Chronic kidney disease (CKD) poses a severe health risk with high morbidity and mortality, profoundly affecting patient quality of life and survival. Despite advancements in research, the pathophysiology of CKD remains incompletely understood. Growing evidence links CKD with shifts in gut microbiota function and composition. Natural compounds, particularly polyphenols, have shown promise in CKD treatment due to their antioxidant and anti-inflammatory properties and their ability to modulate gut microbiota. This review discusses recent progress in uncovering the connections between gut microbiota and CKD, including microbiota changes across different kidney diseases. We also examine metabolite alterations,such as trimethylamine-N-oxide, tryptophan derivatives, branched-chain amino acids, short-chain fatty acids, and bile acids,which contribute to CKD progression. Further, we outline the mechanisms through which polyphenols exert therapeutic effects on CKD, focusing on signaling pathways like nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), mammalian target of rapamycin (mTOR), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), phosphatidylin-ositol-3-kinase (PI3K)/protein kinase B (Akt), and toll like receptors (TLR), as well as their impact on gut microbiota. Lastly, we consider how dietary polyphenols could be harnessed as bioactive drugs to slow CKD progression. Future research should prioritize multi-omics approaches to identify patients who would benefit from polyphenolic interventions, enabling personalized treatment strategies to enhance therapeutic efficacy.

Research indicates that abnormal gut microbiota metabolism is linked to colorectal cancer (CRC) progression, but the role of microbiota-related tryptophan metabolism disruption remains unclear. Using metagenomic sequencing and targeted Trp metabolomics, our research identified that CRC patients had abnormal indole-3-lactic acid (ILA) levels, which were related to tumor malignancy. Exogenous ILA administration suppressed CRC development in AOM/DSS induced and xenograft mice models. Furthermore, in vitro experiments demonstrated that ILA inhibits tumor cell proliferation, migration, and anti-apoptotic capabilities. Mechanistically, ILA appears to directly occupy the phosphorylation sites of STAT3, leading to a reduction in intracellular phosphorylated STAT3 (p-STAT3) levels and the inhibition of the HK2 pathway, thereby downregulating glucose metabolism in cancer cells. Notably, this inhibition is independent of the aryl hydrocarbon receptor (AHR). In conclusion, our research findings demonstrate that alterations in tryptophan metabolism among CRC patients can influence tumor progression and reveal a novel mechanism through which ILA exerts its inhibitory effects on CRC. These findings offer new insights into the role of gut microbiota in CRC and identify potential clinical therapeutic targets.

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.

In addition to the high neurotoxicity, depression, and anxiety are the most prominent characteristics of methamphetamine (Meth) withdrawal. Studies to date on the issue of Meth-associated depression and anxiety are focused on the brain, however, whether peripheral homeostasis, especially the "microbiota-gut" axis participates in these adverse outcomes, remains poorly understood. In the current study, with the fecal microbiota transplantation (FMT) assay, the mice received microbiota from Meth withdrawal mice displayed marked depression and anxiety behaviors. The 16S rRNA sequencing results showed that Meth withdrawal contributed to a striking reduction of Akkermansia, Bacteroides, Faecalibaculum, Desulfovibrio, and Anaerostipes, which are known to be associated with tryptophan (TRP) metabolism. Noteworthily, the substantial decreases of the indole derivatives from the TRP metabolic pathway, including IAA, IPA, ILA, IET, IArA, IAld, and TRM were observed in the serum of both Meth abusing humans and mice during Meth withdrawal with the UHPLC-MS/MS analysis. Combining the high and low TRP diet mouse model, the mice with high TRP diet obviously impeded Meth-associated depression and anxiety behaviors, and these results were further strengthened by the evidence that administration of IPA, IAA, and indole dramatically ameliorated the Meth induced aberrant behaviors. Importantly, these protective effects were remarkably counteracted in aryl hydrocarbon receptor knockout (AhR KO) mice, underlining the key roles of microbiota-indoles-AhR signaling in Meth-associated depression and anxiety. Collectively, the important contribution of the present work is that we provide the first evidence that peripheral gut homeostasis disturbance but not limited to the brain, plays a key role in driving the Meth-induced depression and anxiety in the periods of withdrawal, especially the microbiota and the indole metabolic disturbance. Therefore, targeting AhR may provide novel insight into the therapeutic strategies for Meth-associated psychological disorders.

Tryptophan-derived indoles produced by the gut microbiota, particularly indole-3-propionate (IPA), are key compounds associated with gastrointestinal balance and overall health. Reduced levels of IPA have been associated with inflammatory bowel disease, type 2 diabetes, and colorectal cancer. Since fiber-rich diets have been shown to promote IPA, we aimed to decipher fiber-specific effects and identify associated IPA-producing taxa in a range of healthy individuals. We cultured fecal microbiota from 16 adults with tryptophan and eight different dietary fibers and monitored community shifts by 16S rRNA gene amplicon sequencing and tryptophan-derived indoles using targeted liquid chromatography with diode array detection. The concentrations and types of indoles produced were donor-specific, with pectin strongly promoting IPA production in certain donors. IPA production was not associated with any known IPA producer but with the pectin-utilizing species Lachnospira eligens, which produced indole-3-lactate (ILA) in vitro, the IPA precursor. Supplementation of ILA in additional fecal microbiota cultures (n = 6) revealed its effective use as a substrate for IPA production. We identified a novel IPA producer, Enterocloster aldenensis, which produced IPA exclusively from ILA but not from tryptophan. Co-culture of L. eligens and E. aldenensis resulted in IPA production, providing new evidence for an ILA cross-feeding mechanism that may contribute to the IPA-promoting effects observed with pectin. Overall, we highlight the potential for targeted dietary interventions to promote beneficial gut taxa and metabolites.

Urbanization has significantly transformed dietary habits worldwide, contributing to a globally increased burden of non-communicable diseases and altered gut microbiota landscape. However, it is often overlooked that the adverse effects of these dietary changes can be transmitted from the mother to offspring during early developmental stages, subsequently influencing the predisposition to various diseases later in life. This review aims to delineate the detrimental effects of maternal urban-lifestyle diet (urbanized diet) on early-life health and gut microbiota assembly, provide mechanistic insights on how urbanized diet mediates mother-to-offspring transfer of bioactive substances in both intrauterine and extrauterine and thus affects fetal and neonatal development. Moreover, we also further propose a framework for developing microbiome-targeted precision nutrition and diet strategies specifically for pregnant and lactating women. The establishment of such knowledge can help develop proactive preventive measures from the beginning of life, ultimately reducing the long-term risk of disease and improving public health outcomes.

The microbiome, especially that present in the gut, has emerged as a key modulator of animal behavior. However, the extent of its influence across species and behavioral repertoires, as well as the underlying mechanisms, remains poorly understood. Increasing evidence suggests that microbial metabolites play an important role in driving behavioral variation. In this review, we synthesize findings from vertebrates to invertebrates, spanning both model and non-model organisms, to define key groups of microbial-derived metabolites involved in modulating seven distinct behaviors: nutrition, olfaction, circadian rhythms, reproduction, locomotion, aggression, and social interactions. We discuss how these microbial metabolites interact with host chemosensory systems, neurotransmitter signaling, and epigenetic modifications to shape behavior. Additionally, we highlight critical gaps in mechanistic understanding, including the need to map additional host receptors and signaling pathways, as well as the untapped potential of microbial biosynthetic gene clusters as sources for novel bioactive compounds. Advancing these areas will enhance understanding of the microbiome's role in behavioral modulation and open new avenues for microbiome-based interventions for behavioral disorders.

Persistent organic pollutants (POPs) are known to disrupt gut microbiota composition and host metabolism, primarily through dietary exposure. In this study, we investigate the impact of 2,3,7,8-tetrachlorodibenzofuran (TCDF) on gut microbiota and host metabolic processes. RNA-seq analysis revealed that TCDF exposure significantly affected tryptophan metabolism, lipid metabolic pathways, and immune system function. Metagenomic and metabolomic analyses further showed that TCDF reduced the abundance of Mucispirillum schaedleri and levels of two key tryptophan metabolites, indole-3-carboxaldehyde (3-IAld) and Indole acrylic acid (IA). Supplementation with 3-IAld and IA alleviated TCDF-induced liver toxicity in mouse, as evidenced by reduced Cyp1a1 expression, and mitigated intestinal inflammation, reflected by lower pro-inflammatory cytokines (Ifn-γ and Il-1β) in the colon. Additionally, 3-IAld and IA supplementation enhanced intestinal barrier function, as demonstrated by increased Mucin 2 (MUC2) expression in the gut mucosa of mouse. These findings suggest that TCDF exposure disrupts the gut microbiome and host metabolic balance, and highlight the potential therapeutic role of tryptophan-derived metabolites in mitigating environmental pollutant-induced damage.

Clostridial necrotizing enterocolitis is a severe gastrointestinal disease induced by Clostridium, strongly associated with intestinal dysbiosis. Fecal microbiota transplantation (FMT) has proven effective in treating gastrointestinal diseases by remodeling intestinal microbial homeostasis. However, it remains unclear whether FMT from donors with beneficial microbiota can improve the recipient's intestinal function more efficiently. This study found that probiotic Bacillus paralicheniformis SN-6-mediated gut microbiota effectively prevent Clostridial necrotizing enteritis and explored the underlying molecular mechanisms. Data demonstrated that SN-6 altered gut microbiota composition, ameliorated Clostridium perfringens-induced intestinal microbiota dysbiosis and metabolic reprogramming, particularly enhancing tryptophan metabolism. This led to a marked reduction in intestinal barrier damage and inflammation. FMT from SN-6-treated mice reduced jejunal inflammation in Clostridium perfringens-infected mice, strengthened jejunal barrier and enriched beneficial bacteria, such as Lactobacillus, Blautia, Akkermansia. Furthermore, 3-indoleacetic acid (IAA), a metabolite enriched by SN-6, activated aryl hydrocarbon receptor (AhR), suppressed the P38 mitogen-activated protein kinase (P38 MAPK) signaling, and drove macrophage polarization from M0 to M2-type, thereby reducing apoptosis and excessive inflammation. This study highlights Bacillus paralicheniformis SN-6 as a key modulator of intestinal immunomodulation via the gut microbiota-IAA-AhR-P38 MAPK axis, offering a potential therapeutic target for preventing and controlling clostridial necrotizing enteritis.

Fecal microbiota transplantation (FMT) from humans with specific medical conditions to animal models can demonstrate causality by inducing or exacerbating pathophenotypes, linking the gut microbiota to health outcomes.

We conducted a scoping review searching MEDLINE, EMBASE, Scopus, and Web of Science through July 2024 to identify human noninfectious diseases studied using FMT in animal models, investigate FMT methodologies, and assess the feasibility of systematic reviews on the role of the microbiota in specific diseases.

From 605 reports of 489 studies, we found that inflammatory bowel diseases, irritable bowel syndrome, obesity, colorectal cancer, and depression were the most commonly studied, with cancer research focusing on immunotherapy non-responsiveness. In a random sample of studies, gastrointestinal outcomes were most frequently reported, with remarkably high rates (> 80%) of successful induction of disease-specific alterations for intestinal barrier function, gastrointestinal inflammation, circulating immune parameters, and fecal metabolites. Most studies used C57BL/6 mice and oral gavage administration, with recipients being either germ-free or antibiotic-pretreated. We created tables linking conditions with publications to facilitate future systematic reviews.

Although human-to-animal FMT studies cover diverse conditions, methodological heterogeneity and inconsistent reporting hinder comparability. Standardized protocols and guidelines are needed. For several conditions, sufficient literature exists to assess the role of the gut microbiota in human health through systematic reviews.

Blastocystis, a common protist in the human gut microbiota, has been identified as a key modulator of gut health and disease progression. Research highlights the involvement of Blastocystis in inflammatory bowel disease, cognitive function, and metabolic health. Despite an increasing interest on this topic, the literature on Blastocystis remains fragmented and often contradictory, with subtype-specific effects inadequately defined and their underlying mechanisms insufficiently elucidated. In this Personal View, we provide an in-depth discussion of the dual roles of Blastocystis subtypes that can either exacerbate gut inflammation by disrupting the epithelial barrier or confer protection by enhancing barrier integrity and inducing anti-inflammatory immune responses. We also examine the effect of Blastocystis on the gut-brain axis, identifying associations between Blastocystis colonisation and cognitive and behavioural changes mediated through alterations in gut microbial composition and metabolite profiles. Moreover, we highlight the association of Blastocystis colonisation with healthier dietary patterns and improved cardiometabolic profiles. These findings could contribute to a comprehensive understanding of Blastocystis and its potential as a biomarker of gut health.

Sepsis-related intestinal injury is essential in multi-organ dysfunction induced by the systemic inflammatory response. Agmatine (AGM) has anti-inflammatory, antioxidative, and immunomodulatory properties. However, no reports of AGM alleviating sepsis-related intestinal injury have been found. Therefore, this study intends to investigate the protective effects of AGM on sepsis-related intestinal injury and its potential mechanism.

We first established a sepsis model by lipopolysaccharide (LPS) or cecum ligation perforation (CLP), and then used H&E staining, transmission electron microscopy (TEM), and TUNEL to examine the pathological changes in rat intestines after AGM treatment. ELISA was used to detect expression levels of inflammatory factors in ileal tissues and biochemical indexes of infectionin in serum. TNF-α induced Caco-2 cell inflammation model was established in vitro, and cell activity and proliferative capacity were detected by CCK8 and EdU after AGM treatment. The Caco-2 cell inflammation model with high or low expression of Aryl hydrocarbon receptor (AhR) was established, and whether AGM exerts anti-inflammatory effects via AhR/STAT3/IL-10 pathway was investigated using molecular docking, Co-IP, and Western Blot.

The histopathological staining demonstrated that AGM significantly reduced intestinal injury and the content of inflammatory factors IL-1β, IL-6, and TNF-α, improved systemic infection and the survival rate of septic mice, and restored intestinal barrier function in CLP rats. In vitro, AGM improved cell viability and proliferative capacity of the Caco-2 cell inflammation model. AGM inhibits inflammatory factor expression by activating AhR, decreasing HIF-1 protein expression, and activating the STAT3/IL-10 signaling pathway.

AGM has the potential to ameliorate sepsis-related intestinal injury via the AhR-STAT3-IL-10 pathway, thereby offering theoretical basis for clinical treatment of sepsis.

Diquat (DQ) is extensively utilized as a herbicide in farming, and its intake can result in serious systemic toxicity due to its induction of oxidative stress (OS) and disruption of intestinal homeostasis. The gastrointestinal tract is one of the first systems exposed to DQ, and damage to this system can influence the general health of the host. Our review summarizes the toxic effects of DQ on the intestinal barrier integrity, gut microbiome, and microbial metabolites (e.g., short-chain fatty acids [SCFAs], bile acids). By elucidating the mechanisms linking DQ-induced OS to gut dysbiosis, mitochondrial dysfunction, and inflammation, our work provides critical insights into novel therapeutic strategies, including probiotics, antioxidants (e.g., hydroxytyrosol, curcumin), and selenium nanoparticles. These findings address a pressing gap in understanding environmental toxin-related gut pathology and offer potential interventions to mitigate systemic oxidative damage.

Gut microbiota disturbances can elevate the risk of stroke by contributing to cerebrovascular events. Particularly, the gut tryptophan (TRP) metabolite is an essential mediator of the gut-brain axis. This review highlights the role of TRP metabolism in stroke, the influence of intestinal microbiomes on stroke pathology via TRP metabolism, and the gut-brain axis interactions. Recent studies indicate that various bioactive molecules produced via TRP metabolism can regulate various neurological functions and interrupt stroke pathophysiology. Moreover, the relationship between gut TRP metabolism and stroke development has been verified. TRP metabolism involves three pathways: kynurenine, 5-hydroxytryptamine, and indole, which potentially regulate post-stroke, may function as aryl hydrocarbon receptor agonists to modify neuronal excitotoxicity, and offer crucial targets for stroke treatment. This suggests that modulating TRP metabolite levels through various methods can enhance the prognosis of central nervous system diseases and restore microbiota-gut-brain axis functions.

The co-treatment of ulcerative colitis with berberine hydrochloride (BBR), the Janus kinase(JAK) inhibitor Tofacitinib (TOFA), and Fligotinib (FIGA) is feasible and sophisticated in terms of mechanism. However, no studies have yet explored their interactions. This study aimed to establish a highly sensitive, specific, and reproducible HPLC-MS/MS method for investigating the pharmacokinetic interactions between BBR-TOFA and BBR-FIGA in rats.

The analytes and internal standards were extracted from rat plasma using a mixed solvent of dichloromethane and ether (3:2 ratio). The mobile phase comprised a mixture of methanol (containing 0.1% formic acid) and water (containing 0.1% formic acid and 2 mm ammonium acetate), with a flow rate of 0.6 mL/min. Elution was performed in a gradient mode on a Phenomenex Kinetex column (50×3.0 mm, 2.6 μm). A systematic methodological validation was conducted according to the standards of the Chinese Pharmacopoeia, covering aspects such as specificity, calibration curve and linearity, residual effects, precision and accuracy, recovery, matrix effect, dilution integrity, and stability.

All methodological validation parameters met the standards of the Chinese Pharmacopoeia, confirming the method's suitability for simultaneously determining the concentrations of BBR, TOFA, and FIGA in rat plasma. Pharmacokinetic experimental results indicate that TOFA and FIGA have no significant effect on the plasma concentration of BBR across various pharmacokinetic parameters. However, due to BBR's inhibition or induction of various drug-metabolizing enzymes, it significantly affects some of the pharmacokinetic parameters of TOFA and FIGA.

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, highlighting the urgent need for novel preventive and therapeutic strategies. Emerging research highlights the crucial role of the gut microbiota, including bacteria, fungi, viruses, and their metabolites, in the pathogenesis of CRC. Dysbiosis, characterized by an imbalance in microbial composition, contributes to tumorigenesis through immune modulation, metabolic reprogramming, and genotoxicity. Specific bacterial species, such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis , along with fungal agents like Candida species, have been implicated in CRC progression. Moreover, viral factors, including Epstein-Barr virus and human cytomegalovirus, are increasingly recognized for their roles in promoting inflammation and immune evasion. This review synthesizes the latest evidence on host-microbiome interactions in CRC, emphasizing microbial metabolites, such as short-chain fatty acids and bile acids, which may act as both risk factors and therapeutic agents. We further discuss the latest advances in microbiota-targeted clinical applications, including biomarker-assisted diagnosis, next-generation probiotics, and microbiome-based interventions. A deeper understanding of the role of gut microbiome in CRC pathogenesis could pave the way for diagnostic, preventive, and personalized therapeutic strategies.

The number of chronic kidney disease (CKD) patients is increasing in Japan, and this population is at high risk of death from cardiovascular and cerebrovascular diseases. Therefore, prevention of arteriosclerosis as a common underlying cause of these diseases is required. In this study, we examined whether 11/19-B1 yogurt, which has been proven to reduce serum low-density lipoprotein (LDL) levels, can decrease the serum levels of indoxylsulfate and trimethylamine-N-oxide (TMAO), which are produced by intestinal microbiota and known to cause arteriosclerosis, through improving dysbiosis in hemodialysis patients.

Nineteen dialysis patients consumed 50 g of 11/19-B1 yogurt daily for 8 weeks, and changes in serum lipid profile and uremic toxin levels, intestinal microbiome, as well as the frequency of bowel movement and stool characteristics were observed.

The results demonstrated that an intake of yogurt decreased serum LDL 99.3 to 88.5 (p = 0.049) and indoxylsulfate in seven of nine subjects with previously high concentrations, and improved stool characteristics as estimated by the Bristle stool score, although decreased HDL and no beneficial effect on serum TMAO was observed.

These results may suggest that the ingestion of 11/19-B1 yogurt provides a preventative effect against the progression of atherosclerosis and renal dysfunction.

Despite being one of the most common and debilitating mood disorders, bipolar disorder is often misdiagnosed and undertreated. Its pathogenesis is complex, with significant patient variability and inconsistent treatment effectiveness. The brain-gut-microbiota axis plays a critical role in bipolar disorder by modulating neurotransmitter secretion, gut peptides and systemic inflammation. However, the mechanisms by which psychotropic treatments influence gut microbiota composition and their implications for clinical outcomes remain poorly understood. This systematic review evaluated the impact of psychotropic drugs on gut microbiota and their potential role in bipolar disorder treatment outcomes. A comprehensive search across Ovid MEDLINE, Embase, APA PsycINFO, Scopus and PubMed yielded 314 articles, of which 12 met the inclusion criteria (last search: 13 August 2024). The studies included were those on adults with bipolar disorder type I or II receiving psychopharmacological treatments; those with group comparisons (e.g. healthy controls vs. medicated vs. non-medicated) investigating gut microbiome changes; and no restrictions applied to psychotic features, comorbid anxiety or prior treatment responses. Exclusions involved individual case reports, incomplete conference submissions or early terminated studies lacking efficacy analysis. Cochrane ROBINS-I V2 tool was used to measure the risk of bias, and the GRADE approach was utilized to rate the certainty of evidence in included studies. Two authors independently extracted data into Excel spreadsheets, categorizing demographic and clinical characteristics, describing microbiome analytic methods and summarizing findings on gut microbiome changes post-treatment. Given the high variability in methods and outcome measures across studies, all details were reported without data conversion. Data synthesis reveals that psychotropic treatments, including quetiapine and lithium, influence gut microbiota by increasing the abundance of beneficial bacteria supporting gut health and pathogenic bacteria linked to metabolic dysfunction. Notably, female patients exhibited more significant changes in microbial diversity following psychotropic treatment. Additionally, patients treated with psychotropics showed an increased prevalence of gut bacteria associated with multidrug antibiotic resistance. In bipolar patients treated with quetiapine, responders - those experiencing improved depressive symptom scores - displayed distinct gut microbiome profiles more closely resembling those of healthy individuals compared with non-responders. Responders also exhibited neural connectivity patterns similar to healthy subjects. These findings underscore the complex dual impact of psychotropic medications on gut microbiota, with potential consequences for both gut and mental health. While the enrichment of beneficial bacteria may support gut health, the rise in antibiotic-resistant and metabolically disruptive bacteria is concerning. Study limitations include methodological heterogeneity, inclusions of other psychiatric disorders, a high risk of bias in some studies due to incomplete statistical analyses or insufficient control for confounding factors and potential duplication of study populations arising from overlapping authorship. Further research is essential to elucidate the functional consequences of these microbial shifts and their influence on treatment efficacy. Nevertheless, this review highlights the potential of utilizing gut microbiota profiles to inform personalized treatment strategies, optimize therapeutic outcomes and minimize side effects in bipolar disorder. This study was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/3GUZR).

Gut inflammatory diseases cause microbial dysbiosis. Human immunodeficiency virus-1 (HIV) infection disrupts intestinal integrity, subverts repair/renewal pathways, impairs mucosal immunity and propels microbial dysbiosis. However, microbial metabolic mechanisms driving repair mechanisms in virally inflamed gut are not well understood. We investigated the capability and mechanisms of gut microbes to restore epithelial barriers and mucosal immunity in virally inflamed gut by using a multipronged approach: an in vivo simian immunodeficiency virus (SIV)-infected nonhuman primate model of HIV/AIDS, ex vivo HIV-exposed human colorectal explants and primary human intestinal epithelial cells. SIV infection reprogrammed tryptophan (TRP) metabolism, increasing kynurenine catabolite levels that are associated with mucosal barrier disruption and immune suppression. Administration of Lactiplantibacillus plantarum or Bifidobacterium longum subsp. infantis into the SIV-inflamed gut lumen in vivo resulted in rapid reprogramming of microbial TRP metabolism towards indole-3-lactic acid (ILA) production. This shift accelerated epithelial repair and enhanced anti-viral defenses through induction of IL-22 signaling in mucosal T cells and aryl hydrocarbon receptor activation. Additionally, ILA treatment of human colorectal tissue explants ex vivo inhibited HIV replication by reducing mucosal inflammatory cytokine production and cell activation. Our findings underscore the therapeutic potential of microbial metabolic reprogramming of TRP-to-ILA and mechanisms in mitigating viral pathogenic effects and bolstering mucosal defenses for HIV eradication.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder in women of childbearing age. Numerous studies have indicated a significantly elevated incidence of depression and anxiety in women affected by PCOS, often attributed to dysbiosis of gut microbiota resulting from poor sleep quality. However, the intricate relationship between sleep disorders, gut microbiota, and depression/anxiety in PCOS remains unclear. In this study, we aimed to elucidate the effects of sleep deprivation on the anxiety and depression of PCOS mice through an investigation of the gut-brain axis in order to understand the potential microbial-host interactions contributing to the occurrence of these psychological disorders. We found that sleep deprivation induced symptoms of depression and anxiety in PCOS mice and exacerbated PCOS-like pathology. Moreover, sleep deprivation altered the gut microbiota composition by suppressing beneficial bacteria such as Lactobacillus and Ruminococcus species. Additionally, sleep deprivation upregulated intestinal tryptophan-kynurenine metabolism, increased intestinal wall permeability, promoted systemic inflammation, and compromised blood-brain barrier integrity. Furthermore, the hippocampal metabolomic analysis indicated that sleep deprivation affected the metabolism of fatty acid and oxylipins, upregulated the tryptophan-kynurenine metabolic pathway, and exhibited a significant correlation with anxiety and depressive behaviors. Overall, this study suggests that sleep deprivation plays a pivotal role in the pathological mechanism of depression and anxiety in PCOS mice by modulating tryptophan and lipid metabolism through the gut-brain axis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems, with its pathogenesis intricately tied to genetic, environmental, and immune regulatory factors. In recent years, the aberration of tryptophan metabolism has emerged as a key player in the disease, particularly through the activation of the kynurenine pathway and its influence on immune regulation. This review delves into the critical pathways of tryptophan metabolism and its profound impact on the multi-system manifestations of SLE, including its connections to the nervous system, kidneys, skin, and other organs. Additionally, it examines how tryptophan metabolism modulates the function of various immune cell types. The review also explores potential therapeutic avenues targeting tryptophan metabolism, such as dietary interventions, probiotic modulation, IDO expression inhibition, and immunoadsorption techniques. While current research has underscored the pivotal role of tryptophan metabolism in the onset and progression of SLE, its full therapeutic potential remains to be fully elucidated. This review aims to provide a solid scientific foundation for therapeutic strategies based on modulating tryptophan metabolism in SLE, offering a comprehensive overview of both clinical and basic research in this rapidly evolving field.

Sepsis, a critical organ dysfunction resulting from an aberrant host response to infection, remains a leading cause of mortality in ICU patients. Recent evidence suggests that angiotensin-converting enzyme 2 (ACE2) contributes to intestinal barrier function, the mechanism of which is yet to be explored. Additionally, alterations in intestinal microbiota and microbial metabolites could affect gut homeostasis, thus playing a potential role in modulating sepsis progression.

ACE2 shedding weakens the integrity of the intestinal barrier in sepsis. Mice deficient in ACE2 exhibited increased intestinal permeability and higher mortality rates post-operation compared to their wild-type counterparts. Notably, ACE2 deficiency was associated with distinct alterations in gut microbiota composition and reductions in protective metabolites, such as 5-methoxytryptophan (5-MTP). Supplementing septic mice with 5-MTP ameliorated gut leak through enhanced epithelial cell proliferation and repair. The PI3K-AKT-WEE1 signaling pathway was identified as a key mediator of the beneficial effects of 5-MTP administration.

ACE2 plays a protective role in maintaining intestinal barrier function during sepsis, potentially through modulation of the gut microbiota and the production of key metabolite 5-MTP. Our study enriched the mechanisms by which ACE2 regulates gut homeostasis and shed light on further applications. Video Abstract.

Whether the role of gut microbial features lies in the pathways from lifestyles to dyslipidemia remains unclear. In this cross-sectional study, we conducted a metagenome-wide association analysis and fecal metabolomic profiling in 994 adults from the China Multi-Ethnic cohort. A total of 26 microbial species were identified as mediators between lifestyle factors and risk for dyslipidemia. Specifically, the abundance of [Ruminococcus] gnavus mediated the associations between lifestyles and risks for dyslipidemia, elevated low-density lipoprotein cholesterol, elevated total cholesterol, and elevated triglycerides. [Ruminococcus] gnavus, Alistipes shahii, and Lachnospira eligens were replicated to be associated with dyslipidemia in an external validation cohort. The potential metabolic pathways included arachidonic acid, bile acid, and aromatic amino-acid metabolism.

Pectin, a class of dietary fiber, has received increasing attention in recent years for its ameliorative effects on metabolic diseases. However, the structural variability of pectin leads to differential effects on these diseases. The intrinsic mechanism by which pectin, derived from different sources, differentially influences metabolic syndrome by interacting with gut microbiota and host metabolism remains elusive and warrants thorough investigation. To address this, we investigated the effects of HG-type pectins from apple, citrus, and pomelo on phenotypic expressions, inflammatory factors, oxidative stress, and serum hormone levels in mice with metabolic syndrome. In addition, we sought to identify pivotal bacterial species and metabolites by integrating genomics and metabolomics approaches. Our exploration also extended to the relationship between structural characteristics of pectins, gut microbiota, and metabolic syndrome. Our findings revealed that the three pectins diversely improved metabolic syndrome in mice, which correlated with gut microbiota and their beneficial metabolites. Notably, all three pectins were closely associated with Bacteroides and Bacteroides acidifaciens. Besides, the potential mediators of the therapeutic effects included Bacteroides, Lactococcus, and Lachnoclostriclum for apple pectin; Colidextribacter, Bacteroides, Lachnospiraceae_NK4A136_group, and Lachnoclostriclum for citrus pectin; and Lachnospiraceae_NK4A136_group, Bacteroides, and Mucispirillum for pomelo pectin. Metabolites such as arachidonic acid, kynurenic acid, lithocholic acid, deoxycholic acid, and indoleacetic acid, linked to these microbes, may serve as the mediators of pectin's benefits. Ultimately, the molecular weight, degree of esterification, and monosaccharide composition of pectins significantly influenced the outcomes. This study may contribute to a more nuanced understanding that can inform targeted nutritional strategies to modulate gut microbiota for metabolic syndrome management.

Graves' orbitopathy (GO) is a sight-threatening organ-specific autoimmune disease with complicated pathogenesis. Gut microbiota-derived tryptophan (Trp) metabolites play important roles in immune-related diseases, but their role in GO remains unknown.

Trp metabolism-associated gut flora was analyzed by 16 S sequencing in GO patients and controls. Serum metabolomics profiling was performed to assess Trp metabolic pathway. Trp metabolites levels were measured by ELISA in 401 serum samples from a case-control study, and their effects on inflammation and proliferation in orbital fibroblasts were evaluated in vitro.

Trp metabolism-associated gut flora, including phylum Firmicutes and genus Anaerostipes, were significantly down-regulated in GO patients. Serum metabolomics revealed significant enrichment of Trp metabolic pathway in both GO and Graves' disease (GD) groups. Serum levels of indolepropionic acid (IPA), indole-3-lactate (ILA), and indoleacetic acid (IAA) were significantly decreased in both GD and GO patients compared to controls, with IAA levels further reduced in GO compared to GD patients. Notably, active GO patients had significantly lower IAA levels compared to inactive ones. Moreover, the levels of IAA were negatively correlated with clinical activity score and serum thyrotropin receptor antibody (TRAb) in GO patients. In vitro, IPA, ILA, and IAA mitigated TNFα-induced inflammation and proliferation in orbital fibroblasts by suppressing the Akt signaling pathway.

Trp metabolites IAA maybe a novel biomarker for GO progression. And IPA, ILA and IAA may play a protective role in GO by regulating inflammation and proliferation in orbital fibroblasts, suggesting their potential as therapeutic targets for GO treatment.

Preeclampsia (PE) is a life-threatening condition that is unique to human pregnancy, and it is a leading cause of maternal and neonatal morbidity and mortality. Currently, the only definitive treatment for PE is delivery of the placenta. Several studies have suggested that the gut microbiota and its derived metabolites may be associated with PE. Our previous work indicated that the level of indole-3-lactic acid (ILA), which is a metabolite derived from tryptophan (Trp) metabolism in the gut, is increased in PE patients. However, the effects of ILA on trophoblast function and its underlying mechanisms remain largely unknown.

Transwell assays were conducted to assess the effects of ILA on trophoblast migration and invasion. Moreover, the aryl hydrocarbon receptor (AhR) signaling pathway was examined by qRT-PCR, western blotting and siRNA transfection. Additionally, RNA-seq analysis was performed to explore the mechanism underlying the ILA-mediated effects on trophoblast function. Finally, in vivo trophoblast invasion was evaluated through immunohistochemical analysis.

Our data demonstrated that ILA promoted HTR-8/SVneo cell migration and invasion through AhR signaling pathway activation. Mechanistically, VCAN upregulation played a key role in mediating the effects of ILA on trophoblasts after AhR activation. Notably, ILA supplementation improved spiral artery remodeling and increased trophoblast invasion in PE-like mice, primarily by increasing VCAN levels.

These data strongly suggest that elevated ILA in PE serve as a protective mechanism against trophoblast dysfunction. Therefore, we propose that ILA may be a novel and promising therapeutic approach for treating PE by enhancing trophoblast functions.

Chronic pain is a global health issue that affects as many as 20% of the population. Inflammatory pain, an important form of chronic pain, negatively impacts patients' quality of life. Indolepropionic acid (IPA), a metabolite derived from the gut microbiota, has anti-inflammatory properties. However, its effect on inflammatory pain has not yet been explored. This study aims to investigate the impact of IPA on CFA-induced inflammatory pain.

A mouse model of inflammatory pain was established by injection of Complete Freund's Adjuvant (CFA) into the hind paw, and treated with the IPA supplement. Behavioral assessments were conducted using the Von Frey test, cold or hot plate tests. The expression of pain-related transcripts, such as transient receptor potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) was evaluated. Degree of inflammation was assessed by the thickness of paws, degree of inflammatory infiltration and the changes of serum tumor necrosis factor (TNF)-α, interleukin(IL)-6 and IL-1β.

IPA supplement improved the CFA-induced decrease of the mechanical withdrawal threshold and cold and thermal withdrawal latency. Meanwhile, IPA inhibited the CFA-induced upregulation of TRPV1 and CGRP in DRGs. In addition, IPA treatment also suppressed the CFA-induced local and systemic inflammation, including the swelling and thickening of the paw, local infiltration of inflammatory cells, and increased serum levels of TNF-α, IL-6, and IL-1β.

Our results show that IPA can improve pain-related behavior and alleviate inflammation in the CFA-treated mice, which provides new insight into potential strategies for inflammatory pain management.

Doxorubicin (DOX) is a key chemotherapeutic agent but is also a leading cause of DOX-induced cardiotoxicity (DIC), limiting its clinical use. Akkermansia muciniphila (A. muciniphila), known for its benefits as a probiotic in treating metabolic syndrome, has uncertain effects in the context of DIC. Here, 16S rRNA sequencing of fecal samples from anthracycline-treated patients and DIC mice revealed marked depletion of A. muciniphila. Cardiac transcriptomics, supported by in vitro experiments, showed that A. muciniphila colonization improved mitochondrial function and alleviated DIC by activating the PPARα/PGC1α signaling pathway in both normal and antibiotic-treated C57BL/6 mice. Further analysis uncovered a restructured microbiome-metabolome network following A. muciniphila administration, which contributed to DIC protection. Notably, A. muciniphila supplementation increased serum levels of the tryptophan metabolite indole-3-propionic acid (IPA), which binds to the cardiac aryl hydrocarbon receptor (AhR), leading to the activation of the PPARα/PGC1α signaling pathway. In conclusion, our study sheds light on the potential of A. muciniphila as a probiotic in mitigating DIC.

Alcohol-associated liver disease (ALD) is a major global health challenge, with inflammation playing a central role in its progression. As inflammation emerges as a critical therapeutic target, ongoing research aims to unravel its underlying mechanisms. This review explores the immunological pathways of ALD, highlighting the roles of immune cells and their inflammatory mediators in disease onset and progression. We also examine the complex interactions between inflammatory cells and non-parenchymal liver cells, as well as their crosstalk with extra-hepatic organs, including the gut, adipose tissue, and nervous system. Furthermore, we summarize current clinical research on anti-inflammatory therapies and discuss promising therapeutic targets. Given the heterogeneity of ALD-associated inflammation, we emphasize the need for precision medicine to optimize treatment strategies and improve patient outcomes.

Diet can contribute to the development of metabolic disease including type 2 diabetes (T2D) by inducing metabolic inflammation. While the gut microbiota mediates the effects of diet, the diet can also exert its effects independent of gut microbes. The microbe-dependent and -independent effects of diet on inflammation remain to be elucidated. This review examines recent advances and dissects the specifics of both gut microbe-dependent and independent mechanisms through which diet impacts inflammation and glucose metabolism. We delineate how diet interacts with the gut microbiome and induces metabolic inflammation. We also describe the direct effects of dietary components and their related metabolites on the immune system, and explore how diet-induced sterile inflammation may contribute to metabolic disorders. It is important to consider both microbe-dependent and independent pathways when developing therapeutic approaches aimed at preventing T2D.

We analyzed blood serum samples from two unique female occupational cohorts - 60 nurses and 40 office workers in San Francisco, CA - using liquid chromatography and high-resolution mass spectrometry (quadrupole time-of-flight). Applying a nontargeted analysis (NTA) approach, we sought to isolate occupationally related chemical exposures that were unique to nurses by flagging features that were different from office workers in abundance (mean; 95th percentile) or detection frequency. Of 9828 negative electrospray ionization (ESI-) and 6898 positive electrospray ionization (ESI+) detected chemical features, 1094 and 938, respectively, were higher in nurses, possibly due to workplace exposures. We deciphered the molecular structures of these chemical features by applying data-dependent acquisition (DDA) and targeted MS/MS approaches to pooled samples from each occupational group, and we annotated them using spectral MS/MS databases in MS-DIAL. Nurses had higher concentrations of 14 chemicals that we identified at Schymanski Level 1 (N = 6) or 2 (N = 8), as well as 20 tentatively identified chemicals without spectra. Several chemicals may be occupationally relevant for nurses, including a PFAS (6:2 fluorotelomer sulfonic acid), tridecanedioic acid, salicylic acid, and the medications acetaminophen and theophylline. To our knowledge, this study is the first to apply NTA to elucidate novel chemical exposures in nurses.

Disruption of aryl hydrocarbon receptor (AhR) signaling and aberrant tryptophan metabolism have been shown to be highly associated with aging and age-related disorders. However, the underlying molecular mechanisms by which the AhR-mediated signaling pathway contributes to the aging process remain largely unknown. In this study, we find that aged Drosophila exhibits markedly reduced tryptophan metabolism leading to impaired AhR ligands, especially indole acetic acid (IAA), compared with their young controls. Supplementation with IAA, produced from Lactobacillus spp., dose-dependently extends the lifespan of Drosophila and improves healthy aging with resistance to starvation and oxidative stress. Mechanistically, activation of AhR by IAA markedly enhances Sirt2 activity by binding to its promoter, thereby inhibiting downstream TOR signaling and related fatty acid and amino acid metabolism. Both Ahr and Sirt2 mutant flies with IAA supplementation display a negligible lifespan extension, suggesting that AhR-mediated Sirt2 signaling contributes to lifespan extension in flies upon IAA supplementation. From the perspective of host metabolism, IAA supplementation significantly increases unsaturated fatty acids (UFAs) in aged flies, which are regarded to be beneficial for healthy status. These findings provide new insights into the physiological functions of AhR involved in the aging process by mediating Sirt2 signaling.

Disruption of aryl hydrocarbon receptor (AhR) signaling and aberrant tryptophan metabolism contribute to aging and age-related disorders, but the underlying molecular mechanisms are largely unknown. Using multiomics analyses combined with biochemical assays, this study reveals that AhR activation by indole acetic acid (IAA) effectively extends the lifespan accompanied by improved healthy aging in Drosophila via the AhR-Sirt2 pathway.

This study evaluates the efficacy of the postbiotic Probio-Eco in alleviating constipation in humans and mice. A randomized, double-blind, placebo-controlled crossover trial involving 110 adults with chronic constipation (Rome IV criteria) demonstrates that a 3-week Probio-Eco intervention significantly improves constipation symptoms, stool straining, and worry scores. Gut microbiota and metabolomic analyses reveal modulations in specific gut microbiota, succinate, tryptophan derivatives, deoxycholate, propionate, butyrate, and cortisol, correlating with symptom relief. A loperamide-induced mouse model confirms that Probio-Eco and its bioactive components (succinate, 3-indoleacrylic acid, and 5-hydroxytryptophan) alleviate constipation by stimulating mucin-2 secretion, regulating intestinal transport hormones, and promoting anti-inflammatory responses. Multi-omics integration identifies key pathways, including succinate-short-chain fatty acid, tryptophan-5-hydroxytryptophan-serotonin, and tryptophan-3-indoleacrylic acid, driving intestinal homeostasis and motility. These findings highlight the comprehensive efficacy of Probio-Eco and provide robust evidence for its clinical application in constipation management. This study was registered at Chinese Clinical Trial Registry (ChiCTR2100054376).

A wide variety of human diseases are associated with loss of microbial diversity in the human gut, inspiring a great interest in the diagnostic or therapeutic potential of the microbiota. However, the ecological forces that drive diversity reduction in disease states remain unclear, rendering it difficult to ascertain the role of the microbiota in disease emergence or severity. One hypothesis to explain this phenomenon is that microbial diversity is diminished as disease states select for microbial populations that are more fit to survive environmental stress caused by inflammation or other host factors. Here, we tested this hypothesis on a large scale, by developing a software framework to quantify the enrichment of microbial metabolisms in complex metagenomes as a function of microbial diversity. We applied this framework to over 400 gut metagenomes from individuals who are healthy or diagnosed with inflammatory bowel disease (IBD). We found that high metabolic independence (HMI) is a distinguishing characteristic of microbial communities associated with individuals diagnosed with IBD. A classifier we trained using the normalized copy numbers of 33 HMI-associated metabolic modules not only distinguished states of health vs IBD, but also tracked the recovery of the gut microbiome following antibiotic treatment, suggesting that HMI is a hallmark of microbial communities in stressed gut environments.