-2) where used for in vitro experiments.

Serum IPA levels were associated with the expression of liver genes enriched for apoptosis, mitophagy and longevity pathways in the liver. AKT serine/threonine kinase 1 (AKT1) was the shared and topmost interactive gene from the liver transcript and DNA methylation profile. IPA treatment induced apoptosis, reduced mitochondrial respiration as well as modified cell morphology, and mitochondrial dynamics by modulating the expression of genes known to regulate fibrosis, apoptosis, and survival in LX-2 cells.

In conclusion, these data support that IPA has a plausible therapeutic effect and may induce apoptosis and the HSC phenotype towards the inactivation state, extending the possibilities to suppress hepatic fibrogenesis by interfering with HSC activation and mitochondrial metabolism.

Ruminants including goats have diverse microcosms of microbiota involved in diet digestion, absorption, and assimilation. Moreover, it is well known that changes in dietary regimens including nutrient levels result in varied gut microbiota composition, and ultimately, the performance and health of these animals.

The current study examined the effects of varying dietary energy and protein levels on the cecal fermentation, immune biomarkers, and microbiota characteristics of 80 male Yunshan Black Goats (6 months, ~35.82 ± 2.79 kg), divided into four diets: 1) High Energy-High Protein (HEHP), 2) High Energy-Low Protein (HELP), 3) Low Energy-High Protein (LEHP), and 4) Low Energy-Low Protein (LELP). Twenty goats (five from each treatment group) were randomly slaughtered after a 50-day feeding trial, and cecal digesta and tissue were sampled for microbial analysis.

The cecal content revealed that the high-energy groups (HEHP, HELP) had lower pH levels than the LEHP group (p < 0.05) and significantly higher valeric and isovaleric acid concentrations in HEHP. Although species richness (Chao1 index) remained consistent, the HEHP group showed higher diversity (Shannon and Simpson indices) than LEHP (p < 0.05). Dominant phyla included Bacteroidetes and Firmicutes; LEHP and LELP had significantly higher Bacteroidetes abundance than HELP, while HELP had higher Firmicutes abundance than LEHP (p < 0.05). Verrucomicrobia abundance was lower in LEHP than in HELP and LELP (p < 0.05). At the genus level, 311 genera were identified, with Clostridium, Prevotella, unidentified_BS11, and others showing significant variation. The HELP group had lower unidentified_BS11 than LEHP and LELP, and higher unidentified_Ruminococcaceae, Clostridium, and Lachnospiraceae than LEHP (p < 0.05). VFA metabolism, absorption, cytokine expression, and tight junction protein mRNA in cecal tissue were also analyzed. Genes like MCT-1 and SLC16A4, linked to VFA absorption, positively correlated with Paludibacter, which was associated with immune markers (TLR-3, TLR-4, IFN-γ) and Occludin expression. In contrast, VFA-related genes and tight junction proteins negatively correlated with unidentified Fibrobacterales, suggesting a microbial role in adaptive immunity.

This study demonstrated that dietary energy and protein levels significantly influenced cecal fermentation, immune biomarkers, and microbiota composition in Yunshan Black Goats.

Tryptophan is an essential amino acid that is metabolized in the intestine by gut bacteria into indole derivatives, including tryptamine. However, little is known about which bacterial tryptophan metabolites directly influence obesity. In this study, we identified tryptamine as a bacterial metabolite that significantly reduced fat mass following the intraperitoneal injection of five bacterial tryptophan end-products in a diet-induced obese mouse model. Interestingly, tryptamine, a serotonin analog, inhibited both lipogenesis and lipolysis in adipose tissue, which was further confirmed in a 3T3-L1 adipocyte cell culture study. Moreover, oral tryptamine supplementation markedly reduced fat mass and improved insulin sensitivity in a long-term, high-fat-diet, pair-feeding model. These studies demonstrate the therapeutic potential of tryptamine, a bacterial tryptophan metabolite, in ameliorating obesity and insulin resistance by directly regulating lipogenesis and lipolysis in white adipose tissue.

An increased risk of developing respiratory diseases has been linked to exposure to cigarette smoking (CS). The flower buds of Tussilago farfara L., also known as Farfarae Flos (FF), can be used for the treatment of cough, bronchitis, and asthmatic disorders in China. In the present study, we used lung and fecal metabolomics, as well as the intestinal flora analysis, aimed to investigate the protective effect of FF against the CS exposure induced lung inflammation on mice. The results showed that FF administration could relieve the lung inflammation as demonstrated by lung index, interleukin-6 (IL-6), and interleukin-1β (IL-1β) levels, as well as the pulmonary pathological change. The lung metabolomics coupled with molecular docking showed that FF could alleviate lung inflammation by regulating lysophosphatidylcholine biosynthesis through the caffeoyl quinic acids distributed in the lung tissue. In addition, fecal metabolome coupled with 16S rRNA gene sequencing showed that FF could regulate the tryptophan metabolism by regulating the intestinal flora disorders. This study provided new insights of FF to relieve CS-induced pulmonary inflammation with the multimechanism.

Studies have revealed extensive taxonomic classifications and patterns of gut microbial diversity in snails, with limited focus on community assembly processes. To better understand the balance between stochastic and deterministic processes in the snail gut microbial assembly and their associations with snail fitness, we used the freshwater snail Biomphalaria straminea as a model and analyzed the gut bacterial communities from 118 samples via high-throughput sequencing of the 16S rRNA gene.

This study reveals that Proteobacteria and Bacteroidota dominate the gut microbiota of B. straminea. Snails from different laboratory habitats exhibit similar gut bacterial diversity but significantly different community structures. The assembly of gut bacterial communities in both laboratory and wild samples is predominantly influenced by stochastic processes rather than deterministic processes, as evidenced by the neutral community model (NCM). Furthermore, during the snail invasion and adaptation to a new environment, stochastic processes are more crucial than deterministic ones in shaping the snail gut microbiota. This indicates that the interplay between stochastic and deterministic processes in the snail gut microbial assembly is associated with host fitness during snail adaptation to a new environment. Based on the null model analysis, we also found that stochastic processes (based on dispersal limitation, homogenizing dispersal, and undominated processes) play a larger role than deterministic (based on homogeneous selection and variable selection) in driving the snail gut bacterial community assembly. Furthermore, the significant difference in the proportions of dispersal limitation and undominated processes is linked to both adaptive and non-adaptive snails.

This study demonstrates that stochastic processes govern the assembly of the gut microbiota in B. straminea. Furthermore, snail adaptation is associated with the interplay between stochastic and deterministic processes in gut microbial composition. This study provides a better understanding of the dynamic patterns of the gut microbial community in freshwater gastropods and may contribute to the development of strategies for controlling intermediate hosts and schistosomiasis.

The host-microbiome axis has been implicated in promoting anti-inflammatory immune responses. Yet, the underlying molecular mechanisms of commensal-mediated IL-10 production by regulatory B cells (Bregs) are not fully elucidated. Here, we demonstrate that bacterial CpG motifs trigger the signaling downstream of TLR9 promoting IκBNS-mediated expression of Blimp-1, a transcription regulator of IL-10. Surprisingly, this effect was counteracted by the NF-κB transcription factor c-Rel. A functional screen for intestinal bacterial species identified the commensal Clostridium sporogenes, secreting high amounts of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs), as an amplifier of IL-10 production by promoting sustained mTOR signaling in B cells. Consequently, enhanced Breg functionality was achieved by combining CpG with the SCFA butyrate or the BCFA isovalerate thereby synergizing TLR- and mTOR-mediated pathways. Collectively, Bregs required two bacterial signals (butyrate and CpG) to elicit their full suppressive capacity and ameliorate T cell-mediated intestinal inflammation. Our study has dissected the molecular pathways induced by bacterial factors, which might contribute not only to better understanding of host-microbiome interactions, but also to exploration of new strategies for improvement of anti-inflammatory cellular therapy.