Alcohol-associated liver disease (ALD) is a prevalent global health issue primarily caused by excessive alcohol consumption. Recent studies have highlighted the gut-liver axis's protective role against ALD, mainly through gut microbiota. However, the precise mechanism remains ill-defined. Our results showed a significant reduction in Lachnospiraceae bacterium in the gut microbiota of ALD patients and ethanol (EtOH)-fed mice, as revealed by 16S rDNA sequencing. Supplementation with Lachnospiraceae bacterium strains in mice significantly reduced inflammation, hepatic neutrophil infiltration, oxidative stress, and improved gut microbiota and intestinal permeability. Multi-omics analysis identified N-Acetyl-glutamic acid (NAG) as the most significantly altered metabolite following Lachnospiraceae bacterium supplementation, with levels positively correlated to Lachnospiraceae bacterium colonization. NAG treatment exhibited significant protective effects in EtOH-exposed hepatocyte cell lines and EtOH-fed mice. Mechanistically, NAG confers hepatoprotection against ALD by activating the KEAP1-NRF2 pathway, inhibiting ferroptosis. Notably, the protective effects of NAG were reversed by the NRF2 inhibitor. In conclusion, oral supplementation with Lachnospiraceae bacterium mitigates alcohol-induced liver damage both in vivo and in vitro by inhibiting ferroptosis through NAG-mediated activation of the KEAP1-NRF2 pathway. Lachnospiraceae bacterium may serve as promising probiotics for future clinical applications.

Previous studies have shown changes in gut microbiota after human immunodeficiency virus (HIV) infection, but there is limited research linking the gut microbiota of people living with HIV (PLWHIV) to metabolic diseases.

A total of 103 PLWHIV were followed for 48 weeks of anti-retroviral therapy (ART), with demographic and clinical data collected. Gut microbiome analysis was conducted using metagenomic sequencing of fecal samples from 12 individuals. Nonalcoholic fatty liver disease (NAFLD) was diagnosed based on controlled attenuation parameter (CAP) values of 238 dB/m from liver fibro-scans. Participants were divided based on the presence of metabolic disorders, including NAFLD, overweight, and hyperlipidemia. Akkermansia abundance in stool samples was measured using RT-qPCR, and Pearson correlation and logistic regression were applied for analysis.

Metagenomic sequencing revealed a significant decline in gut Akkermansia abundance in PLWHIV with NAFLD. STAMP analysis of public datasets confirmed this decline after HIV infection, while KEGG pathway analysis identified enrichment of metabolism-related genes. A prospective cohort study with 103 PLWHIV followed for 48 weeks validated these findings. Akkermansia abundance was significantly lower in participants with NAFLD, overweight, and hyperlipidemia at baseline, and it emerged as an independent predictor of NAFLD and overweight. Negative correlations were observed between Akkermansia abundance and both CAP values and body mass index (BMI) at baseline and at week 48. At the 48-week follow-up, Akkermansia remained a predictive marker for NAFLD.

Akkermansia abundance was reduced in PLWHIV with metabolic disorders and served as a predictive biomarker for NAFLD progression over 48 weeks of ART.

Alcohol-associated organ damage is a major cause of morbidity and mortality worldwide, with the liver being the primarily affected organ. Emerging evidence highlights the gut microbiota as a key driver in alcohol-associated liver disease. Changes in the microbiota composition, microbial translocation, and a dysregulated immune response culminate in inflammation and tissue injury. Persistent liver injury eventually promotes disease progression from steatohepatitis to fibrosis and cirrhosis. In this review, we provide an overview of microbiota alterations observed in patients with chronic alcohol consumption and explore the mechanisms by which microbiota contributes to alcohol-associated damage across various organ systems. Emphasis is placed on changes in the gut microbiota and its role in alcohol-associated liver disease, the disease condition with the most robust evidence linking microbiota-related changes to organ injury. Additionally, we highlight key areas where further research is needed to address unresolved questions. Finally, we discuss emerging therapeutic strategies targeting the microbiota to treat alcohol use disorders and prevent alcohol-associated liver diseases.

Chronic alcohol consumption induces oxidative stress not only in the liver but also in the gastrointestinal tract, where prolonged intestinal ethanol absorption plays a pivotal and underrecognized role. This review reframes ethanol pharmacokinetics to emphasize sustained jejunal and ileal uptake, which maintains elevated blood alcohol levels and perpetuates redox imbalance across the gut-liver axis. We integrate recent findings on ethanol-induced barrier dysfunction, CYP2E1-mediated ROS production, microbial dysbiosis, and mitochondrial disruption, proposing that the intestine is an active site of injury and a driver of systemic inflammation. Key mechanistic insights reveal that gut-derived endotoxins, compromised epithelial integrity, and microbiome-mitochondria interactions converge to exacerbate hepatic and extrahepatic damage. We further explore emerging therapeutic strategies-ranging from NAD+ repletion and probiotics to fecal microbiota transplantation-that target this upstream pathology. Recognizing prolonged intestinal ethanol absorption as a clinically meaningful phase offers new directions for early intervention and redox-based treatment in alcohol-associated disease.

The liver disorders caused by alcohol abuse are termed alcoholic-related liver disease (ALD), including alcoholic steatosis, alcoholic steatohepatitis, alcoholic hepatitis, and alcoholic cirrhosis, posing a significant threat to human health. Currently, ALD pathogenesis has not been completely clarified, which is likely to be related to the direct damage caused by alcohol and its metabolic products, oxidative stress, gut dysbiosis, and exosomes.

The existing studies suggest that both the gut microbiota and exosomes contribute to the development of ALD. Moreover, there exists an interaction between the gut microbiota and exosomes. We discuss whether this interaction plays a role in the pathogenesis of ALD and whether it can be a potential therapeutic target for ALD treatment.

Chronic alcohol intake alters the diversity and composition of gut microbiota, which greatly contributes to ALD's progression. Some approaches targeting the gut microbiota, including probiotics, fecal microbiota transplantation, and phage therapy, have been confirmed to effectively ameliorate ALD in many animal experiments and/or several clinical trials. In ALD, the levels of exosomes and the expression profile of microRNA have also changed, which affects the pathogenesis of ALD. Moreover, there is an interplay between exosomes and the gut microbiota, which also putatively acts as a pathogenic factor of ALD.

Various types of liver or hepatic diseases cause the death of about 2 million people worldwide every year, of which 1 million die from the complications of cirrhosis and another million from hepatocellular carcinoma and viral hepatitis. Currently, the second most common solid organ transplant is the liver, and the current rate represents less than 10% of global transplant requests. Hence, finding new approaches to treat and prevent liver diseases is essential. In liver diseases, the interaction between the liver, gut, and immune system is crucial, and probiotics positively affect the human microbiota. Probiotics are a non-toxic and biosafe alternative to synthetic chemical compounds. Health promotion by lowering cholesterol levels, stimulating host immunity, the natural gut microbiota, and other functions are some of the activities of probiotics, and their metabolites, including bacteriocins, can exert antimicrobial effects against a broad range of pathogenic bacteria. The present review discusses the available data on the results of preclinical and clinical studies on the effects of probiotic administration on different types of liver diseases.

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

Alcohol-associated liver disease (ALD)-encompassing conditions including steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma-refers to hepatic damage arising from excessive or hazardous alcohol consumption, and is now recognized as a significant global health burden. Although the mechanisms underlying ALD remain incompletely understood, several pathways have been substantiated over the last five decades, notably the involvement of intestinal microorganisms and the involvement of the gut-liver axis in alcohol metabolism and ALD pathogenesis. Ethanol intake disrupts the intestinal microbial balance and compromises the gut barrier, resulting in increased permeability to microbial products. The subsequent translocation of microbial metabolites and other antigenic substances to the liver activates hepatic immune responses, thereby contributing to liver injury. In addition, gastrointestinal hormones are also implicated in ALD progression through various mechanisms. Although no therapies for ALD have been approved by the Food and Drug Administration, various therapeutic strategies targeting the intestinal microbiota and gut barrier have been identified. In conclusion, this review discusses the role of the gut-liver axis in alcohol metabolism and ALD pathogenesis and explores the emerging therapeutic strategies.

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

Dysbiosis, characterized by imbalanced gut microbiota, is common in patients with inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). While probiotics theoretically offer promise for IBD treatment, their actual efficacy remains uncertain, leading to non-recommendation in current guidelines. Akkermansia muciniphila (AKK) is a potential next-generation probiotic strain with benefits in obesity, diabetes and gut protection. Recent study showed reduced AKK abundance in IBD patients and mice with colitis and CAC. Hence, we administered AKK treatment to these mice to assess its effects.

Using a mouse model of colitis and CAC induced by azoxymethane/dextran sodium sulfate (AOM/DSS) in BALB/c mice, we administered AKK orally to mice on the AOM/DSS protocol with 5 × 108 CFU of AKK three times a week for a total 27 times. The treatment effect of AKK were evaluated.

Despite AKK supplementation, mice showed no significant differences in body weight, colon length, histological inflammation, or short chain fatty acid composition compared to those on the AOM/DSS protocol alone. Unexpectedly, AKK-treated mice exhibited decreased AKK abundance in stool samples, suggesting poor adherence and colonization despite supplementation. These results parallel our previous findings with Clotridium butyricum, indicating challenges in probiotic intervention for severe colitis and CAC due to mucosal barrier damage.

Our study highlights the limitations of probiotic therapy in IBD, attributing its failure to inadequate adherence and colonization in damaged mucosal barriers. Further research is warranted to clarify the role of probiotics in IBD management.

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.

Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality. ALD covers a spectrum of diseases, ranging from mild and reversible hepatic steatosis to the development of fibrosis, cirrhosis, and alcohol-associated hepatitis (AH). AH is marked by a rapid onset of jaundice and elevated serum levels of aspartate aminotransferase in individuals with heavy alcohol use. It can progress to acute-on-chronic liver failure, with a mortality rate of approximately 30% within the first month. Unfortunately, treatment options for AH are still limited. Cholestasis refers to an impairment in bile formation or flow, leading to clinical symptoms, such as fatigue, pruritus, and jaundice. Cholestasis and biliary dysfunction are commonly seen in patients with AH and can significantly worsen the prognosis. However, the mechanisms and roles of cholestasis in ALD are not yet fully understood. In this review, we will summarize recent findings and explore the potential roles and mechanisms of cholestasis in the progression of ALD.

The hepatoprotective effect of the fruit of Lycium barbarum has been documented in China over millennia. Lycium barbarum polysaccharides (LBPs) were the first macromolecules reported to mitigate liver fibrosis in carbon tetrachloride (CCl4)-treated mice. Herein, a neutral peptidoglycan, named as LBPW, was extracted from the fruit of Lycium barbarum. In this study, we investigated the hepatoprotective mechanisms of LBPW. CCl4-induced liver fibrosis mice were administered LBPW (50, 100, 200 mg ·kg-1 ·d-1, i.p.) or (100, 200, 300 mg· kg-1 ·d-1, i.g.) for 6 weeks. We showed that either i.p. or i.g. administration of LBPW dose-dependently attenuated liver damage and fibrosis in CCl4-treated mice. Pharmacokinetic analysis showed that cyanine 5.5 amine (Cy5.5)-labeled LBPW (Cy5.5-LBPW) could be detected in the liver through i.p. and i.g. administration with i.g.-administered Cy5.5-LBPW mainly accumulating in the intestine. In TGF-β1-stimulated LX-2 cells as well as in the liver of CCl4-treated mice, we demonstrated that LBPW significantly upregulated Smad7, a negative regulator of TGF-β/Smad signaling, to retard the activation of hepatic stellate cells (HSCs) and prevent liver fibrosis. On the other hand, LBPW significantly boosted the abundance of Akkermansia muciniphila (A. muciniphila) and fortified gut barrier function. We demonstrated that A. muciniphila might be responsible for the efficacy of LBPW since decreasing the abundance of this bacterium by antibiotics (Abs) blocked the effectiveness of LBPW. Overall, our results show that LBPW may exert the hepatoprotective effect via rebalancing TGF-β/Smad7 signaling and propagating gut commensal A. muciniphila, suggesting that LBPW could be leading components to be developed as new drug candidates or nutraceuticals against liver fibrosis.

The gut contains a diverse array of commensal microorganisms, forming a vital biological barrier within the intestine that contributes to the overall intestinal mucosal barrier. However, research on the rectal barrier during early development remains limited. This study aims to investigate the relationship between intestinal microbiota and rectal barrier function in young rats.

We evaluated the rectal barrier structure and function in rats at 2-, 4-, and 10-week-old. Methodology included histological analysis, Muc2 expression quantification, immunofluorescence localization of tight junction proteins (ZO-1, Occludin, Claudins), blood glucose monitoring after rectal insulin administration, and 16S rDNA sequencing of rectal microbiota. Spearman correlation analysis was used to explore mechanisms linking age-dependent changes in rectal permeability to microbiota dynamics.

Physiological rectal permeability was significantly higher in 2-week-old rats compared to 4- and 10-week-old rats (p < 0.01), although systemic biomarkers (LPS, D-LA, and LBP) showed no significant differences. The rectal microbiota exhibited marked age-dependent shifts in composition, α/β-diversity, and metabolic pathways, with increased abundance of beneficial taxa (e.g., Muribaculaceae, Akkermansia) in older rats. Correlation analysis revealed strong associations between reduced permeability, elevated Occludin expression, and microbiota maturation (R = 0.65, p < 0.001).

This study demonstrates that age-dependent maturation of the rectal barrier is closely linked to microbiota composition and tight junction protein expression, providing insights into developmental mechanisms and potential strategies for pediatric rectal drug delivery.

Inflammatory bowel disease is a long-standing inflammatory disorder that influences the intestinal tract. The intent of this research is to explore whether the relative abundance of Akkermansia muciniphila is related to the IL6/STAT3 pathway and the fundamental molecular mechanisms of A. muciniphila on a trinitrobenzene sulfonic acid (TNBS)-induced enteritis mouse model, including the expression of inflammatory cytokines and proteins in the IL6/STAT3 signaling pathway.

The association between the A. muciniphila and IL6/STAT3 was investigated by using mucosal biopsies and fecal samples. TNBS-induced colitis mouse models were performed to elucidate the underlying mechanisms. The alteration of intestinal microbiota was organized by 16s rRNA sequencing.

In Crohn's disease patients, the level of STAT3 and IL-6 presented a negative relationship with A. muciniphila. The expression of IL-6, p-STAT3, and STAT3 was downregulated in A.m+TNBS group, indicating A. muciniphila may inhibit the IL6/STAT3 pathway in TNBS-induced enteritis in vivo. To investigate the potential defensive role of A. muciniphila supplementation in vivo with TNBS-induced enteritis, 16S rRNA sequencing was performed to analyze changes in the intestinal microbiota composition. The results revealed a marked increase in microbial diversity and abundance within the A. muciniphila-treated group, suggesting a beneficial modulation of the gut microbiome associated with the supplementation.

Our findings declared that A. muciniphila supplementation alleviates gastrointestinal inflammation through IL-6/STAT3 signaling pathway. This protective effect was mediated by the downregulation of the IL-6 and STAT3, highlighting a potential mechanism by which A. muciniphila modulates inflammatory responses. This work disclosed that A. muciniphila demonstrates a defensive influence against TNBS-induced enteritis in vivo, proposing it qualified as a unique therapeutic focusing on modulating IL-6, STAT3, or p-STAT3 in the treatment of colitis.

The trillions of commensal microorganisms living in the gut lumen profoundly influence the physiology and pathophysiology of the liver through a unique gut-liver axis. Disruptions in the gut microbial communities, arising from environmental and genetic factors, can lead to altered microbial metabolism, impaired intestinal barrier and translocation of microbial components to the liver. These alterations collaboratively contribute to the pathogenesis of liver disease, and their continuous impact throughout the disease course plays a critical role in hepatocarcinogenesis. Persistent inflammatory responses, metabolic rearrangements and suppressed immunosurveillance induced by microbial products underlie the pro-carcinogenic mechanisms of gut microbiota. Meanwhile, intrahepatic microbiota derived from the gut also emerges as a novel player in the development and progression of liver cancer. In this review, we first discuss the causes of gut dysbiosis in liver disease, and then specify the pivotal role of gut microbiota in the malignant progression from chronic liver diseases to hepatobiliary cancers. We also delve into the cellular and molecular interactions between microbes and liver cancer microenvironment, aiming to decipher the underlying mechanism for the malignant transition processes. At last, we summarize the current progress in the clinical implications of gut microbiota for liver cancer, shedding light on microbiota-based strategies for liver cancer prevention, diagnosis and therapy.

Hepatotoxicity is one of the biggest health challenges, particularly in the context of liver diseases, often aggravated by gut microbiota dysbiosis. The gut-liver axis has been regarded as a key idea in liver health. It indicates that changes in gut flora caused by various hepatotoxicants, including alcoholism, acetaminophen, carbon tetrachloride, and thioacetamide, can affect the balance of the gut's microflora, which may lead to increased dysbiosis and intestinal permeability. As a result, bacterial endotoxins would eventually enter the bloodstream and liver, causing hepatotoxicity and inducing inflammatory reactions. Many treatments, including liver transplantation and modern drugs, can be used to address these issues. However, because of the many side effects of these approaches, scientists and medical experts are still hoping for a therapeutic approach with fewer side effects and more positive results. Thus, probiotics have become well-known as an adjunctive strategy for managing, preventing, or reducing hepatotoxicity in treating liver injury. By altering the gut microbiota, probiotics offer a secure, non-invasive, and economical way to improve liver health in the treatment of hepatotoxicity. Through various mechanisms such as regulation of gut microbiota, reduction of pathogenic overgrowth, suppression of inflammatory mediators, modification of hepatic lipid metabolism, improvement in the performance of the epithelial barrier of the gut, antioxidative effects, and modulation of mucosal immunity, probiotics play their role in the treatment and prevention of hepatotoxicity. This review highlights the mechanistic effects of probiotics in environmental toxicants-induced hepatotoxicity and current findings on this therapeutic approach's experimental and clinical trials.

Patients afflicted with Wilson's disease (WD) may encounter hepatic and extraneous manifestations due to the progressive accumulation of copper in the liver and other subsequent organs. Copper-chelating agents, such as D-penicillamine (DPA), are commonly utilized in the medical treatment of copper overload in WD. Manipulating the composition of gut microbiota appropriately can enhance drug efficacy and safety. This study aims to investigate how targeted intervention on gut microbiota influences the effectiveness of copper removal in a WD model during DPA treatment. First, following a 4-week treatment of DPA, the liver copper concentration and gut microbial composition were assessed in the WD mice model to identify potential candidates for targeted regulation of gut microbiota. Second, after 8 weeks of manipulating the gut microbiota during DPA treatment, various parameters including blood liver function indicators, tissue copper load, hepatic histopathological features, and gut microbiota were investigated in WD mice. The findings demonstrated that the presence of Akkermansia significantly enhances the efficacy of DPA, leading to a more efficient elimination of copper from tissues and a greater improvement in liver injury, liver dysfunction, and gut dysbiosis. In contrast, Butyricimonas has an antagonistic effect. The results of gene function prediction analysis indicated that the altered gut microbial function by DPA and Akk is primarily linked to energy generation/utilization, amino acid, fatty acid, lipid, and nucleic acid metabolisms. To summarize, this study provides experimental evidence for the potential application of targeted regulation of gut microbiota in the adjunctive therapy of copper dysregulation disease.IMPORTANCECopper is an essential element in virtually all living organisms. Wilson's disease (WD) is a representative disorder caused by the disruption of copper homeostasis. Oral-chelating agents are the first-line treatment for copper-overloaded diseases, with D-penicillamine (DPA) being the prototypical drug. However, the efficacy and adverse effects of DPA remain challenging in its use for WD treatment. In our study, the supplementation of Akkermansia muciniphila (Akk), a key gut microbe, along with DPA was demonstrated to enhance copper removal, ameliorate liver injury and dysfunction, and restore gut dysbiosis in a mouse model of WD. These findings highlight the significant potential applications of targeted modulation of gut microbiota as "pharmacomicrobiomics" in adjunctive therapy for disorders involving copper dysregulation.

The gut microbiota (GM) is a highly dynamic ecology whose density and composition can be influenced by a wide range of internal and external factors. Thus, "How do GM, which can have commensal, pathological, and mutualistic relationships with us, affect human health?" has become the most popular research issue in recent years. Numerous studies have demonstrated that the trillions of microorganisms that inhabit the human body can alter host physiology in a variety of systems, such as metabolism, immunology, cardiovascular health, and neurons. The GM may have a role in the development of a number of clinical disorders by producing bioactive peptides, including neurotransmitters, short-chain fatty acids, branched-chain amino acids, intestinal hormones, and secondary bile acid conversion. These bioactive peptides enter the portal circulatory system through the gut-liver axis and play a role in the development of chronic liver diseases, cirrhosis, and hepatic encephalopathy. This procedure is still unclear and quite complex. In this study, we aim to discuss the contribution of GM to the development of liver diseases, its effects on the progression of existing chronic liver disease, and to address the basic mechanisms of the intestinal microbiota-liver axis in the light of recent publications that may inspire the future.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders primarily comprising two main conditions: ulcerative colitis and Crohn's disease. The gut microbiota's role in driving inflammation in IBD has garnered significant attention, yet the precise mechanisms through which the microbiota influences IBD pathogenesis remain largely unclear. Given the limited therapeutic options for IBD, alternative microbiota-targeted therapies-including prebiotics, probiotics, postbiotics, and symbiotics-have been proposed. While these approaches have shown promising results, microbiota modulation is still mainly considered an adjunct therapy to conventional treatments, with a demonstrated impact on patients' quality of life. Fecal microbiota transplantation (FMT), already approved for treating Clostridioides difficile infection, represents the first in a series of innovative microbiota-based therapies under investigation. Microbial biotherapeutics are emerging as personalized and cutting-edge tools for IBD management, encompassing next-generation probiotics, bacterial consortia, bacteriophages, engineered probiotics, direct metabolic pathway modulation, and nanotherapeutics. This review explores microbial modulation as a therapeutic strategy for IBDs, highlighting current approaches and examining promising tools under development to better understand their potential clinical applications in managing intestinal inflammatory disorders.

The gut microbiome of women can change after menopause, and during this phase women can also be more susceptible to vaginal dysbiosis. Recent studies have explored the probiotic potential of Lactobacillus crispatus BC4 and Lactobacillus gasseri BC9 against various pathogens and their use as co-starters in foods. However, their effects on the gut microbiota of post-menopausal women, who are more prone to dysbiosis, have not been examined. This study investigated the effects of predigested soy beverages (INFOGEST) containing BC4 and BC9 (encapsulated or not) on the composition and metabolic activity of the gut microbiota in post-menopausal women, using a fecal batch culture model. Parameters such as pH, gas, SCFAs, and microbiota composition (targeted qPCR and 16S rRNA gene sequencing) were assessed. The study, while highlighting a strong variability among donors, showed differences in gut microbiota response to the tested products. For instance, donor 2 showed a significant increase in bifidobacteria with BC4 + BC9 and E-BC9, while BC4 increased Ruminococcaceae in donors 1 and 3, and E-BC4 and E-BC9 enhanced Akkermansia in donor 1. BC4, E-BC4, E-BC9, and E-BC4 + BC9 significantly impacted metabolic activity, as measured by SCFAs, compared to other samples. However, no significant differences in gas production were observed.

Colorectal liver metastasis (CRLM) represents a major therapeutic challenge in colorectal cancer (CRC), with complex interactions between the gut microbiota and the liver tumor microenvironment (TME) playing a crucial role in disease progression via the gut-liver axis. The gut barrier serves as a gatekeeper, regulating microbial translocation, which influences liver colonization and metastasis. Through the gut-liver axis, the microbiota actively shapes the TME, where specific microbial species and their metabolites exert dual roles in immune modulation. The immunologically "cold" nature of the liver, combined with the influence of the gut microbiota on liver immunity, complicates effective immunotherapy. However, microbiota-targeted interventions present promising strategies to enhance immunotherapy outcomes by modulating the gut-liver axis. Overall, this review highlights the emerging evidence on the role of the gut microbiota in CRLM and provides insights into the molecular mechanisms driving the dynamic interactions within the gut-liver axis.

Symbiotic microbiota plays a crucial role in the education, development, and maintenance of the host immune system, significantly contributing to overall health. Through the gut-liver axis, the gut microbiota and liver have a bidirectional relationship that is becoming increasingly evident as more research highlights the translocation of the gut microbiota and its metabolites. The focus of this narrative review is to examine and discuss the importance of the gut-liver axis and the enterohepatic barrier in maintaining overall health. Additionally, we emphasize the crucial role of the gut microbiome in liver diseases and explore potential therapeutic strategies for liver diseases by manipulating the microbiota.

This study aims to compare intestinal mucosal damage and the expression levels of occludin, zonula occludens-1 (ZO-1), vascular endothelial (VE)-cadherin, β-catenin, and plasmalemma vesicle-associated protein (PLVAP) in the gut vascular barrier (GVB) among people living with HIV (PLWH), asymptomatic PLWH, and healthy volunteers (non-PLWH). Three groups were selected for the study: PLWH, asymptomatic PLWH, and healthy volunteers. Colonic mucosal tissue samples were collected via colonoscopy from all participants. Histological examination of the colonic mucosa was conducted using hematoxylin and eosin staining. The expression levels of occludin, ZO-1, VE-cadherin, β-catenin, and PLVAP were assessed using RT-qPCR, immunohistochemistry, and western blot analyses. Pathological scores of colonic mucosa in PLWH and asymptomatic PLWH were significantly higher than those in non-PLWH (p < .001 and p = .0056, respectively). CD4+ T cell counts in asymptomatic PLWH and non-PLWH were significantly higher than in PLWH (p < 0.05). The CD4+/CD8+ T cell ratio in non-PLWH significantly exceeded those in PLWH and asymptomatic PLWH (p < .05). Analysis of protein and mRNA expression revealed: (1) no statistically significant differences in PLVAP-mRNA expression across all groups (p > .05); (2) higher PLVAP protein levels in PLWH compared with asymptomatic PLWH and non-PLWH (p < .05), with no significant differences between asymptomatic PLWH and non-PLWH (p = .632); (3) significantly higher PLVAP expression in the colonic mucosa of PLWH and asymptomatic PLWH compared with non-PLWH (p = .034 and p = .011, respectively), with no significant differences between PLWH and asymptomatic PLWH (p > .999). ZO-1 expression was significantly lower in PLWH than in non-PLWH (p = .012), with no notable differences between asymptomatic PLWH and other groups. PLWH, compared with healthy controls, exhibit significant inflammatory changes in the intestinal mucosa. PLVAP expression serves as a potential indicator to assess the extent of GVB damage and disease progression in PLWH.

Patients with Alcohol-related Liver Disease (ALD) are advised increased protein supplementation. These nutrients are also available to gut microbiota. We evaluated the effects of protein supplementation from two sources, soya (veg) or egg, on gut microbiota modulation and ALD remission.

ALD was induced in mice using the Lieber-DeCarli diet and incremental ethanol + thioacetamide (150 mg/kg body-weight,i.p.) twice-a-week. After 8wks, mice were fed standard (std.), egg (ovalbumin) or veg diet (20 % increase protein) for 7days. Biochemical parameters, hepatic proteome and gut microbiota composition were analyzed and correlated to capture liver and intestinal recovery.

Veg-diet decreased hepatic steatosis and fibrosis compared with std diet (83.3 %, p = 0.001 and 75 %, p = 0.01, respectively) or egg-diet (66.6 %, p = 0.03 and 25 %, p = 0.04, respectively). ALT and AST levels reduced by 40 % (p = 0.04) and 27.3 % (p = 0.04), respectively in veg diet compared to egg diet. Veg-diet increased intestinal claudin-3 (61 %, p = 0.02) and occludin (80 %, p = 0.001) compared to egg-diet. Plasma endotoxin levels in veg were reduced by 64 % and 32 % compared to std. (p = 0.04) or egg (p = 0.06). Veg-diet increased beneficial taxa, Lachnospiraceae UCG-006 (8.06-folds, p = 1.64E-25), Prevotellaceae NK3B31 (9.96-folds, p = 1.58E-36), Kurthia (8.11-folds, p = 3.98E-16) and Akkermansia (5.9-folds, p = 5.01E-75), while decreasing pathogenic Roseburia (-3.28-folds, p = 1.60E-06), Klebsiella (-5.7-folds, p = 1.55E-06), Staphylococcus (-5.3-folds, p = 1.62E-12). Hepatic proteome showed an increase in pyruvate, cysteine, methionine metabolism, bile acid biosynthesis, and glycolysis.

Alteration in protein alone can affect variable outcomes in ALD, with protein from vegetable sources resulting in enhanced improvement in the gut-liver axis. Vegetable protein-supplemented diet enhances fatty acid beta oxidation and energy metabolism accompanied by improvement in gut-dysbiosis and ALD associated hepatic injury.

The liver regenerative capacity is crucial for patients with end-stage liver disease following partial hepatectomy (PHx). The specific bacteria and mechanisms regulating liver regeneration post-PHx remain unclear. This study demonstrated dynamic changes in the abundance of Parabacteroides distasonis (P. distasonis) post-PHx, correlating with hepatocyte proliferation. Treatment with live P. distasonis significantly promoted hepatocyte proliferation and liver regeneration after PHx. Targeted metabolomics revealed a significant positive correlation between P. distasonis and β-hydroxybutyric acid (BHB), as well as hyodeoxycholic acid and 3-hydroxyphenylacetic acid in the gut after PHx. Notably, treatment with BHB, but not hyodeoxycholic acid or 3-hydroxyphenylacetic acid, significantly promoted hepatocyte proliferation and liver regeneration in mice after PHx. Moreover, STAT3 inhibitor Stattic attenuated the promotive effects of BHB on cell proliferation and liver regeneration both in vitro and in vivo. Mechanistically, P. distasonis upregulated the expression of fatty acid oxidation-related proteins, and increased BHB levels in the liver, and then BHB activated the STAT3 signaling pathway to promote liver regeneration. This study, for the first time, identifies the involvement of P. distasonis and its associated metabolite BHB in promoting liver regeneration after PHx, providing new insights for considering P. distasonis and BHB as potential strategies for promoting hepatic regeneration.

Over the last four decades, clinical research and experimental studies have established that lipopolysaccharide (LPS)-a component of the outer membrane of gram-negative bacteria-is a potent hepatotoxic molecule in humans and animals. Alcohol abuse is commonly associated with LPS endotoxemia. This review highlights LPS molecular structures and modes of release from bacteria, plasma LPS concentrations, induction of microbiota dysbiosis, disruption of gut epithelial barrier, and translocation of LPS into the portal circulation impacting the pathophysiology of hepatic cells via the gut-liver axis. We describe and illustrate the portal vein circulation and its distributaries draining the gastrointestinal tract. We also elaborate on the gut-liver axis coupled with enterohepatic circulation that represents a bidirectional communication between the gut and liver. The review also updates the data on how circulating LPS is cleared in a coordinated effort between Kupffer cells, hepatocytes, and liver sinusoidal endothelial cells. Significantly, the article reviews and updates the modes/mechanisms of action by which LPS mediates the diverse pathophysiology of Kupffer cells, hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells primarily in association with alcohol consumption. Specifically, we review the intricate linkages between ethanol, microbiota dysbiosis, LPS production, gut-liver axis, and pathophysiology of various hepatic cells. The maintenance of the gut barrier structural and functional integrity and microbiome homeostasis is essential in mitigating alcoholic liver disease and improving liver health.

Alcohol abuse-triggered alcohol-related liver disease (ALD) has become as a global public health concern that substantially affects the well-being and clinical status of patients. Although modern medicine provides various treatments for ALD, their effectiveness is limited and can lead to adverse side effects. Probiotics have been employed to prevent, alleviate, and even treat ALD, with promising results. However, few comprehensive reviews are available on how they mitigate ALD by targeting the gut-liver axis. This review systematically clarifies the specific mediators of the gut-liver axis in healthy states. It also describes the alterations observed in ALD. Furthermore, this review thoroughly summarizes the underlying mechanisms through which probiotics act on the gut-liver axis to relieve ALD. It also discusses the current status and challenges faced in clinical research applications. Finally, we discuss the challenges and future prospects of using probiotics to treat ALD. This review improves our understanding of ALD and supports the development and application of probiotics that target the gut-liver axis for therapeutic use.

Alcohol-associated liver disease (ALD) is a major clinical issue characterized by progressive stages, including hepatic steatosis, liver fibrosis, cirrhosis, and HCC. Patients with long-term chronic alcoholism often present with gut microbiota dysbiosis and reduced plasma levels of vitamin B6. This study aimed to verify that gut microbiota disruption in ALD significantly contributes to reduced in vivo production of vitamin B6 and to investigate the role of this reduction in the pathogenesis of ALD.

The ALD was investigated utilizing the Gao-binge mouse model. Fecal microbial composition was analyzed in pair-fed mice and ALD mice to identify alcohol-induced functional changes in the microbiota. Additionally, liver protein expression profiles and liver and plasma metabolomic profiles were characterized to elucidate the role of vitamin B6 in ALD pathogenesis through integrated proteomic and metabolomic analyses. The findings were further validated using animal models and clinical patient samples.

Alcohol consumption disrupted the gut microbiota in the mice, impairing the vitamin B6 synthesis by intestinal microorganisms. Vitamin B6 deficiency aggravated the disorder of amino acid metabolism in the liver and inhibited ornithine aminotransferase expression, thereby worsening oxidative stress damage. In patients with ALD, significant disturbances of gut microbiota were observed, along with decreased intestinal vitamin B6 levels, which were negatively correlated with serum biochemical markers.

The imbalance of gut microbiota in ALD mice reduces vitamin B6 synthesis, which affects amino acid metabolism and glutathione synthesis in the liver, thereby exacerbating ALD. These findings suggest that vitamin B6 may play a critical protective role in ALD progression by regulating amino acid metabolism.

Secretory IgA (SIgA) is the first line of defense in protecting the intestinal epithelium against pathogenic bacteria, regulating gut microbiota composition, and maintaining intestinal homeostasis. Early weaning strategies may disrupt SIgA levels in piglet intestines, causing a decline in immune response and early weaning stress. However, the specific microbial mechanisms modulating SIgA in early-weaned piglets are not well understood.

We hypothesized that Akkermansia muciniphila increases intestinal SIgA production in the early-weaned piglets.

Fecal SIgA levels, SIgA-coated bacteria abundance, and fecal metagenomes were compared between 6 Huanjiang miniature (HM) and 6 Duroc×Landrace×Yorkshire (DLY) early-weaned piglets to identify bacterial species involved in SIgA modulation. Four bacterial species were investigated using 5 groups (Control, A. muciniphila, L. amylovorus, L. crispatus, and L. acidophilus) of male specific pathogen-free C57BL/6J mice, weaned 3 wk postbirth (n = 8/group). Subsequently, 10-d-old Landrace×Yorkshire (LY) piglets were randomly assigned to 3 groups (Control, 109A. muciniphila, and 108A. muciniphila) (n = 10/group) to evaluate the effect of orally administered A. muciniphila on intestinal SIgA production and microbial composition.

HM early-weaned piglets showed significantly higher SIgA levels [7.59 μg/mg, 95% confidence interval (CI): 3.2, 12, P = 0.002] and SIgA-coated bacteria abundance (8.64%, 95% CI: 3.2, 14, P = 0.014) than DLY piglets. In the mouse model, the administration of A. muciniphila significantly increased SIgA levels (3.50 μg/mg, 95% CI: 0.59, 6.4, P = 0.018), SIgA-coated bacteria abundance (9.06%, 95% CI: 4, 14, P = 0.018), and IgA+ plasma cell counts (6.1%, 95% CI: 4.3, 8, P = 0.005). In the pig experiments, the oral administration of A. muciniphila to LY piglets significantly enhanced intestinal SIgA concentrations (4.22 μg/mg, 95% CI: 0.37, 8.5, P = 0.034) and altered the SIgA-coated bacterial landscape.

Early intervention with A. muciniphila in nursing piglets can increases intestinal SIgA production and alter the reactivity toward commensal bacteria upon early weaning.

Severe liver fibrosis may be accompanied by intestinal barrier damage, such as bacterial peritonitis, suggesting that the role of the gut-liver axis is nonnegligible. Dachengqi decoction (DCQD) was reported to improve bowel movements, but whether DCQD was effective for intestinal damage caused by liver fibrosis remained unclear.

To investigate the role of DCQD in liver fibrosis-related gut vascular barrier (GVB) damage in mice.

DCQD was verified to reduce the imbalance of the intestinal vascular barrier and restore intestinal homeostasis to prove that DCQD acts through the gut-liver axis.

Three graded doses of DCQD were gavaged into the CCL4-induced mice for 12 weeks to evaluate the resistance to liver and intestinal damage. Immunoblotting and primary flow cytometry were used to assess organ damage; PV-1 to indicate gut vascular barrier damage; serum endotoxin, fecal SCFAs, and liver microbiota translocation to examine the gut-liver axis's crosstalk. Network pharmacology and RNA sequencing were used to analyze and verify the signaling pathway of DCQD.

DCQD significantly ameliorated fibrosis and inflammatory response in the CCL4-induced mice, alleviated gut leakage, downregulated PV-1, relieved liver enterobacterial translocation, restored intestinal homeostasis, and reduced infiltration of myeloid cells in the lamina propria. Network pharmacology and RNA sequencing results indicated that DCQD exerted anti-fibrotic and anti-inflammatory effects in the liver through inhibition of the ESR1/NF-κB/TNFα pathway and maintained GVB homeostasis through the FUT2/Wnt/β-Catenin pathway.

DCQD broke the closed-loop damage of the gut-liver axis to improve GVB injury in mice with liver fibrosis.

The global incidence and mortality rates of alcohol-related liver disease are on the rise, reflecting a growing health concern worldwide. Alcohol-related liver disease develops due to a complex interplay of multiple reasons, including oxidative stress generated during the metabolism of ethanol, immune response activated by immunogenic substances, and subsequent inflammatory processes. Recent research highlights the gut microbiota's significant role in the progression of alcohol-related liver disease. In patients with alcohol-related liver disease, the relative abundance of pathogenic bacteria, including Enterococcus faecalis, increases and is positively correlated with the level of severity exhibited by alcohol-related liver disease. Supplement probiotics like Lactobacillus, as well as Bifidobacterium, have been found to alleviate alcohol-related liver disease. The gut microbiota is speculated to trigger specific signaling pathways, influence metabolite profiles, and modulate immune responses in the gut and liver. This research aimed to investigate the role of gut microorganisms in the onset and advancement of alcohol-related liver disease, as well as to uncover the underlying mechanisms by which the gut microbiota may contribute to its development. This review outlines current treatments for reversing gut dysbiosis, including probiotics, fecal microbiota transplantation, and targeted phage therapy. Particularly, targeted therapy will be a vital aspect of future alcohol-related liver disease treatment. It is to be hoped that this article will prove beneficial for the treatment of alcohol-related liver disease.

The mechanism(s) underlying gut microbial metabolite (GMM) contribution towards alcohol-mediated cardiovascular disease (CVD) is unknown. Herein we observe elevation in circulating phenylacetylglutamine (PAGln), a known CVD-associated GMM, in individuals living with alcohol use disorder. In a male murine binge-on-chronic alcohol model, we confirm gut microbial reorganization, elevation in PAGln levels, and the presence of cardiovascular pathophysiology. Fecal microbiota transplantation from pair-/alcohol-fed mice into naïve male mice demonstrates the transmissibility of PAGln production and the CVD phenotype. Independent of alcohol exposure, pharmacological-mediated increases in PAGln elicits direct cardiac and vascular dysfunction. PAGln induced hypercontractility and altered calcium cycling in isolated cardiomyocytes providing evidence of improper relaxation which corresponds to elevated filling pressures observed in vivo. Furthermore, PAGln directly induces vascular endothelial cell activation through induction of oxidative stress leading to endothelial cell dysfunction. We thus reveal that the alcohol-induced microbial reorganization and resultant GMM elevation, specifically PAGln, directly contributes to CVD.

Chicken yolk immunoglobulin (IgY) is a natural immunologically active antibody extracted from egg yolk and can be used as a natural dietary supplement for the treatment of inflammation and damage to the intestines. In our study, IgY was embedded in a double emulsion (W/O/W; DE) to explore the therapeutic effect of the embedded IgY on Lipopolysaccharide (LPS)-induced jejunal injury in mice. The results showed that W/O/W-embedded IgY as a dietary supplement (IgY + DE) attenuated LPS-induced damage to mouse small intestinal structures and protected the integrity of the jejunal mucosal barrier. IgY + DE increased the amount of related transcription factors (Math1, Spdef, Elf3, and Klf4) and promoted thrush cell differentiation. IgY + DE ameliorated LPS-induced reduction in mucin quantity and markers. It promoted the expression of Muc1 and Muc2 and increased the mRNA expression levels of Muc1, Muc2, Muc3, Muc4, Muc13, and Agr2 (p < 0.05). IgY + DE increased the expression of several glycosyltransferases involved in mucin glycosylation. IgY + DE also neutralized the LPS attack on the expression of jejunal inflammatory factors IL-1β, IL-6, IL-4, and TNF-α. In conclusion, the IgY-embedded double emulsion can be used as a dietary supplement for immunotherapy to prevent LPS-induced jejunal injury in mice.

Metabolic disease is a worldwide epidemic that has become a public health problem. Gut microbiota is considered to be one of the important factors that maintain human health by regulating host metabolism. As an abundant bacterium in the host gut, A. muciniphila regulates metabolic and immune functions, and protects gut health. Multiple studies have indicated that alterations in the abundance of A. muciniphila are associated with various diseases, including intestinal inflammatory diseases, obesity, type 2 diabetes mellitus, and even parasitic diseases. Beneficial effects were observed not only in live A. muciniphila, but also in pasteurized A. muciniphila, A. muciniphila-derived extracellular vesicles, outer membrane, and secreted proteins. Although numerous studies have only proven the simple correlation between multiple diseases and A. muciniphila, an increasing number of studies in animal models and preclinical models have demonstrated that the beneficial impacts shifted from correlations to in-depth mechanisms. In this review, we provide a comprehensive view of the beneficial effects of A. muciniphila on different diseases and summarize the potential mechanisms of action of A. muciniphila in the treatment of diseases. We provide a comprehensive understanding of A. muciniphila for improving host health and discuss the perspectives of A. muciniphila in the future studies.