Liver cancer is usually diagnosed at an advanced stage and is the third most common cause of cancer-related death worldwide. In addition to the lack of effective treatment options, resistance to therapeutic drugs is a major clinical challenge. The gut microbiota has recently been recognized as one of the key factors regulating host health. The microbiota and its metabolites can directly or indirectly regulate gene expression in the liver, leading to gut-liver axis dysregulation, which is closely related to liver cancer occurrence and the treatment response. Gut microbiota disturbance may participate in tumor progression and drug resistance through metabolite production, gene transfer, immune regulation, and other mechanisms. However, systematic reviews on the role of the gut microbiota in drug resistance in liver cancer are lacking. Herein, we review the relationships between the gut microbiota and the occurrence and drug resistance of hepatocellular carcinoma, summarize the emerging mechanisms underlying gut microbiota-mediated drug resistance, and propose new personalized treatment options to overcome this resistance.

Postmenopausal osteoporosis (PMOP) was caused by significant deviations in gut microbiota and metabolites. Gushudan (GSD), a small traditional Chinese medicine formula, exerted therapeutic effects including kidney-nourishing and bone-strengthening properties. The therapeutic mechanism of GSD in alleviating kidney-yang deficiency syndrome and secondary osteoporosis was systematically investigated through metabolomics and network pharmacology. However, the mechanisms and impact on gut microbiota through which GSD mitigated PMOP remained to be elucidated. In this study, fecal metabolomics was integrated with gut microbiota analysis to comprehensively investigate modification in intestinal flora and metabolic profiles in PMOP rat models from the gut-bone axis framework. Therefore, the GC-MS-based method integrating non-targeted and targeted metabolomics was established to analyze fecal metabolites. The comprehensive analysis of gut microbial communities was performed using 16S rRNA on fecal samples. In the result, 20 potential biomarkers were successfully identified in the non-targeted metabolomics analysis. Subsequently, 12 metabolites related to amino acid metabolism, energy metabolism and bile acid biosynthesis were quantitatively. Then, ten gut microorganisms with significant changes were discovered through 16S rRNA. Furthermore, alterations in fecal metabolites demonstrated a significant correlation with dysbiosis within the gut microorganisms such as [Ruminococcus]_torques_group, Elusimicrobium, Intestinimonas and Papillibacter. GSD effectively modulated abnormal levels of metabolites such as glycine, lactic acid, succinic acid, cholesterol and deoxycholic acid. Specifically, GSD improved the abundance of [Ruminococcus]_torques_group, Elusimicrobium, Intestinimonas. In conclusion, the gut-bone axis was validated as a novel framework, and gut microbiota modulation was further identified as a promising therapeutic target for the prevention of PMOP.

The combined toxic effects of microplastics (MPs) and their carried contaminants on organisms have been widely concerned; however, the health risks and its mechanism of "gut microbiota-host metabolism (bile acids, BA)" remain unknown. Herein, Xenopus tropicalis were exposured to aged polystyrene MPs carried triclosan (aPS+TCS) and single (a)PS-MPs & TCS, respectively. The bioaccumulation of TCS in the gut of X. tropicalis was significantly increased in aPS+TCS group, which was 89 % higher than that of PS+TCS group, causing more severe oxidative stress, inflammation and intestinal barrier disruption (leaky gut). The expressions of TNF-α, IL-6 and IL-10 in aPS+TCS group were enhanced by 276 % and 19 % and decreased by 81 %, respectively, compared to that in PS+TCS group. Moreover, co-exposure to aPS+TCS increased the number of Escherichia coli, and reduced levels of DCA and LCA (secondary BAs). Multiomics analysis further revealed that the intestinal toxicity of aPS+TCS to X. tropicalis was mainly influenced by the gut flora, BA metabolism and inflammation-related pathways. Co-exposure may exacerbate inflammation by increasing the blood levels of lipopolysaccharides and inhibiting secondary BA production, which are regulated by the gut microbiota-bile acid axis. This study provides new insights in the potential mechanisms of intestinal damage from pollutant-loaded aged MPs.

Geniposide (GE) has potential efficacy in treating ulcerative colitis (UC). However, its reactivity can be affected by rapid degradation after oral administration. Furthermore, increasing oral doses may lead to hepatotoxicity. Thus, We used enema administration, characterized by smaller dose and higher localized concentration in the lesion, to improve the above situation.

We aimed to confirm that enema administration is a better modality than oral administration for GE against UC and to explore its mechanism.

We established UC mouse model, monitoring Disease Activity Index (DAI), inflammatory cytokines levels, and histopathology. Macrogenomics and bile acid (BAs) metabolomics analysed the major intestinal flora and BAs. Simultaneouslly, we conducted quantitative proteomics analysis and screened core proteins and pathway. In vitro validation was taken by qPCR, immunofluorescence and immunoblotting experiments.

GE via enema alleviate UC by inhibiting inflammatory factor production through downregulating S100A8/S100A9/NF-κB pathway. Analysis of the intestinal flora and BAs revealed that the enhanced abundance of Lachnospiraceae, which improves the ratio of primary to secondary BAs, and the reduced abundance of Provocaceae, which increases intestinal permeability and promotes inflammation, favored the restoration of the intestinal barrier. In addition, in vitro experiments confirmed that the key BA metabolites (mainly UDCA, DCA, and LCA) stimulated TGR5 signal to inhibit the assembly of the NLRP3 inflammasome and alleviated inflammation.

We firstly confirmed that GE alleviates UC via the enema route in a better manner than the oral route, through enhancing the intestinal barrier, restoring intestinal flora and BAs homeostasis, and inhibiting inflammatory injury. This study initially revealed that GE can alleviate UC through elevating UDCA, DCA, and LCA levels at the colonic site to activate TGR5 receptor for inhibiting the NLRP3 inflammasome, in addition to downregulating the S100A8/S100A9/-TLR4-NF-κB pathway related inflammatory response directly. The evidences offer a promising strategy and profround meaning for UC treatment.

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

Pouchitis is the most common complication after restorative proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis. The authors review the role of the microbiota in both the pathogenesis of pouchitis, primarily via dysbiosis, as well as the resultant treatment strategies focused on correcting dysbiosis among patients with pouchitis. These include the role of antibiotics, probiotics, and potentially metabolomics in both treatment and risk stratification.

Bidirectional communications between the gut and the brain play an important role in the regulation of food intake, pain perception, mood, and cognitive function. The involved communication pathways are modulated by signals generated by the gut microbiome. Alterations in these communications have been implicated in several chronic brain and gut disorders, including food addiction, mood disorders, neurodevelopmental and neurodegenerative disorders, and functional and inflammatory bowel disorders. The gut microbiome holds great promise for the development of novel therapies normalizing altered brain-gut interactions.

Bile acids are a family of signaling molecules synthesized in the liver and metabolized by gut bacteria. As metabolites of the intestinal microbiota, bile acids bind to various receptors, and affect the metabolism and immune function of the host, including glucose and lipid metabolism, energy homeostasis, and inflammatory response. Conversely, bile acids also shape the composition of the gut microbiota. Given their critical role in physiological regulation, disrupted bile acid signaling is closely linked to metabolic diseases. Consequently, therapeutic strategies targeting bile acids are increasingly being explored. The size, composition, and function of the bile acid pool can be modulated through direct treatments (e.g., bile acid replacement therapy, administration of bile acid receptor agonists/antagonists) or indirect treatments (e.g., gut microbiota modulation, probiotic supplementation), providing new ideas for preventing and treating metabolic diseases.

Autism spectrum disorder is a serious neurodevelopmental disorder whose early onset significantly affects an individual's social interactions and cognitive function. Recent research suggests that modulating the gut microbiota could be a potential intervention strategy for autism spectrum disorder symptoms. 2'-Fucosyllactose has been identified as a regulator of gut microbiota homeostasis, however, its effectiveness in addressing autism spectrum disorder remains unclear. In this study, the effects of daily supplementation of 2'-FL in 3-week-old male offspring mice for 5 weeks were examined. The results showed that 2'-fucosyllactose significantly improved autism spectrum disorder-like behavioral deficits. Furthermore, supplementation with 2'-fucosyllactose restored intestinal barrier integrity and increased relative abundance of beneficial gut bacteria, particularly Akkermansia and Bifidobacterium that are closely related to bile acid metabolism. Notably, 2'-fucosyllactose treatment elevated the content of bile acids and upregulated the expression of bile acid receptors in the brain. Co-housing experiments further confirmed the crucial role of gut microbiota in mediating the beneficial effects of 2'-fucosyllactose. Overall, this study suggests that 2'-fucosyllactose could alleviate maternal immune activation-induced behavioral deficits and neuroinflammation through the regulation of the gut-brain axis, offering potential therapeutic value.

This study investigates the roles of gut microbiome and secondary bile acid dysfunctions in type 1 diabetes (T1D) and explores targeted interventions to address them. It finds that T1D is associated with reduced gut microbial diversity and imbalance favoring harmful bacteria over beneficial ones. Additionally, patients with T1D exhibited impaired secondary bile acid metabolism. Interventions aimed at modulating the gut microbiome and metabolites are safe and improve glycemic control, reduce daily insulin dose, and reduce inflammation. These interventions reshape the gut microbiome toward a healthier state and enhance secondary bile acid production. Responders to the interventions show increased levels of beneficial bacteria and secondary bile acids, along with improved C-peptide responses. Overall, these findings suggest that targeted modulation of the gut microbiome and secondary bile acid metabolism could be a promising therapeutic approach for T1D management. The trial is registered at Chinese Clinical Trial Registry (ChiCTR-ONN-17011279).

This study investigated the intestinal protective effects of a probiotic mixture (PM) composed of Limosilactobacillus fermentum HF07 and Lactococcus lactis HF08 on d-gal/DSS-induced aging colitis in mice. The PM alleviated age-related colitis symptoms including weight loss, increased disease activity index scores, colonic shortening, and tissue damage. PM supplementation reshaped the gut microbiota by restoring the relative abundances of Lactobacillus, Dubosiella, Odoribacter, and Clostridia_UCG-014, thereby enhancing levels of bile acids (BAs) such as alpha-muricholic acid, isolithocholic acid, and ursodeoxycholic acid. Moreover, transcriptomic analysis revealed that PM administration activated the cAMP pathway through the gut microbiota-secondary BAs axis. Western blot analysis further demonstrated that the effects of anti-inflammatory and intestinal barrier repair induced by PM were associated with downregulation of key proteins in the NLRP3 and RhoA/ROCK pathways, both of which are downstream of the cAMP pathway. Additionally, the role of gut metabolites in mediating these effects via G protein-coupled receptor 5 (TGR5) activation was confirmed through in vitro experiments using Caco-2 cells. These findings provided a comprehensive understanding of how probiotics target intestinal metabolites and leverage the gut microbiota-BAs axis to mitigate age-related gastrointestinal diseases.

Rheumatoid arthritis (RA) with cold pattern is an important type of RA according to the theory of traditional Chinese medicine. Fuzi (also known as the lateral roots of Aconitum carmichaelii Debx.) represents a typical traditional Chinese medicine that has been clinically used for treatment of the RA especially cold-related RA for thousands of years, yet its mechanism remains unknown.

The purpose of the research was to study the therapeutic effects of Fuzi on cold-related RA, and to investigate the mechanism of its action.

Here, we investigated the pharmacological effects of Fuzi on cold-related RA using micro-CT, histopathological analysis, and inflammatory cytokine test. Then, a gut microbiota composition analysis in combination with fecal microbiota transplantation were used to confirm the role of gut microbiota in the therapeutic effects of Fuzi. Further, targeted bile acid metabolomics was used to screen the possible differential microbial bile acids involved in the mechanism of Fuzi. In vitro bioactivity analysis of differential bile acids was used to assess their anti-inflammation activity. Finally, western blot was used to investigate the signaling pathways of Fuzi in reducing the inflammation of cold-related RA.

The results showed that Fuzi alleviates cold-related RA by improving arthritis index, paw swelling, bone damage, and inflammatory cytokines. In addition, the ameliorative effect of Fuzi is dependent on gut microbiota such as the taxa Lachnospiraceae and Ruminococcaceae. Targeted analysis of fecal and serum bile acids showed that TCA and THDCA were the main differential metabolites. In vitro, TCA and THDCA showed anti-inflammation effects on RAW264.7 cells. Western blot showed that Fuzi regulates TGR5-cAMP-PKA signaling and NLRP3 inflammasome to reduce cold-related arthritis.

Overall, our results demonstrated that Fuzi could regulate gut microbiota and microbial bile acid metabolism, the microbial metabolite THDCA acts on TGR5-cAMP-PKA signaling pathway and NLRP3 inflammasome to reduce cold-related arthritis. Our study suggests that supplementation of Fuzi or THDCA can be of great value for the prevention and clinical treatment of cold-related RA.

Immune checkpoint inhibitors (ICIs) constitute a major breakthrough in the field of cancer therapy; their use has resulted in improved outcomes across various tumour types. However, ICIs can cause a diverse range of immune-related adverse events (irAEs) that present a considerable challenge to the efficacy and safety of these treatments. The gut microbiota has been demonstrated to have a crucial role in modulating the tumour immune microenvironment and thus influences the effectiveness of ICIs. Accumulating evidence indicates that alterations in the composition and function of the gut microbiota are also associated with an increased risk of irAEs, particularly ICI-induced colitis. Indeed, these changes in the gut microbiota can contribute to the pathogenesis of irAEs. In this Review, we first summarize the current clinical challenges posed by irAEs. We then focus on reported correlations between alterations in the gut microbiota and irAEs, especially ICI-induced colitis, and postulate mechanisms by which these microbial changes influence the occurrence of irAEs. Finally, we highlight the potential value of gut microbial changes as biomarkers for predicting irAEs and discuss gut microbial interventions that might serve as new strategies for the management of irAEs, including faecal microbiota transplantation, probiotic, prebiotic and/or postbiotic supplements, and dietary modulations.

Probiotics have gained increasing recognition for their potential to mitigate antibiotic-associated diarrhea (AAD). However, the precise mechanisms underlying their effects remain unclear. This study developed a mouse model of AAD using ceftriaxone to investigate the alleviating effects and mechanisms of Bifidobacterium animalis A6 (A6). The findings indicated that A6 supplementation effectively attenuated ceftriaxone-associated diarrhea in mice. The morphological damage to the villi and crypts was partially restored and more neatly reorganized following the A6 intervention. Additionally, intestinal morphology observations revealed a significant increase in the thickness of the mucus layer in the A6-treated group. Further examination of key regulatory genes associated with mucus secretion demonstrated that the A6 intervention effectively upregulated the expression of mucin1, thereby reinforcing the mucus layer. Concurrently, the A6 intervention upregulated the expression of the AQP4 and SLC26A3 genes in the intestine, which is responsible for restoring water absorption capacity in AAD mice. Additionally, the A6 treatment reduced ceftriaxone-induced harm to the intestinal microbiota of the mice, boosting beneficial bacteria like Bacteroidales, Akkermansia, Bifidobacterium, and Lactobacillus. Overall, this study offers valuable insights into the potential therapeutic role of A6 in restoring intestinal homeostasis and alleviating symptoms associated with AAD.

Bile acids, derived from cholesterol in the liver, consist a steroidal core. Primary bile acids and secondary bile acids metabolized by the gut microbiota make up the bile acid pool, which modulate nuclear hormone receptors to regulate immunity. Disruptions in the crosstalk between bile acids and the gut flora are intimately associated with the development and course of gastrointestinal inflammation.

This review provides an extensive summary of bile acid production, transport and metabolism. It also delves into the impact of bile acid metabolism on the body and explores the involvement of bile acid-microbiota interactions in various disease states. Furthermore, the potential of targeting bile acid signaling as a means to prevent and treat inflammatory bowel disease is proposed.

In this review, we primarily address the functions of bile acid-microbiota crosstalk in diseases. Firstly, we summarize bile acid signalling and the factors influencing bile acid metabolism, with highlighting the immune function of microbially conjugated bile acids and the unique roles of different receptors. Subsequently, we emphasize the vital role of bile acids in maintaining a healthy gut microbiota and regulating the intestinal barrier function, energy metabolism and immunity. Finally, we explore differences of bile acid metabolism in different disease states, offering new perspectives on restoring the host's health and the gastrointestinal ecosystem by targeting the gut microbiota-bile acid-bile acid receptor axis.

Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease. Glycyrrhiza pallidiflora polysaccharide (GPP) is an important constituent of a species of Glycyrrhiza pallidiflora, but its therapeutic mechanism in UC mice is not clear. A dextran sulphate sodium salt (DSS)-induced mouse model of UC was established, and GPP was extracted by ultrasound-assisted extraction, optimised to a GPP content of 25.66% by one-factor optimisation. The effects of different doses (100, 200, 300 mg/kg) of GPP on UC were investigated. The results showed that GPP could delay the trend of weight loss, reduce the DAI score and decrease colon damage in mice, and GPP had a better ameliorative effect on enteritis, which provided a theoretical basis for studying the effect of natural products on UC.

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the intestine, frequently complicated by intestinal fibrosis. As fibrosis progresses, it can result in luminal stricture and compromised intestinal function, significantly diminishing patients' quality of life. Emerging evidence suggests that gut microbiota and their metabolites contribute to the pathogenesis of IBD-associated intestinal fibrosis by influencing inflammation and modulating immune responses. This review systematically explores the mechanistic link between gut microbiota and intestinal fibrosis in IBD and evaluates the therapeutic potential of traditional Chinese medicine (TCM) interventions. Relevant studies were retrieved from PubMed, Web of Science, Embase, Scopus, CNKI, Wanfang, and VIP databases. Findings indicate that TCM, including Chinese herbal prescriptions and bioactive constituents, can modulate gut microbiota composition and microbial metabolites, ultimately alleviating intestinal fibrosis through anti-inflammatory, immunemodulatory, and anti-fibrotic mechanisms. These insights highlight the potential of TCM as a promising strategy for targeting gut microbiota in the management of IBD-associated fibrosis.

The intestinal tract, a complex organ responsible for nutrient absorption and digestion, relies heavily on a balanced gut microbiome to maintain its integrity. Disruptions to this delicate microbial ecosystem can lead to intestinal inflammation, a hallmark of inflammatory bowel disease (IBD). While the role of the gut microbiome in IBD is increasingly recognized, the underlying mechanisms, particularly those involving endoplasmic reticulum (ER) stress, autophagy, and cell death, remain incompletely understood. ER stress, a cellular response to various stressors, can trigger inflammation and cell death. Autophagy, a cellular degradation process, can either alleviate or exacerbate ER stress-induced inflammation, depending on the specific context. The gut microbiome can influence both ER stress and autophagy pathways, further complicating the interplay between these processes. This review delves into the intricate relationship between ER stress, autophagy, and the gut microbiome in the context of intestinal inflammation. By exploring the molecular mechanisms underlying these interactions, we aim to provide a comprehensive theoretical framework for developing novel therapeutic strategies for IBD. A deeper understanding of the ER stress-autophagy axis, the gut microbial-ER stress axis, and the gut microbial-autophagy axis may pave the way for targeted interventions to restore intestinal health and mitigate the impact of IBD.

Host-microbiome communication is frequently perturbed in gut pathologies due to microbiome dysbiosis, leading to altered production of bacterial metabolites. Among these, 7α-dehydroxylated bile acids are notably diminished in inflammatory bowel disease patients. Herein, we investigated whether restoration of 7α-dehydroxylated bile acids levels by Clostridium scindens, a human-derived 7α-dehydroxylating bacterium, can reestablish intestinal epithelium homeostasis following colon injury. Gnotobiotic and conventional mice were subjected to chemically-induced experimental colitis following administration of Clostridium scindens. Colonization enhanced the production of 7α-dehydroxylated bile acids and conferred prophylactic and therapeutic protection against colon injury through epithelial regeneration and specification. Computational analysis of human datasets confirmed defects in intestinal cell renewal and differentiation in ulcerative colitis patients while expression of genes involved in those pathways showed a robust positive correlation with 7α-dehydroxylated bile acid levels. Clostridium scindens administration could therefore be a promising biotherapeutic strategy to foster mucosal healing following colon injury by restoring bile acid homeostasis.

Dysbiosis refers to the disruption of the gut microbiota balance and is the pathological basis of various diseases. The main pathogenic mechanisms include impaired intestinal mucosal barrier function, inflammation activation, immune dysregulation, and metabolic abnormalities. These mechanisms involve dysfunctions in the gut-brain axis, gut-liver axis, and others to cause broader effects. Although the association between diseases caused by dysbiosis has been extensively studied, many questions remain regarding the specific pathogenic mechanisms and treatment strategies. This review begins by examining the causes of gut microbiota dysbiosis and summarizes the potential mechanisms of representative diseases caused by microbiota imbalance. It integrates clinical evidence to explore preventive and therapeutic strategies targeting gut microbiota dysregulation, emphasizing the importance of understanding gut microbiota dysbiosis. Finally, we summarized the development of artificial intelligence (AI) in the gut microbiota research and suggested that it will play a critical role in future studies on gut dysbiosis. The research combining multiomics technologies and AI will further uncover the complex mechanisms of gut microbiota dysbiosis. It will drive the development of personalized treatment strategies.

Proline rich-39 (PR-39) is a natural antimicrobial protein with good antibacterial and anti-inflammatory activities. The miniature Wuzhishan pig (WZSP) has important similarities to humans in anatomical structure, physiological characteristics, and nutrient metabolism that make it an important model animal for biomedical research. This study aimed to investigate the protective effect and therapeutic mechanism of PR-39 on intestinal barrier function using the LPS-induced enteritis model in WZSPs. We found that PR-39 treatment reversed the decrease in growth performance and peripheral organ damage, regulated serum indices (IL-1β, IL-6, TNF-α, IL-10, TGF-β, IgA, IgG, DAO, D-LA) and enhanced the antioxidant capacity (MDA, CAT, GSH-Px, T-AOC) of piglets. PR-39 protected the integrity of the jejunal barrier by upregulating the density of goblet cells and the expression of tight junction proteins ZO-1, Claudin-1, and Occludin. Additionally, PR-39 increased the abundance of jejunal probiotics (e.g., Lactococcus), and increased the cecal abundance of Lactobacillus johnsonii, then promoted the production of 7-keto deoxycholic acid to activate the bile acid receptor TGR5, which in turn inhibited the NF-κB-MLCK-MLC signaling pathway and the secretion of proinflammatory factors by macrophages. In summary, these findings suggest that PR-39 supplementation may be an effective strategy to improve the intestinal damage and dysfunction.

Crohn's disease (CD) and ulcerative colitis (UC) are the two major entities of inflammatory bowel disease (IBD). These disorders are known for their relapsing disease course and severe gastrointestinal symptoms including pain, diarrhoea and bloody stool. Accumulating evidence suggests that IBD is not only restricted to the gastrointestinal tract and that disease processes are able to reach distant organs including the brain. In fact, up to 35 % of IBD patients also suffer from neuropsychiatric disorders such as generalized anxiety disorder and major depressive disorder. Emerging research in this area indicates that in many cases these neuropsychiatric disorders are a secondary condition as a consequence of the disturbed communication between the gut and the brain via the microbiota-gut-brain axis. In this review, we summarise the current knowledge on IBD-associated neuropsychiatric disorders. We examine the role of different pathways of the microbiota-gut-brain axis in the development of CNS disorders highlighting altered neural, immunological, humoral and microbial communication. Finally, we discuss emerging therapies targeting the microbiota-gut-brain axis to alleviate IBD and neuropsychiatric symptoms including faecal microbiota transplantation, psychobiotics, microbial metabolites and vagus nerve stimulation.

Microbial-derived metabolites are important mediators of host-microbial interactions. In recent years, the role of intestinal microbial metabolites in colorectal cancer has attracted considerable attention. These metabolites, which can be derived from bacterial metabolism of dietary substrates, modification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyamines, microbial tryptophan metabolites, and polyphenols are involved in the tumorigenesis and development of CAC through inflammation and immunity. Given the heated debate on the metabolites of microbiota in maintaining gut homeostasis, serving as tumor molecular markers, and affecting the efficacy of immune checkpoint inhibitors in recent years, strategies for the prevention and treatment of CAC by targeting intestinal microbial metabolites are also discussed in this review.

Obesity rates are rising globally and have become a major public health issue. Recent research emphasizes the bidirectional communication between gut microbiota and mitochondrial function in obesity development. Gut microbiota regulates energy metabolism through metabolites that impact mitochondrial processes, such as oxidative phosphorylation, biogenesis, and autophagy. In turn, alterations in mitochondrial function impact microbiota homeostasis. Traditional Chinese medicine (TCM), which encompasses TCM formulas and the metabolites of botanical drugs, employs a holistic and integrative approach that shows promise in regulating gut microbiota-mitochondrial crosstalk. This review systematically explores the intricate interactions between gut microbiota and mitochondrial function, underscoring their crosstalk as a critical mechanistic axis in obesity pathogenesis. Furthermore, it highlights the potential of TCM in developing innovative, targeted interventions, paving the way for personalized approaches in obesity treatment through the precise modulation of gut microbiota-mitochondrial interactions, offering more effective and individualized therapeutic options.

Systemic hypertension is a major risk factor for cardiovascular disease and remains challenging to manage despite the widespread use of antihypertensive medications and lifestyle modifications. This review explores the role of gut microbiota in hypertension development and regulation, highlighting key mechanisms such as inflammation, gut-brain axis modulation, and bioactive metabolite production. We also assess the potential of microbiota-targeted therapies for hypertension management.

Emerging evidence indicates that microbial dysbiosis, high-salt diets, and gut-derived metabolites such as short-chain fatty acids (SCFAs) and bile acids significantly influence blood pressure regulation. Preclinical and early clinical studies suggest that interventions targeting gut microbiota, including probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), and dietary modifications, may help modulate hypertension. However, variability in gut microbiota composition among individuals and limited human trial data pose challenges to translating these findings into clinical practice. While microbiota-based therapies show promise for hypertension management, further research is needed to establish their efficacy and long-term effects. Large-scale, standardized clinical trials are crucial for understanding the therapeutic potential and limitations of gut microbiota interventions. A deeper understanding of the gut-hypertension axis could lead to novel, personalized treatment strategies for hypertension.

Pouchitis, defined as inflammation of the ileal pouch, is the most common complication following restorative proctocolectomy for refractory ulcerative colitis. Antibiotics remain the first line of therapy for pouchitis, but the majority of patients develop subsequent episodes and some are refractory to antibiotic therapy. This highlights the need for more effective treatment options and points to a more complex pathophysiology beyond the role of th pouch microbiome, similar to what is seen in inflammatory bowel disease. In this review, we outline the putative mechanisms of pouchitis, including genetic predisposition, microbiome alterations, dysfunction of the intestinal barrier and the immune system and review the available animal models of pouchitis. In addition, we introduce the concept of pouchitis as a possible transmural disease and discuss the potential role of non-immune cells, including stromal cells, in perpetuating inflammation and intestinal barrier dysfunction. We discuss future directions, implications for novel therapies and propose novel multicellular disease models that can better capture the complexity of pouchitis pathogenesis.

Structural variations (SVs) have significant effects on microbial phenotypes. The underlying mechanism of functional changes caused by gut microbial SVs in the development of ulcerative colitis (UC) need further investigation.

We performed long-read (Oxford Nanopore Technology-based) and short-read (Illumina-based) metagenomic sequencing on stool samples from 93 patients with UC and 100 healthy controls (HCs) and analyzed microbial SVs. A total of 648 Escherichia coli strains from fecal samples of patients with UC (UC-strains) and HCs (HC-strains) were isolated. SV-associated scrK gene deletion was verified via whole-genome sequencing or targeted polymerase chain reaction. Then, representative UC-strains, HC-strains, and scrK-knockout E coli were used for the in vitro and in vivo experiments to investigate the effects of specific SVs in E coli on fructose utilization ability and colitis.

E coli in UC with the highest fold change had SV-affected functional differences on fructose metabolism to that of HCs. The fructose utilization gene deletion was common in UC-strains, ostensibly reducing fructose utilization in vitro and leading to fructose-dependent aggravation of colitis in murine models. UC-strains and HC-strains induced comparable colitis under low fructose. However, high fructose exacerbated colitis severity exclusively in UC-strain-colonized mice, with elevated intestinal fructose residues, significant microbiome/metabolome changes, increased inflammation, and gut barrier disruption. These changes were mechanistically dependent on the deletion of the fructose utilization gene scrK.

SV-caused difference in fructose utilization and proinflammatory properties in E coli from patients with UC influence the development of UC, emphasizing the importance of fine-scale metagenomic studies in disease.

The commensal gut microbiota has a role in the pathogenesis of extra-intestinal autoimmune diseases such as multiple sclerosis (MS) with unknown mechanisms. Deoxycholic acid (DCA) and lithocholic acid (LCA) are secondary bile acid metabolites (BAMs) produced from primary bile acids by gut microbiota that play key immune regulatory functions by promoting FOXP3+ regulatory T (Treg) cell differentiation at the expense of Th17 cells. Here, we show that bacteria releasing enzymes responsible for secondary BAMs production are under-represented in the gut of MS patients, resulting in significantly reduced intestinal concentration of DCA and immune dysregulation with increased percentage of Th17 cells. We validated our human findings in a preclinical model of MS by showing that DCA/LCA administration prevents experimental autoimmune encephalomyelitis (EAE) by dampening Th17 cell differentiation and the effector phenotype of myelin-reactive T cells. Our data highlight the key role of immune regulatory BAMs for the prevention of central nervous system (CNS) autoimmunity.

Conjugated bile acids (BAs) are multi-functional detergents in the gastrointestinal (GI) tract produced by the liver enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) and by the microbiome from the acyltransferase activity of bile salt hydrolase (BSH). Humans with inflammatory bowel disease (IBD) have an enrichment in both host and microbially conjugated BAs (MCBAs), but their impacts on GI inflammation are not well understood. We investigated the role of host-conjugated BAs in a mouse model of colitis using a BAAT knockout background. Baat-/- KO mice have severe phenotypes in the colitis model that were rescued by supplementation with taurocholate (TCA). Gene expression and histology showed that this rescue was due to an improved epithelial barrier integrity and goblet cell function. However, metabolomics also showed that TCA supplementation resulted in extensive metabolism to secondary BAs. We therefore investigated the BSH activity of diverse gut bacteria on a panel of conjugated BAs and found broad hydrolytic capacity depending on the bacterium and the amino acid conjugate. The complexity of this microbial BA hydrolysis led to the exploration of bsh genes in metagenomic data from human IBD patients. Certain bsh sequences were enriched in people with Crohn's disease particularly that from Ruminococcus gnavus. This study shows that both host and microbially conjugated BAs may provide benefits to those with IBD, but this is dictated by a delicate balance between BA conjugation/deconjugation based on the bsh genes present.

The landscape of clinical microbiome research has dramatically evolved over the past decade. By leveraging in vivo and in vitro experimentation, multiomic approaches and computational biology, we have uncovered mechanisms of action and microbial metrics of association and identified effective ways to modify the microbiome in many diseases and treatment modalities. This Review explores recent advances in the clinical application of microbiome research over the past 5 years, while acknowledging existing barriers and highlighting opportunities. We focus on the translation of microbiome research into clinical practice, spearheaded by Food and Drug Administration (FDA)-approved microbiome therapies for recurrent Clostridioides difficile infections and the emerging fields of microbiome-based diagnostics and therapeutics. We highlight key examples of studies demonstrating how microbiome mechanisms, metrics and modifiers can advance clinical practice. We also discuss forward-looking perspectives on key challenges and opportunities toward integrating microbiome data into routine clinical practice, precision medicine and personalized healthcare and nutrition.

Microbiome modulation is one of the novel strategies in medicine with the greatest future to improve the health of individuals and reduce the risk of different conditions, including metabolic, immune, inflammatory, and degenerative diseases, as well as cancer. Regarding the latter, many studies have reported the role of the gut microbiome in carcinogenesis, formation and progression of colorectal cancer (CRC), as well as its response to different systemic therapies. Likewise, obesity, one of the most important risk factors for CRC, is also well known for its association with gut dysbiosis. Moreover, obesity and CRC display, apart from microbial dysbiosis, chronic inflammation, which participates in their pathogenesis. Although human and murine studies demonstrate the significant impact of the microbiome in regulating energy metabolism and CRC development, little is understood about the contribution of the microbiome to the development of obesity-associated CRC. Therefore, this systematic review explores the evidence for microbiome changes associated with these conditions and hypothesizes that this may contribute to the pathogenesis of obesity-related CRC. Two databases were searched, and different studies on the relationship among obesity, intestinal microbiota and CRC in clinical and preclinical models were selected. Data extraction was carried out by two reviewers independently, and 101 studies were finally considered. Findings indicate the existence of a risk association between obesity and CRC derived from metabolic, immune, and microbial disorders.

Inflammatory Bowel Disease (IBD) is a set of chronic intestinal inflammatory disorders affecting the gastrointestinal (GI) tract. Beside compromised intestinal barrier function and immune hyperactivation, a common IBD feature is dysbiosis, characterized by a reduction of some strains of Firmicutes, Bacteroidetes, Actinobacteria and an increase in Proteobacteria and pathobionts. Emerging evidence points to diet and nutrition-dependent gut microbiota (GM) modulation, as etiopathogenetic factors and adjuvant therapies in IBD. Currently, no nutritional regimen shows universal efficacy, and advice are controversial, especially those involving restrictive diets potentially resulting in malnutrition. This review provides an overview of the role of macronutrients, dietary protocols and GM modulation in IBD patients. A Western-like diet contributes to an aberrant mucosal immune response to commensal bacteria and impairment of the intestinal barrier integrity, thereby triggering intestinal inflammation. Conversely, a Mediterranean nutritional pattern appears to be one of the most beneficial dietetic regimens able to restore the host intestinal physiology, by promoting eubiosis and preserving the intestinal barrier and immune function, which in turn create a virtuous cycle improving patient adherence to the pattern. Further clinical studies are warranted, to corroborate current IBD nutritional guidelines, and develop more accurate models to move forward precision nutrition and ameliorate patients' quality of life.

Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colorectum, posing a significant global health burden. Recent studies highlight the critical role of gut microbiota and its metabolites, particularly bile acids (BAs), in UC's pathogenesis. The relationship between BAs and gut microbiota is bidirectional: microbiota influence BA composition, while BAs regulate microbiota diversity and activity through receptors like Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Targeting bile-acid metabolism to reshape gut microbiota presents a promising therapeutic strategy for UC. This review examines the classification and synthesis of BAs, their interactions with gut microbiota, and the potential of nutritional and microbial interventions. By focusing on these therapies, we aim to offer innovative approaches for effective UC management.

Pomegranate peel is a by-product generated during the processing of pomegranate (Punica granatum L.) fruit, accounting for approximately 50% of the total mass of the fruit. Although pomegranate peel is usually regarded as waste, it is rich in various bioactive metabolites such as polyphenols, tannins, and flavonoids, demonstrating significant medicinal and nutritional value. In recent years, Pomegranate peel extract (PPE) has shown broad application prospects in the biomedical field due to its multiple effects, including antioxidant, anti-inflammatory, antibacterial, anti-apoptotic properties, and promotion of cell regeneration. This review consolidates the major bioactive metabolites of PPE and explores its applications in biomedical materials, including nanodrug carriers, hydrogels, and tissue engineering scaffolds. By synthesizing the existing literature, we delve into the potential value of PPE in biomedicine, the challenges currently encountered, and the future directions for research. The aim of this review is to provide a scientific basis for optimizing the utilization of PPE and to facilitate its broader application in the biomedical field.

Background/Objectives: Endometrial cancer (EC) is a prevalent gynecological malignancy with an increasing incidence, particularly in developed countries. Recent research has demonstrated the significant involvement of gut and endometrial microbiomes in the pathogenesis and progression of EC. This review provides a comprehensive overview of the existing knowledge on the interactions between these microbial communities and their influence on EC. Methodology: A literature review was conducted using electronic databases including Google Scholar, Scopus, and PUBMED, covering the period from 2017 to 2024. The following keywords were used for the literature search: (1) gut microbiome and endometrial cancer, (2) endometrium microbiome and endometrial cancer, and (3) endometrial cancer and microbial dysbiosis. The selected articles were chosen based on inclusion and exclusion criteria. Scale for Assessment of Narrative Review Articles (SANRA) was used for evaluating and assessing the quality of articles. Results: The gut microbiome modulates systemic inflammation, immune responses, and estrogen metabolism, all of which are crucial factors in EC development. Dysbiosis is an imbalance in the composition of microbes that can cause chronic inflammation and hormonal imbalances, which can contribute to the EC. Similarly, the endometrial microbiome, while less extensively studied, has been implicated in EC through mechanisms involving local immune modulation and the production of harmful metabolites. Probiotics, prebiotics, fecal microbiota transplantation (FMT), and personalized microbiota-based therapies can be used as clinical interventions for EC management. This review emphasizes the need for further research to explore the gut-endometrium axis and its potential for innovative therapeutic approaches. Understanding these complex interactions will become a novel strategy to prevent and treat EC, ultimately enhancing patient outcomes.

As a probiotic strain isolated from Hongqu rice wine (a traditional Chinese fermented food), Limosilactobacillus fermentum FZU501 (designated as Lf) demonstrates exceptional gastric acid and bile salt tolerance, showing potential application as a functional food. The aim of this study was to investigate the protective effect of dietary Lf intervention on alcohol-induced liver injury (ALI) in mice. The results demonstrated that oral administration of Lf effectively ameliorated alcohol-induced lipid metabolism disorders by reducing the serum levels of TC, TG and LDL-C and increasing the serum levels of HDL-C. In addition, oral administration of Lf effectively prevented alcohol-induced liver damage by increasing the hepatic activities of antioxidant enzymes (CAT, SOD, GSH-Px) and alcohol-metabolizing enzymes (ADH and ALDH). Interestingly, 16S amplicon sequencing showed that oral administration of Lf increased the number of Prevotella, Lachnospiraceae_NK4A136_group and Lactobacillus, but decreased the proportion of Faecalibaculum, Adlercreutzia and Alistipes in the intestines of mice that consumed excessive alcohol, which was highly associated with improved liver function. As revealed by liver untargeted metabolomics studies, oral Lf clearly changed liver metabolic profiles, with the signature biomarkers mainly involving purine metabolism, taurine metabolism, tryptophan, alanine, aspartic acid and glutamate metabolism, etc. Additionally, Lf intervention regulated liver gene transcription in over-drinking mice for cholesterol metabolism, bile acid metabolism, fatty acid β-oxidation, alcohol metabolism and oxidative stress. Taken together, the above research results provide solid scientific support for the biological activity of Lf in ameliorating alcohol-induced liver metabolism disorder and intestinal microbiota imbalance.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC), and IBD unclassified (IBD-U), is a complex intestinal disorder influenced by genetic, environmental, and microbial factors. Recent evidence highlights the gut microbiota as a pivotal biomarker and modulator in IBD pathogenesis. Dysbiosis, characterized by reduced microbial diversity and altered composition, is a hallmark of IBD. A consistent decrease in anti-inflammatory bacteria, such as Faecalibacterium prausnitzii, and an increase in pro-inflammatory species, including Escherichia coli, have been observed. Metabolomic studies reveal decreased short-chain fatty acids (SCFAs) and secondary bile acids, critical for gut homeostasis, alongside elevated pro-inflammatory metabolites. The gut microbiota interacts with host immune pathways, influencing morphogens, glycosylation, and podoplanin (PDPN) expression. The disruption of glycosylation impairs mucosal barriers, while aberrant PDPN activity exacerbates inflammation. Additionally, microbial alterations contribute to oxidative stress, further destabilizing intestinal barriers. These molecular and cellular disruptions underscore the role of the microbiome in IBD pathophysiology. Emerging therapeutic strategies, including probiotics, prebiotics, and dietary interventions, aim to restore microbial balance and mitigate inflammation. Advanced studies on microbiota-targeted therapies reveal their potential to reduce disease severity and improve patient outcomes. Nevertheless, further research is needed to elucidate the bidirectional interactions between the gut microbiome and host immune responses and to translate these insights into clinical applications. This review consolidates current findings on the gut microbiota's role in IBD, emphasizing its diagnostic and therapeutic implications, and advocates for the continued exploration of microbiome-based interventions to combat this debilitating disease.