The gut microbiome plays a key role in human health, influencing various biological processes and disease outcomes. The historical roots of probiotics are traced back to Nobel Laureate Élie Metchnikoff, who linked the longevity of Bulgarian villagers to their consumption of sour milk fermented by Lactobacilli. His pioneering work led to the global recognition of probiotics as beneficial supplements, now a multibillion-dollar industry. Modern probiotics have been extensively studied for their immunomodulatory effects. Limosilactobacillus reuteri (L. reuteri), a widely used probiotic, has garnered significant attention for its systemic immune-regulatory properties, particularly in relation to autoimmunity and cancer. This review delves into the role of L. reuteri in modulating immune responses, with a focus on its impact on systemic diseases.

Pancreatic cancer remains one of the most challenging malignancies to treat due to its late-stage diagnosis, aggressive progression, and high resistance to existing therapies. Rosuvastatin (ROV), known for its hypolipidemic effects, which significantly inhibited clonogenic capacity and epithelial-mesenchymal transition (EMT) in prostate cancer cells. However, the anti-cancer mechanisms of ROV in PC have not yet been fully explored.

This study aimed to investigate the potential anti-cancer effects of ROV on PC cells and to elucidate the underlying mechanisms.

Cytotoxicity was detected via MTT assay, while epithelial-mesenchymal transition (EMT) markers, Ca2+ levels, and endoplasmic reticulum (ER) stress were observed with fluorescence microscopy. RNA-seq analysis was used to identify significantly changed mRNA expression following ROV treatment. Additionally, western blotting and immunohistochemistry (IHC) were conducted to examine proteins involving in the cell cycle, EMT, Ca2+ signaling, and endoplasmic reticulum stress (ERS) in vitro and in vivo.

ROV inhibited PC cell proliferation by arresting the cell cycle at the G1/S phase and partially reducing cell mobility during the EMT process. A total of 1336 significantly different RNAs (P < 0.05 and |logFC|>1) were identified and analyzed through RNA-seq, revealing the Ca2+ and ER pathways in PC cells treated with ROV. ROV treatment significantly altered the level of intracellular Ca2+, triggering the ERS pathway and modulating the Ca2+/CaM/CaMKII/ERK pathway. Furthermore, ROV inhibited key proteins within the Ca2+ and ERS pathways, leading to reduced cell proliferation, mobility and G1/S phase arrest. In tumor tissues, the expression of Ki67, EMT markers, Calmodulin, and ATF6 corroborated the in vitro findings.

ROV inhibited proliferation and metastasis in PC cells by inhibiting the EMT process through the Ca2+/CaM/CaMKII/ERK and Ca2+-mediated ERS pathways, highlighting its potential as a prophylactic and therapeutic agent for PC.

Humans are home to a diverse community of bacteria, many of which form symbiotic relationships with their host. Notably, tumors can also harbor their own unique bacterial populations that can influence tumor growth and progression. These bacteria, which selectively colonize hypoxic and acidic tumor microenvironments, present a novel therapeutic strategy to combat cancer. Advancements in synthetic biology enable us to safely and efficiently program therapeutic drug production in bacteria, further enhancing their potential. This review provides a comprehensive guide to utilizing bacteria for cancer treatment. We discuss key considerations for selecting bacterial strains, emphasizing their colonization efficiency, the delicate balance between safety and anti-tumor efficacy, and the availability of tools for genetic engineering. We also delve into strategies for precise spatiotemporal control of drug delivery to minimize adverse effects and maximize therapeutic impact, exploring recent examples of engineered bacteria designed to combat tumors. Finally, we address the underlying challenges and future prospects of bacterial cancer therapy. This review underscores the versatility of bacterial therapies and outlines strategies to fully harness their potential in the fight against cancer.

As the heart and kidneys are closely connected by the circulatory system, primary dysfunction of either organ usually leads to secondary dysfunction or damage to the other organ. These interactions play a major role in the pathogenesis of a clinical entity named cardiorenal syndrome (CRS). The pathophysiology of CRS is complicated and involves multiple body systems. In early studies, CRS was classified into five subtypes according to the organs associated with the vicious cycle and the acuteness and chronicity of CRS. Increasing evidence shows that CRS is associated with a variety of pathological mechanisms, such as haemodynamics, neurohormonal changes, hypervolemia, hypertension, hyperuraemia and hyperuricaemia. In this review, we summarize the classification and currently available diagnostic biomarkers of CRS. We highlight the recently revealed molecular pathogenesis of CRS, such as oxidative stress and inflammation, hyperactive renin‒angiotensin‒aldosterone system, maladaptive Wnt/β-catenin signalling pathway and profibrotic TGF‒β1/Smad signalling pathway, as well as other pathogeneses, such as dysbiosis of the gut microbiota and dysregulation of noncoding RNAs. Targeting these CRS-associated signalling pathways has new therapeutic potential for treating CRS. In addition, various chemical drugs, natural products, complementary therapies, blockers, and agonists that protect against CRS are summarized. Since the molecular mechanisms of CRS remain to be elucidated, no single intervention has been shown to be effective in treating CRS. Pharmacologic therapies designed to block CRS are urgently needed. This review presents a critical therapeutic avenue for targeting CRS and concurrently illuminates challenges and opportunities for discovering novel treatment strategies for CRS.

Polymorphic microbiomes play important roles in colorectal cancer (CRC) occurrence and development. In particular, Fusobacterium nucleatum (F. nucleatum) is prevalent in patients with CRC, and eliminating it is beneficial for treatment. Here, multiple metagenomic sequencing cohorts are combined with multiomics to analyze the microbiome and related functional alterations. Furthermore, local human metagenome and metabolomics are used to discover commensal consortia. A synthetic microbial community (SynCom) is then designed by metabolic network reconstruction, and its performance is validated using coculture experiments and an AOM-DSS induced mouse CRC model. The sequencing result shows that F. nucleatum is more abundant in both the feces and tumor tissues of CRC patients. It causes alterations through various pathways, including microbial dysbiosis, lipid metabolism, amino acid metabolism, and bile acid metabolism disorders. The designed SynCom contains seven species with low competition interrelationship. Furthermore, the SynCom successfully inhibits F. nucleatum growth in vitro and achieves colonization in vivo. Additionally, it promotes F. nucleatum decolonization, and enhances tryptophan metabolism and secondary bile acid conversion, leading to reduced lipid accumulation, decreased inflammatory reaction, and enhanced tumor inhibition effect. Overall, the bottom-up designed SynCom is a controllable and promising approach for treating F. nucleatum-positive CRC.

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.

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.

This study investigates the potential of Bifidobacterium bifidum 1007478 (BB478) and its metabolite indole-3-lactic acid (ILA) in alleviating non-alcoholic steatohepatitis (NASH) induced by a high-fat diet (HFD) and fructose exposure.

A zebrafish model of NASH was established by exposure to HFD and fructose. BB478 was administered, and the effects on liver lipid accumulation, oxidative stress, and inflammation were assessed. ILA production by BB478 was confirmed, and its impact on hepatic lipogenesis and inflammatory pathways was evaluated. The involvement of the aromatic hydrocarbon receptor (AhR) was also examined using an AhR inhibitor.

BB478 supplementation inhibited lipid accumulation in the liver, reduced triglycerides (TG) and total cholesterol (TC), and mitigated oxidative stress, as evidenced by lower levels of reactive oxygen species (ROS) and malondialdehyde (MDA). ILA, produced by BB478, could alleviate the hepatic damage and fat deposition in liver. Mechanistically, it suppressed hepatic lipogenesis by downregulating lipogenesis-related genes, including sterol response element binding protein 1 (SREBP1) and fatty acid synthase (FASN). ILA also inhibited the expression of pro-inflammatory cytokines to suppress inflammation. The therapeutic effects of ILA were reversed by the AhR inhibitor, indicating that ILA's actions are AhR-dependent.

These findings reveal the potential of ILA, produced by Bifidobacterium bifidum, as a therapeutic agent for NASH. The mechanistic insights into AhR-mediated effects provide a foundation for further exploration of ILA as a novel approach for managing liver diseases.

Cholesterol, as a major component of cell membranes, is closely related to the metabolic regulation of cells and organisms; tumor-associated macrophages play an important push role in tumor progression. We know that tumor-associated macrophages are polarized from macrophages, and the abnormalities of cholesterol metabolism that may be induced during their polarization are worth discussing. This manuscript focuses on metabolic abnormalities in tumor-associated macrophages, and first provides a basic summary of the regulatory mechanisms of abnormal macrophage polarization. Subsequently, it comprehensively describes the features of abnormal glucose, lipid and cholesterol metabolism in TAMs as well as the different regulatory pathways. Then, the paper also discusses the link between abnormal cholesterol metabolism in TAMs and tumors, chronic diseases and aging. Finally, the paper summarizes cancer therapeutic strategies targeting cholesterol metabolism that are already in clinical trials, as well as nanomaterials capable of targeting cholesterol metabolism that are in the research stage, in the hope of providing value for the design of targeting materials. Overall, elucidating metabolic abnormalities in tumor-associated macrophages, particularly cholesterol metabolism, could provide assistance in tumor therapy and the design of targeted drugs.

Radiotherapy-induced DNA damage can lead to apoptotic cell death and trigger an anti-tumor immune response via the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which senses cytoplasmic double-stranded DNA. However, radiotherapy resistance poses a significant challenge in treating cancers, including colorectal cancer (CRC). Understanding the mechanisms underlying this resistance is crucial for developing effective therapies. Here we report that radiotherapy enhances cholesterol synthesis, which subsequently inhibits the cGAS-STING pathway, leading to radiotherapy resistance. Mechanistically, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) levels increase rapidly in response to radiation, resulting in increased cholesterol synthesis. This increased cholesterol sequesters STING in the endoplasmic reticulum, hindering its activation and downstream interferon signaling. Elevated HMGCR and cholesterol levels correlate with poor prognosis and reduced response to radiation therapy in patients with CRC. Importantly, pharmacological inactivation of HMGCR significantly enhanced radiotherapy responsiveness in animal models, dependent on cGAS-STING signaling-mediated anti-tumor responses. Our findings reveal that radiotherapy-induced cholesterol inhibits cGAS-STING signaling, facilitating tumor immune escape. Therefore, combining statins with radiotherapy represents a promising therapeutic strategy for treating CRC.

Long-term exposure to nanoplastics causes chronic toxicity in mammals, particularly in the gut and lung tissues. The gut-lung-microbiota axis plays a pivotal role in organisms through the management of gut bacteria amino acid metabolic homeostasis. However, chronic toxicity of nanoplastics from gut to lungs have yet to be fully elucidated. In this study, nanoplastics exposure not only causes colon inflammation but also results in lung fibrosis. The abundance of Akkermansia muciniphila (AKK) is decreased after nanoplastics exposure. Interestingly, a positive correlation is observed between AKK and indole-3-lactic (ILA). Supplementation with AKK or ILA ameliorated nanoplastics-induced gut-derived lung injury by restoring the balance of tryptophan metabolism. Furthermore, knocking down indoleamine 2,3-dioxygenase 1 (ido1) upregulated ILA levels, contributing to defense against damage from nanoplastics. These results suggest that regulating ido1 expression and AKK abundance, involved in tryptophan metabolic homeostasis (especially ILA production), maybe a strategy to reduce the biological toxicity induced by nanoplastics. Mogroside V, a natural product, is found to promote AKK growth and inhibit ido1, thereby ameliorating chronic toxicity induced by nanoplastics. The study offers a new understanding of how nanoplastics cause chronic toxicity by dysregulating gut-lung-microbiota axis, as well as strategies for preventing and treating nanoplastics.

Digestive diseases have a high incidence worldwide, with various geographic, age, and gender factors influencing the occurrence and development of the diseases. The main etiologic factors involve genetics, environment, lifestyle, and dietary habits. In a low-oxygen environment, however, the body's tissue cells activate hypoxia-inducible factor (HIF), which produces different inflammatory mediators. Hypoxia impacts health at the molecular level by modulating cellular stress responses, metabolic pathways, and immune functions. It also alters gene expression and cellular behavior, thereby affecting gastrointestinal function. Under normal physiological conditions, the gastrointestinal mucus system serves as a crucial protective barrier, defending against mechanical injury, pathogenic invasion, and exposure to harmful chemicals. The integrity and functionality of this barrier are dependent on the synthesis and regulation of mucins and mucus, which are influenced by multiple factors. Additionally, the composition and diversity of the gastric microbiota are shaped by factors such as Helicobacter pylori infection, diet, and lifestyle. A balanced gastric microbiota supports gastrointestinal health and fortifies the mucus barrier. However, hypoxia can disrupt this equilibrium, leading to inflammation, alterations in the mucus layer, and destabilization of the gastric microbiota. Understanding the interplay between hypoxia, the mucus system, and the gastric microbiota is essential for identifying novel therapeutic strategies. Future research should elucidate the mechanisms through which hypoxia influences these systems and develop interventions to mitigate its adverse effects on gastrointestinal health. We examined the impact of hypoxia on the gastrointestinal mucus system and gastric microbiota, highlighting its implications for human health and potential therapeutic approaches.

Supplementation with short-chain fatty acids (SCFAs) is a potential therapeutic approach for inflammatory bowel disease (IBD). However, the therapeutic effects and mechanisms of action of isobutyrate in IBD remain unclear. Clinical data indicate that the fecal levels of isobutyrate are markedly lower in patients with Crohn's disease than in healthy controls. Compared with healthy mice and healthy pigs, mice and pigs with colitis presented significantly lower isobutyrate levels. Furthermore, the level of isobutyrate in pigs was significantly negatively correlated with the disease activity index. We speculate that isobutyrate may play a crucial role in regulating host gut homeostasis. We established a model of dextran sulfate sodium-induced colitis in pigs, which have gastrointestinal structure and function similar to those of humans; we performed multiomic analysis to investigate the therapeutic effects and potential mechanisms of isobutyrate on IBD at both the animal and cellular levels and validated the results. Phenotypically, isobutyrate can significantly alleviate diarrhea, bloody stools, weight loss, and colon shortening caused by colitis in pigs. Mechanistically, isobutyrate can increase the relative abundance of Lactobacillus reuteri, thereby increasing the production of indole-3-lactic acid, regulating aryl hydrocarbon receptor expression and downstream signaling pathways, and regulating Foxp3+ CD4+ T cell recruitment to alleviate colitis. Isobutyrate can directly activate G protein-coupled receptor 109A, promote the expression of Claudin-1, and improve intestinal barrier function. In addition, isobutyrate can increase the production of intestinal SCFAs and 3-hydroxybutyric acid and inhibit the TLR4/MyD88/NF-κB signaling pathway to suppress intestinal inflammation. In conclusion, our findings demonstrate that isobutyrate confers resistance to IBD through host-microbiota interactions, providing a theoretical basis for the use of isobutyrate in alleviating colitis.

Cancer has long been associated with genetic and environmental factors, but recent studies reveal the important role of gut microbiota in its initiation and progression. Around 13% of cancers are linked to infectious agents, highlighting the need to identify the specific microorganisms involved. Gut microbiota can either promote or inhibit cancer growth by influencing oncogenic signaling pathways and altering immune responses. Dysbiosis can lead to cancer, while certain probiotics and their metabolites may help reestablish micro-ecological balance and improve anti-tumor immune responses. Research into targeted approaches that enhance therapy with probiotics is promising. However, the effects of probiotics in humans are complex and not yet fully understood. Additionally, methods to counteract harmful bacteria are still in development. Early clinical trials also indicate that modifying gut microbiota may help manage side effects of cancer treatments. Ongoing research is crucial to understand better how gut microbiota can be used to improve cancer prevention and treatment outcomes.

Tryptophan (Trp) is an essential amino acid obtained from human diet. It is involved not only in de novo biosynthesis of proteins but also in complex metabolic pathways. Redox transformation of tryptophan is under-explored in comparison with kynurenine, serotonin and indole pyruvate pathways. We described herein a mass spectrometric approach that can not only detect electron transfer-associated changes in masses and charges, but also identify electron-directed bond cleavages and radical-radical cross-coupling reactions in redox transformation of tryptophan. Photoactive TiO2 that is widely applied in cosmetic products is used as electron donor and receptor because of the capability to generate photoelectrons and holes. It was demonstrated tryptophan undergoes redox transformation through the removal of an electron from amino nitrogen atom by hole oxidization along with an electron capture in the indole ring. The back and forth electron-shuttle converts electric energy into chemical energy that enforces bond cleavages. Sodium-coupled electron transfer (SCET) was found in complementary with proton-coupled electron transfer in tryptophan. The movement of sodium ions avoids electric charge buildup caused by electron transfer. Various redox products were detected on both light irradiated TiO2 and skins, among which β-carboline shows extensive radical scavenging ability for diverse cross-coupling with indole derivatives. Light-independent redox products have been detected in vivo such as in mouse brain, indicating the presence of in vivo electron transfer-directed redox transformation. It has also been revealed that tryptophan can be arylated on Cα and Cβ atoms in response to the exposure of halogenated aromatics.

Gastrointestinal tract of humans provides a niche to thousands of microbes, referred as gut microbiota (GM). GM establishes an intricate relationship with other organs via gut-organ axis, and modulates host health. The structure and functioning of these gut microbes can be influenced by the type of external exposome an individual experiences. Depending upon GM perturbations and host genotype, this can result in variable health implications. On the other hand, the huge arsenal of enzymes possessed by GM can chemically alter the xenobiotic structure. Its consequences can be numerous, including formation of harmful metabolites that cause organ damage, reversal of host detoxification pathways, or favourable health effects. Additionally, GM-mediated bio-transformation of pharmaceuticals can alter their pharmacokinetics and pharmacodynamics, potentially yielding variable drug responses, resulting into prolonged or ineffective treatments. To address this bi-facial relationship and the pivotal role of GM, this review incorporates recent in vitro, in vivo, and multiomics studies. It also suggests the need of machine learning approaches to decode the complex host-microbiota-xenobiotics interactions. These knowledge will aid in comprehending recent rise in chronic lifestyle-diseases which poses a huge burden on the health sector, and can also be a learning curve in making formulations and therapies for personalized treatment.

Tryptophan (Trp) is an essential amino acid and key intermediate in a range of biological processes. Early studies identified altered Trp utilization in cancer cells favoring cancer survival and growth. Seminal findings linking Trp metabolism and suppression of immunity led to an explosion of interest ultimately culminating in clinical trials targeting these pathways in melanoma. The failure of these trials led to a clinical retreat in this approach; however, recent insights into the complex interplay of the various Trp circuits and between tumor cells, immune cells, and the microbiota have shown that reconsideration of Trp metabolism is needed. Here, we discuss recent developments in our understanding of Trp metabolism and apparent contradictions in the field. We also discuss adaptations that occur when Trp pathways are manipulated, which may impact therapy responses.

Statins, commonly used to lower cholesterol, are associated with improved prognosis in colorectal cancer (CRC), though their effectiveness varies. This study investigates the anti-cancer effects of atorvastatin in CRC using patient-derived organoids (PDOs) and PDO-derived xenograft (PDOX) models. Our findings reveal that atorvastatin induces mitochondrial dysfunction, leading to apoptosis in cancer cells. In response, cancer cells induce mitophagy to clear damaged mitochondria, enhancing survival and reducing statin efficacy. Analysis of a clinical cohort confirms mitophagy's role in diminishing statin effectiveness. Importantly, inhibiting mitophagy significantly enhances the anti-cancer effects of atorvastatin in CRC PDOs, xenograft models, and azoxymethane (AOM)-dextran sulfate sodium (DSS) mouse models. These findings identify mitophagy as a critical pro-survival mechanism in CRC during statin treatment, providing insights into the variable responses observed in epidemiological studies. Targeting this vulnerability through combination therapy can elicit potent therapeutic responses.

Chronic pancreatitis (CP) is characterized by irreversible fibrotic destruction and impaired pancreatic function. CP disrupts lipid metabolism and causes the imbalance of gut microbiota which in turn exacerbates pancreatic fibrosis. Statins alter gut microbiota and exert anti-inflammatory effects, but its role in CP has not been fully elucidated. Here, we found that statins-associated higher abundance of Lactobacillus intestinalis (L.intestinalis) maintained gut homeostasis that restrained bacteria translocation from gut to the pancreas, which eventually aggravated pancreatic fibrosis through inhibiting CD8+T cells-dependent immunity. Fecal microbiota transplantation (FMT) or L.intestinalis administration inhibited the infiltration of CD8+T cells and macrophages that delayed CP progression. L.intestinalis restrained the recruitment of M1 macrophages and limited the release of Ccl2/7 in the colon, which prevented epithelial damage and epithelial barrier dysfunction through blocking Ccl2/7-Ccr1 signaling. Our findings elucidate that the utilization of statin therapy or supplementation of L.intestinalis can be potential approach for the therapies of CP.

In vitro studies have demonstrated the modulation of vaginal microbiota (VM) by cervical peptides which levels varied with the status of HPV infection and cervical intraepithelial neoplasia (CIN) grades. However, there is a deficiency in population-based studies investigating the modulation of VM compositions and metabolome by cervical differentially expressed genes (DEGs) across different grades of CIN.

This study included 43 HPV-positive women, classified into low-grade (CIN1, n = 23) and high-grade (CIN2 + , n = 20) groups. Vaginal swabs were collected for both microbiota and metabolome analysis. Cervical exfoliated cells were collected for RNA-Seq analysis.

We identified 258 differentially expressed genes (DEGs), among which 176 CIN1-enriched genes were linked to immune responses, cell chemotaxis, negative regulation of cell migration, and B cell differentiation, activation, and proliferation. Eighty-two genes upregulated in CIN2 + cohorts were associated with epidermis development and keratinization. Then, we identified 5,686 paired correlations between DEGs, VM, and metabolome, with 2,320 involving Lactobacillus. Further analysis revealed Lactobacillus as the primary determinant of metabolic profiles, followed by Gardnerella, Faecalibacterium, Aerococcus and Streptococcus, such as the notable positive correlation between Lactobacillus with D-lactic acid and DL-indole-3-lactic acid. Applying mediation analysis, we found that Lactobacillus mediated the association of 14 CIN1-enriched DEGs, such as COL4A2, CCBE1 and SPON1, with the production of 57 metabolites, including D-lactic acid, oleic acid and various amino acids. Additional analysis indicated significant mediation effects of 79 metabolites on the association of DEGs with the growth of Lactobacillus, Gardnerella, Fannyhessea and Aerococcus.

Our findings provide valuable population-based evidence for the inferred modulation of correlated VM and metabolome by cervical DEGs across different CIN stages.

Thalidomide (THA) is renowned for its potent anti-inflammatory properties. This study aimed to elucidate its underlying mechanisms in the context of Crohn's disease (CD) development. Mouse colitis models were established by dextran sulfate sodium (DSS) treatment. Fecal microbiota and metabolites were analyzed by metagenomic sequencing and mass spectrometry, respectively. Antibiotic-treated mice served as models for microbiota depletion and transplantation. The expression of forkhead box P3+ (FOXP3+) regulatory T cells (Tregs) was measured by flow cytometry and immunohistochemical assay in colitis model and patient cohort. THA inhibited colitis in DSS-treated mice by altering the gut microbiota profile, with an increased abundance of probiotics Bacteroides fragilis, while pathogenic bacteria were depleted. In addition, THA increased beneficial metabolites bile acids and significantly restored gut barrier function. Transcriptomic profiling revealed that THA inhibited interleukin-17 (IL-17), IL-1β and cell cycle signaling. Fecal microbiota transplantation from THA-treated mice to microbiota-depleted mice partly recapitulated the effects of THA. Specifically, increased level of gut commensal B. fragilis was observed, correlated with elevated levels of the microbial metabolite 3alpha-hydroxy-7-oxo-5beta-cholanic acid (7-ketolithocholic acid, 7-KA) following THA treatment. This microbial metabolite may stable FOXP3 expression by targeting the receptor FMR1 autosomal homolog 1 (FXR1) to inhibit autophagy. An interaction between FOXP3 and FXR1 was identified, with binding regions localized to the FOXP3 domain (aa238-335) and the FXR1 domain (aa82-222), respectively. Conclusively, THA modulates the gut microbiota and metabolite profiles towards a more beneficial composition, enhances gut barrier function, promotes the differentiation of FOXP3+ Tregs and curbs pro-inflammatory pathways.

The human gut microbiota plays a critical role in maintaining host homeostasis through metabolic activities. Among these, amino acid (AA) metabolism by the microbiota in the large intestine is highly heterogeneous and relevant to host health. Despite increasing interest, microbial AA metabolism remains relatively unexplored. This review highlights recent advances in colonic microbial AA metabolism, including auxotrophies, AA synthesis, and dissimilatory AA metabolites, and their implications in gut health, focusing on major gastrointestinal diseases including colorectal cancer, inflammatory bowel disease, and irritable bowel syndrome.

Inflammatory bowel disease (IBD) is characterized by compromised intestinal barrier function and a lack of effective treatments. Probiotics have shown promise in managing IBD due to their ability to modulate the gut microbiota, enhance intestinal barrier function, and exert anti-inflammatory effects. However, the specific mechanisms through which probiotics exert these therapeutic effects in IBD treatment remain poorly understood. Our research revealed a significant reduction of Lactiplantibacillus plantarum (L. plantarum) in the gut microbiota of IBD patients. L. plantarum is a well-known probiotic strain in the list of edible probiotics, recognized for its beneficial effects on gut health, including its ability to strengthen the intestinal barrier and reduce inflammation. We demonstrated that supplementation with L. plantarum could alleviate IBD symptoms in mice, primarily by inhibiting apoptosis in intestinal epithelial cells through L. plantarum's bacterial extracellular vesicles (L. plant-EVs). This protective effect is dependent on the efficient uptake of L. plant-EVs by intestinal cells. Intriguingly, watermelon enhances L. plantarum colonization and L. plant-EVs release, further promoting intestinal barrier repair. Our findings contribute to the understanding of L. plant-EVs in the probiotic-based therapeutic approach for IBD, as they are promising candidates for nanoparticle-based therapeutic methods that are enhanced by natural diets such as watermelon. This study thereby offers a potential breakthrough in the management and treatment of IBD.

Infectious complications (ICs) in acute pancreatitis (AP) are primarily driven by intestinal bacterial translocation, significantly increasing mortality and hospital stays. Despite this, the role of the gut microenvironment, particularly its metabolic aspects, in AP remains poorly understood. In this study, we investigated a cohort of patients with AP, and conducted supplemental murine studies, to explore the relationship between the gut metabolome and the development of ICs. Metabolomic analysis revealed that disruptions in gut tryptophan metabolism - especially reductions in serotonin and indole pathways - are key features associated with IC occurrence. Additionally, elevated plasma levels of tryptophan metabolites within the kynurenine pathway were identified as valuable predictive biomarkers for ICs. Mechanistic studies in murine models demonstrated that an impaired intestinal Th17 response, modulated by these tryptophan metabolites, plays a critical role in IC development. Serotonin supplementation enhanced Th17 responses, reducing IC incidence, while administration of kynurenic acid, a kynurenine metabolite, exacerbated pancreatic infections, potentially through immunosuppressive effects. These findings highlight the pivotal role of tryptophan metabolites in AP pathogenesis, emphasizing their potential as both predictive markers and therapeutic targets in IC management.

Natural killer/T-cell lymphoma (NKTCL) is a highly aggressive malignancy with a dismal prognosis, and gaps remain in understanding the determinants influencing disease outcomes.

To characterise the gut microbiota feature and identify potential probiotics that could ameliorate the development of NKTCL.

This cross-sectional study employed shotgun metagenomic sequencing to profile the gut microbiota in two Chinese NKTCL cohorts, with validation conducted in an independent Korean cohort. Univariable and multivariable Cox proportional hazards analyses were applied to assess associations between identified marker species and patient outcomes. Tumour-suppressing effects were investigated using comprehensive in vivo and in vitro models. In addition, metabolomics, RNA sequencing, chromatin immunoprecipitation sequencing, Western blot analysis, immunohistochemistry and lentiviral-mediated gene knockdown system were used to elucidate the underlying mechanisms.

We first unveiled significant gut microbiota dysbiosis in NKTCL patients, prominently marked by a notable reduction in Faecalibacterium prausnitzii which correlated strongly with shorter survival among patients. Subsequently, we substantiated the antitumour properties of F. prausnitzii in NKTCL mouse models. Furthermore, F. prausnitzii culture supernatant demonstrated significant efficacy in inhibiting NKTCL cell growth. Metabolomics analysis revealed butyrate as a critical metabolite underlying these tumour-suppressing effects, validated in three human NKTCL cell lines and multiple tumour-bearing mouse models. Mechanistically, butyrate suppressed the activation of Janus kinase-signal transducer and activator of transcription pathway through enhancing histone acetylation, promoting the expression of suppressor of cytokine signalling 1.

These findings uncover a distinctive gut microbiota profile in NKTCL and provide a novel perspective on leveraging the therapeutic potential of F. prausnitzii to ameliorate this malignancy.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide; however, current treatment options are inadequate, necessitating the exploration of new therapeutic strategies. The microbiota significantly influences the tumor microenvironment, suggesting that probiotics may serve as promising candidates for cancer treatment. We previously identified a novel probiotic, Lactobacillus plantarum MM89 (L. plantarum MM89), which was found to regulate the immune microenvironment. However, its specific role in CRC remained unclear. In this study, we employed an azoxymethane/dextran sodium sulfate-induced carcinogenesis mouse model to evaluate the therapeutic effects of L. plantarum MM89 in vivo. Transcriptome analysis was conducted to elucidate the mechanisms of action of L. plantarum MM89. Ferroptosis induction in tumor cells was assessed through cell viability assays and C11-BODIPY staining. Liquid chromatography/mass spectrometry was used to identify metabolites derived from L. plantarum MM89. MitoTracker and MitoTracker CMXRos staining and ATP content measurements were performed to assess mitochondrial damage. L. plantarum MM89 significantly inhibited tumor growth in vivo and alleviated intestinal inflammation at non-tumor foci. Transcriptome analysis and immunohistochemistry revealed that L. plantarum MM89 enhanced arachidonic acid metabolism. Small molecules present in the L. plantarum MM89 supernatant induced ferroptosis in cancer cells, as indicated by cell viability and C11-BODIPY assays. Furthermore, γ-linolenic acid (γ-LA) derived from L. plantarum MM89 was shown to induce ferroptosis via mitochondrial damage. In conclusion, γ-LA derived from L. plantarum MM89 triggers ferroptosis in tumor cells by inducing mitochondrial damage, highlighting its potential as a novel therapeutic agent for CRC treatment.

Numerous associations have been identified between cancer and the composition and function of the human microbiome. As cancer remains the second leading global cause of mortality, investigating the carcinogenic contributions of microbiome members could advance our understanding of cancer risk and support potential therapeutic interventions. Although fluctuations in bacterial species have been associated with cancer progression, studying their small molecule metabolites offers one avenue to establish support for causal relationships and the molecular mechanisms governing host-microorganism interactions. In this Review, we explore the expanding repertoire of small molecule metabolites and their mechanisms implicated in the risk of developing gastrointestinal cancers.

Emerging evidence indicates a correlation between inflammation and the development and progression of cancer. Among the various inflammatory signals, interleukin-17 (IL-17) family cytokines serve as a critical link between inflammation and cancer. IL-17 is a highly versatile pro-inflammatory cytokine that plays a pivotal role in host defense, tissue repair, the pathogenesis of inflammatory diseases, and cancer progression. During the early stages of tumorigenesis, IL-17 signaling directly promotes the proliferation of tumor cells. Conversely, IL-17 has been shown to exhibit antitumor immunity in several models of grafted subcutaneous tumors. Additionally, dynamic changes in the microbiome can influence the secretion of IL-17, thereby affecting tumor development. The specific role of IL-17 is contingent upon its functional classification, spatiotemporal characteristics, and the stage of tumor development. In this review, we introduce the fundamental biology of IL-17 and the expression profile of its receptors in cancer, while also reviewing and discussing recent advancements regarding the pleiotropic effects and mechanisms of IL-17 in inflammation-related cancers. Furthermore, we supplement our discussion with insights into the mechanisms by which IL-17 impacts cancer progression through interactions with the microbiota, and we explore the implications of IL-17 in cancer therapy. This comprehensive analysis aims to enhance our understanding of IL-17 and its potential role in cancer treatment.

Cardiovascular diseases are one of the leading causes of mortality and morbidity worldwide, with the total number of cases increasing to 523 million in 2019. Despite the advent of new drugs, cardiovascular mortality has increased at an alarming rate of 53.7 % from 12.1 million deaths in 1990. Recently, the role of gut microbiome metabolites, such as Trimethylamine N-Oxide (TMAO), in the pathogenesis of cardiovascular disease (CVD) has attracted significant attention. The gut microbiome is critical in various physiological processes including metabolism, immune function, and inflammation. Elevated TMAO levels are associated with atherosclerosis, heart failure, arrhythmia, and atrial fibrillation. TMAO accelerates atherosclerosis by promoting vascular inflammation and reducing reverse cholesterol transport, which leads to lipid accumulation and vessel narrowing. Previous research has indicated that a Mediterranean diet rich in fiber and phytochemicals can reduce TMAO levels by limiting precursors and fostering beneficial gut microbiota. Prebiotics and probiotics also decrease TMAO, while drugs such as meldonium, aspirin, and antibiotics have shown promise. However, recent studies have demonstrated major potential for the use of statins in reducing TMAO levels. Statin therapy can significantly reduce TMAO levels independent of their cholesterol-lowering effects. This reduction may involve direct interactions with the gut microbiome, changes in cholesterol metabolism, and changes in bile acid composition. This review aims to comprehensively evaluate the therapeutic potential of statins in reducing TMAO levels to improve CV outcomes.

Lactic acid Bacteria (LAB) convert tryptophan to indole derivatives and induce protective IL-22 production in vivo. However, differences in metabolizing capabilities among LAB species have not been widely investigated. In the present study, we compared the capabilities of 186 LAB strains to produce four kinds of indole derivatives, including indole-3-carboxaldehyde (IAId), indole-3-lactic acid (ILA), indole-3-propanoic acid (IPA), and indole-3-acetic acid (IAA). These strains were isolated from fermented foods, dairy products, and the feces of healthy individuals, as well as from fish and shrimp from Shanxi and Jiangsu provinces. They represent 15 genera, including Bifidobacterium, Enterococcus, Lacticaseibacillus, Lactiplantibacillus, Lactobacillus, Lactococcus, Limosilactobacillus, Pediococcus, Streptococcus, Weissella, Latilactobacillus, Levilactobacillus, Ligilactobacillus, and Loigolactobacillus. The results indicate widespread IAId-producing capabilities in LAB strains, with positive rates of approximately 90% (106/117) and 100% (69/69) among strains from Shanxi and Jiangsu provinces, respectively. The concentrations of IAId ranged from 72.42 ng/mL to 423.14 ng/mL in all positive strains from Shanxi Province and from 169.39 ng/mL to 503.51 ng/mL in strains from Jiangsu Province. Intriguingly, we also observed specific ILA-producing capabilities in Lactiplantibacillus strains, with positive rates of 55.17% (16/29) and 80.95% (17/21) among strains isolated from Shanxi and Jiangsu provinces, respectively. The overall detection rates of ILA among all tested strains (including both Lactiplantibacillus and other genus strains) were 17.9% (21/117) and 26.1% (18/69). The concentrations of ILA in positive strains ranged from 12.22 ng/mL to 101.86 ng/mL and from 5.75 ng/mL to 62.96 ng/mL from Shanxi and Jiangsu provinces, respectively. IPA and IAA were not detected in any strains. Finally, these indole derivative-producing capabilities were not related to their geographical origins or isolation sources. The current study provides insights into the species- or genus-dependent capabilities for metabolizing indole derivatives. Defining the specific roles of LAB in indole derivative metabolism will uncover the exact physiological mechanisms and be helpful for functional strain screening.

The immunosuppressive tumor microenvironment (TME) is a key characteristic of human cancer. Immunotherapy has emerged as a promising treatment strategy to overcome immune escape and has gained widespread use in recent years. In particular, the blockade of PD-1/PD-L1 interaction holds significant importance in oncotherapy. Combining anti-PD-1/PD-L1 with small molecule inhibitors targeting key pathways represents an emerging trend in therapeutic development.

To validate our findings biologically, we employed qRT-PCR or Western blotting and immunofluorescence staining techniques to assess the expression levels of DIAPH1 and PD-L1 in cells. Additionally, CCK8 and clone formation assays were utilized to evaluate cell proliferation ability, while flow assays were conducted to detect apoptosis in T cells.

Knockdown of DIAPH1 restored the tumor-killing capacity of T cells, effectively suppressing tumor immune escape. We observed a highly positive correlation between the expression levels of DIAPH1 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), which can be competitively inhibited by lovastatin. Through Sybyl analysis followed by confirmation via micro scale thermophoresis, we identified lovastatin as a potential inhibitor targeting DIAPH1. Lovastatin downregulated DIAPH1 expression both in tumor cell lines and xenograft lung cancer tissues within a mouse lung cancer model. Furthermore, we found that lovastatin degraded DIAPH1 through lysosomal degradation pathway. Treatment with lovastatin was strongly associated with improved response rates and prolonged overall survival among patients with lung adenocarcinoma. Finally, overexpression of DIAPH1 reversed the inhibitory effects mediated by lovastatin on tumor development.

Lovastatin downregulates PD-L1 expression by targeting DIAPH1 and restores the tumor-killing ability of T cells to block tumor immune escape. Lovastatin may become a potential drug for cancer patients to enhance immunotherapy response in the clinic.

Limosilactobacillus reuteri, a recognized probiotic, improves intestinal health in animals, but the mechanism remains unclear. This study investigates the mechanisms by which L. reuteri ZY15, isolated from healthy pig feces, mitigates intestinal barrier damage and inflammation caused by oxidative stress in Enterotoxigenic Escherichia coli (ETEC) K88-challenged mice. The results indicated that L. reuteri ZY15 increased antioxidant capacity by reducing serum reactive oxygen species (ROS) and superoxide dismutase (SOD) levels. L. reuteri ZY15 enhanced the intestinal barrier by upregulating mucin 1, mucin 2, occludin, zonula occludens-1 (ZO-1), and claudin-1 expressions in protein and mRNA levels. It significantly alleviated intestinal inflammation by reducing the proinflammatory cytokines interleukin-1β (IL-1β), interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17 (IL-17) mRNA and protein levels. Notably, L. reuteri ZY15 suppressed intestinal inflammation by inhibiting AKT/mTOR/HIF-1α/RORγt/IL-17 pathway activation. Additionally, it significantly altered the structure of gut microorganisms by enriching Akkermansia and Clostridia_UCG.014, and thereby re-establishing colonization resistance and alleviating ETEC K88-induced intestinal barrier damage and inflammation in mice. Taken together, our findings reveal the protective mechanism of L. reuteri ZY15 in mice challenged with ETEC K88 by regulating AKT/mTOR/HIF-1α/RORγt/IL-17 signaling and microbial imbalance. Leveraging these properties, live L. reuteri ZY15 offers a promising alternative treatment for Escherichia coli-induced diarrhea in weaned piglets.

Bladder cancer (BCa) remains a significant global health challenge, with increasing interest in the role of the bladder microbiome in its pathogenesis, progression and treatment outcomes. The complex relationship between bladder cancer and the microbiome, as well as the potential impact of probiotics on treatment effectiveness, is currently under investigation. Research suggests that the microbiota may influence BCa recurrence prevention and enhance the efficacy of the Bacillus Calmette-Guérin (BCG) vaccine. Recent studies reveal differences in the bladder microbiome between individuals without bladder cancer and those with the disease. In the healthy bladder, Streptococcus and Lactobacillus are consistently identified as the most prevalent genera. However, in men, the predominant bacterial genera are Staphylococcus, Corynebacterium and Streptococcus, while in women with bladder cancer, Gardnerella and Lactobacillus are dominant. Probiotics, particularly Lactobacillus spp., can exhibit anti-tumor properties by competing with pathogenic strains involved in carcinogenesis or by producing regulatory substances. They regulate cancer signaling, induce apoptosis, inhibit mutagenic activity, downregulate oncogene expression, induce autophagy, inhibit kinases, reactivate tumor suppressors and prevent metastasis. These mechanisms have shown promising results in both preclinical and some clinical studies.

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Although the risk of developing CRC increases with age, approximately 10% of newly diagnosed cases occur in individuals under the age of 50. Significant changes in dietary habits in young adults since industrialization create a favorable microenvironment for colorectal carcinogenesis. We aim here to shed light on the complex interplay between diet and gut microbiome in the pathogenesis and prevention of early-onset CRC (EO-CRC). We provide an overview of dietary risk factors associated with EO-CRC and contrast them with the general trends for CRC. We delve into gut bacteria, fungi, and phages with potential benefits against CRC and discuss the underlying molecular mechanisms. Furthermore, based on recent findings from human studies, we offer insights into how dietary modifications could potentially enhance gut microbiome composition to mitigate CRC risk. All together, we outline the current research landscape in this area and propose directions for future investigations that could pave the way for novel preventive and therapeutic strategies.

The gut microbiota plays a crucial role in maintaining homeostasis and promoting health. A growing number of studies have indicated that gut microbiota can affect cancer development, prognosis, and treatment through their metabolites. By remodeling the tumor microenvironment and regulating tumor immunity, gut microbial metabolites significantly influence the efficacy of anticancer therapies, including chemo-, radio-, and immunotherapy. Several novel therapies that target gut microbial metabolites have shown great promise in cancer models. In this review, we summarize the current research status of gut microbial metabolites in cancer, aiming to provide new directions for future tumor therapy.

This article discusses the interplay between colorectal cancer (CRC) stem cells, tumor microenvironment (TME), and gut microbiota, emphasizing their dynamic roles in cancer progression and treatment resistance. It highlights the adaptability of CRC stem cells, the bidirectional influence of TME, and the multifaceted impact of gut microbiota on CRC. The manuscript proposes innovative therapeutic strategies focusing on these interactions, advocating for a shift towards personalized and ecosystem-targeted treatments in CRC. The conclusion underscores the importance of continued research in these areas for developing effective, personalized therapies.

Observational studies have reported changes in gut microbiota abundance caused by long-term statin medication therapy. However, the causal relation between statin medication and gut microbiota subsets based on genetic variants remains unclear.

We used genome-wide association study (GWAS) data on statin medication from the FinnGen database and gut microbiota abundance GWAS data from the IEU OpenGWAS project. A Mendelian randomization (MR) analysis was conducted to evaluate the causal effect of statin medication on gut microbiota abundance using the inverse variance weighting (IVW) method, MR-Egger regression, and weighted median approach. Meanwhile, heterogeneity and pleiotropy analyses were also undertaken in this study.

Statin medication was negatively correlated with five species of gut microbiota abundance: Parabacteroides (BetaIVW = -0.2745, 95% CI = (-0.4422, -0.1068), and P IVW = 0.0013), Ruminococcaceae UCG-009 (BetaIVW = -0.1904, 95% CI = (-0.3255, -0.0553), and P IVW = 0.0057), Coprococcus 1 (BetaIVW = -0.1212, 95% CI = (-0.2194, -0.0231), and P IVW = 0.0154), Ruminococcaceae UCG-010 (BetaIVW = -0.1149, 95% CI = (-0.2238, -0.0060), and P IVW = 0.0385), and Veillonellaceae (BetaIVW = -0.0970, 95% CI = (-0.2238, 0.0060), and P IVW = 0.0400) and positively correlated with one species of gut microbiota: Desulfovibrio (BetaIVW = 0.2452, 95% CI = (0.0299, 0.4606), and P IVW = 0.0255). In addition, no significant heterogeneity or pleiotropy was detected in the abovementioned gut microbiota.

This Mendelian randomization analysis indicates a causal relationship between statin medication and six gut microbiota species. These findings may provide new strategies for health monitoring in populations taking long-term statin medications.

The rapidly rising prevalence of metabolic diseases has turned them into an escalating global health concern. By producing or altering metabolic products, the gut microbiota plays a pivotal role in maintaining human health and influencing disease development. These metabolites originate from the host itself or the external environment. In the system of interactions between microbes and the host, tryptophan (Trp) plays a central role in metabolic processes. As the amino acid in the human body that must be obtained through dietary intake, it is crucial for various physiological functions. Trp can be metabolized in the gut into three main products: The gut microbiota regulates the transformation of 5-hydroxytryptamine (5-HT, serotonin), kynurenine (Kyn), and various indole derivatives. It has been revealed that a substantial correlation exists between alterations in Trp metabolism and the initiation and progression of metabolic disorders, including obesity, diabetes, non-alcoholic fatty liver disease, and atherosclerosis, but Trp metabolites have not been comprehensively reviewed in metabolic diseases. As such, this review summarizes and analyzes the latest research, emphasizing the importance of further studying Trp metabolism within the gut microbiota to understand and treat metabolic diseases. This carries potential significance for improving human health and may introduce new therapeutic strategies.