The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance, which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.

Atherosclerosis is the primary cause of cardiovascular and cerebrovascular diseases. However, current anti-atherosclerosis drugs have shown conflicting therapeutic outcomes, thereby spurring the search for novel and effective treatments. Recent research indicates the crucial involvement of oral and gastrointestinal microbiota in atherosclerosis. While gut microbiota metabolites, such as choline derivatives, have been extensively studied and reviewed, emerging evidence suggests that bacterial extracellular vesicles (BEVs), which are membrane-derived lipid bilayers secreted by bacteria, also play a significant role in this process. However, the role of BEVs in host-microbiota interactions remains insufficiently explored. This review aims to elucidate the complex communication mediated by BEVs along the gut-heart axis. In this review, we summarize current knowledge on BEVs, with a specific focus on how pathogen-derived BEVs contribute to the promotion of atherosclerosis, as well as how BEVs from gut symbionts and probiotics may mitigate its progression. We also explore the potential and challenges associated with engineered BEVs in the prevention and treatment of atherosclerosis. Finally, we discuss the benefits and challenges of using BEVs in atherosclerosis diagnosis and treatment, and propose future research directions to address these issues.

Genetic predispositions can shape the gut microbiome, which in turn modulates host gene expression and impacts host physiology. The complex interplay between host genetics and the gut microbiome likely contributes to the development of neuropsychiatric disorders, yet the mechanisms behind these interactions remain largely unexplored. In this study, we investigated the gut microbiota in Negr1 knockout (KO) mice, which exhibit anxiety- and depression-like behaviors, as NEGR1 (neuronal growth regulator 1) is a cell adhesion molecule linked to neuronal development and neuropsychiatric disorders. Our findings show significant early-life alterations in the gut microbiota composition of Negr1 KO mice, most notably a marked reduction in Akkermansia spp. along with reduced dendritic arborization and spine density in the nucleus accumbens (NAc) and the dentate gyrus (DG) of the hippocampus. Remarkably, daily administration of an Akkermansia strain isolated from wild-type mice reversed the neuronal structural abnormalities and ameliorated anxiety- and depression-like behaviors in Negr1 KO mice. Transcriptomic profiling revealed upregulation of mitochondrial genome-encoded genes in the NAc and hippocampus of Negr1 KO mice, along with a predisposition toward a pro-inflammatory state in the colon of Negr1 KO mice. The Akkermansia supplementation downregulated these mitochondrial genes in the NAc and hippocampus and upregulated genes involved in T cell activation and immune homeostasis in the colon. These findings demonstrate a novel gene-microbiome interaction in the pathophysiology of Negr1 KO mice, positioning Akkermansia spp. as a key mediator that improves neuronal atrophy and modulates anxiety- and depression-like behaviors. Our study provides compelling evidence for bidirectional interactions between host genetics and the gut microbiome in modulating neuropsychiatric phenotypes, offering new insights for addressing genetically influenced mental disorders.

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

Dysbiosis of gut microbiota is well established in coronavirus disease 2019 (COVID-19). While studies have attempted to establish a link between the gut commensal Akkermansia muciniphila (A. muciniphila) and COVID-19, the findings have been inconsistent and sometimes controversial. The intestinal microbial abundance information of COVID-19 patients was acquired and analysed from GMrepo database. Subsequently, A. muciniphila's metabolites, target-genes, and metabolite-target relationships was extracted from GutMGene database. Lastly, coronascape module in Metascape database is used for gene annotation and enrichment analysis in various host cells and tissues after SARS-CoV-2 infection. The results indicated that, in comparison to healthy people, A. muciniphila was significantly elevated in COVID-19 patients. This bacterium was found to be associated with heightened expression of IL-10, TLR2, TLR4, CLGN, CLDN4, TJP2, and TJP3, while concurrently experiencing a reduction in the expression of IL-12A and IL-12B in humans. The regulatory genes of A. muciniphila primarily enhance responses to viruses and cytokines, positively regulate cell migration, and control epithelial cell proliferation. Our study revealed a significant increase in the gut commensal A. muciniphila in COVID-19 patients. This bacterium can modulate host immune responses and may also serve as a probiotic with antiviral properties.

The most prevalent non-motor symptoms in individuals with Parkinson's disease (PD) such as constipation and bloating that significantly impact patients' quality of life. However, the pathophysiological mechanisms underlying these symptoms remain unclear. PD model with typical and stable symptoms was induced by individualized dosing of MPTP with Kurlan score increased to 10 or above and remained steady for three months or more. TH-positive neurons in the injured substantia nigra (SN) of the brain of PD monkeys showed up to 83.95 % reduction. Histopathological examination indicated severe damage to both enteric nerve and TH neurons, along with significant disruption of mucosal structure, intestinal barrier integrity and motility in PD monkeys across all four intestinal segments, including the duodenum, ileum, transverse colon, and rectum. The association between dopaminergic neuronal deficits in SN and these above mentioned intestinal disorders, that might be attributed to the abnormal regulation of gastrointestinal function due to the breakdown of the integrity of the nigrostriatal dopaminergic nervous system. Therefore, the abnormal alterations found in gut of PD monkeys and its triggered possible secondary pathophysiological cascade reactions might be a potential mechanism underlying the presence of constipation and other intestinal symptoms observed in PD patients. These findings in this study provide a valuable scientific basis for investigating the pathogenesis of gastrointestinal symptoms in PD patients and potential therapeutic approaches. (The graphical abstract is by Figdraw).

Akkermansia muciniphila (A. muciniphila), a Gram-negative anaerobic mucus-layer-degrading bacterium found in the intestinal mucosa, exhibits potential as a probiotic, showing promise in mitigating autoimmune and chronic inflammatory diseases. This study aims to investigate whether A. muciniphila supplementation might confer protection against type 1 diabetes (T1D) and to elucidate the immunological pathways through which it exerts its beneficial effects.

Non-obese diabetic (NOD) mice and streptozotocin (STZ)-induced type 1 diabetes (T1D) models were used to evaluate the protective effects of A. muciniphila during T1D course. Body weight, blood glucose levels, and T1D incidence were monitored. Immune responses in the pancreas, pancreatic (PLN) and cecal lymph nodes (CLN) and bone marrow-derived dendritic cells (BMDC) were evaluated by flow cytometry and ELISA.

Viable A. muciniphila supplementation conferred protection against T1D onset in STZ-induced T1D and NOD mouse models. T1D modulation by A. muciniphila in the STZ model was independent of the gut microbiota, and it was associated with increased tolerogenic type-2 dendritic cells (SIRP-α+CD11b+CD103+) and regulatory T (Treg) cells in PLN and pancreas. BMDC differentiated in the presence of A. muciniphila exhibited a tolerogenic profile and induced Treg cell generation in vitro. A. muciniphila-induced protection in T1D outcome was abrogated in FOXP3-DTR mice depleted of Treg cells, indicating that its mechanism of action is dependent on the CD4+Foxp3+ Treg cells.

A. muciniphila supplementation attenuates T1D development in mice by modulating the tolerogenic immune response and is a promising new therapeutic tool for this autoimmune disease.

Iron homeostatic is closely linked to the development of metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanisms remain poorly understood. HFE knockout (KO) mice were used to generate mild iron-overload models. MASH was induced by feeding mice a methionine- and choline-deficient (MCD) diet for 4 weeks. Iron overload significantly exacerbated the pathologies of MCD-induced MASH, including liver injury, hepatic lipid accumulation, inflammation, and fibrosis. Additionally, iron overload reshaped the composition of gut microbiota, and fecal microbiota transplantation assay proved that gut microbiota from iron-overload mice contributed to hepatic lipid accumulation in control mice. Furthermore, iron overload-induced dysbacteriosis altered the metabolite profiles, reducing short-chain fatty acid levels and increasing lipopolysaccharide (LPS) levels. Notably, elevated LPS levels upregulated the expression of aldo-keto reductase family 1 member B8 (Akr1b8), which accelerated lipid accumulation and inflammation in hepatocytes. Above results indicated that iron overload promoted MASH progression through the microbiota-gut-liver axis, mediated by LPS-induced activation of Akr1b8. These findings highlight the critical role of iron homeostasis and gut microbiota in MASH pathogenesis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disease that affects the health of approximately one-third of the world's population. It is the primary cause of end-stage liver disease, liver malignancy, and liver transplantation, resulting in a great medical burden. No medications have yet been approved by the US Food and Drug Administration for treating MASLD without liver inflammation or scarring. Therefore, the development of specific drugs to treat MASLD remains a key task in the ongoing research objective. Extracellular vesicles (EVs) play an important role in the communication between organs, tissues, and cells. Recent studies have found that intestinal microbiota are closely related to the pathogenesis and progression of MASLD. EVs produced by bacteria (BEVs) play an indispensable role in this process. Thus, this study provides a new direction for MASLD treatment. However, the mechanism by which BEVs affect MASLD remains unclear. Therefore, this study investigated the influence and function of intestinal microbiota in MASLD. Additionally, we focus on the research progress of BEVs in recent years and explain the relationship between BEVs and MASLD from the perspectives of glucose and lipid metabolism, immune responses, and intestinal homeostasis. Finally, we summarized the potential therapeutic value of BEVs and EVs from other sources, such as adipocytes, immunocytes, stem cells, and plants.

In this work the relationship between Schistosoma mansoni (Sm) and the induction and progression of colorectal cancer (CRC) is examined. Various clinical studies reviewed here yield inconsistent results, with some reporting no association between Sm infection and CRC and others suggesting a probable to strong association. Here we propose a number of plausible mechanisms whereby Sm infection might contribute to CRC induction and/or progression. These factors are (1) chronic inflammation, (2) exposure to parasite linked antigens and genotoxic products, especially soluble egg antigens (SEAs) and (3) alteration of the intestinal microbiota. These factors probably predispose humans towards CRC and can help in CRC progression however only widespread epidemiological, clinical and pathological studies can firmly establish their role or a complete lack of it.

The gut microbiota plays an essential role in host health by regulating gut barrier function and immune system homeostasis. However, research into the physiological and immunological functions of the gut microbiota using In Vitro models that mimic the immune environment of the gut remains limited. Herein, we developed the Gut Microbial Immune & Epithelial Cellular System (GutMICS), a device for coculturing anaerobic gut microbes with host cells, including intestinal epithelial and immune cells. Coculturing Akkermansia muciniphila with GutMICS sustained host cell viability and microbial activity for 72 h. In a lipopolysaccharide- and tumor necrosis factor-α (TNF-α)-induced inflammation model, A. muciniphila enhanced the intestinal barrier function, prevented barrier disruption, reduced pro-inflammatory cytokines (interleukin (IL)-6, TNF-α), and increased anti-inflammatory cytokines (IL-10). Additionally, A. muciniphila protected against Salmonella Typhimurium infection by reducing adhesion and invasion, thereby preventing pathogen-induced cell death. This study used GutMICS to characterize the anti-inflammatory properties of A. muciniphila and its ability to inhibit pathogen infection, demonstrating that GutMICS is a valuable tool for assessing the effects of anaerobic gut microbes on host cells. The ability of the system to simulate various inflammatory environments is expected to have broad applications in the study of host-microbe interactions.

Probiotics such as Lactobacillus and Bifidobacterium spp. have been shown to be critical for maintaining host homeostasis. In recent years, key compounds of postbiotics derived from probiotic metabolism and cellular secretion have been identified for their role in maintaining organ immunity and regulating intestinal inflammation. In particular, probiotic-derived extracellular vesicles (PEVs) can act as postbiotics, maintaining almost the same functional activity as probiotics. They also have strong biocompatibility and loading capacity to carry exogenous or parental active molecules to reach distal organs to play their roles. This provides a new direction for understanding the intrinsic microbiota-host communication mechanism. However, most current studies on PEVs are limited to their functional effects/benefits, and their specific physicochemical properties, composition, intrinsic mechanisms for maintaining host homeostasis, and possible threats remain to be explored. Here, we review and summarize the unique physicochemical properties of PEVs and their bioactivities and mechanisms in mediating microbiota-host communication, and elucidate the limitations of the current research on PEVs and their potential application as postbiotics.

Bacterial extracellular vesicles (EVs) are produced by both Gram-negative and Gram-positive bacteria. These EVs are composed of lipid bilayers and various components derived from parent bacteria, including proteins, lipids, and nucleic acids. Previous studies have indicated the significant role of bacterial EVs in interactions between bacteria and between bacteria and hosts. Moreover, bacterial EVs are emerging as promising delivery vectors capable of transporting drug molecules over long distances to tissues. Therefore, understanding the biogenesis of bacterial EVs and how to regulate their production holds great importance for expanding their applications. In this review, we provide an overview of bacterial EVs, especially focusing on the distinct mechanisms of EVs biogenesis and the regulation of EVs production in both Gram-negative and Gram-positive bacteria. Additionally, we discuss various methods for cargos loading into bacteria EVs, as well as their diverse applications in vaccines, cancer therapy, and drug delivery. We anticipate that this review will advance the field of bacterial EVs, contributing to both the enhancement of existing applications and the emergence of novel applications.

The main role of bacterial extracellular vesicles (BEVs) has been associated with various processes such as intercellular communication and host-pathogen interactions. This comprehensive review explores the multifaceted functions of BEVs across different biological domains, emphasizing their dual nature as contributors to disease and potential vehicles for therapeutic intervention. We examine the intricate interactions of BEVs within bacterial communities and between bacteria and hosts, their involvement in disease development through cargo delivery mechanisms, and their beneficial impact on microbial ecology. The review also highlights BEVs' applications in biomedical field, where they are revolutionizing vaccine development, targeted drug delivery, and cancer therapy. By utilizing the inherent properties of BEVs for controlled drug release, targeted antigen delivery, and immune modulation, they offer a promising frontier in precision medicine. In addition, the diagnostic potential of BEVs is explored through their utility as biomarkers, providing valuable insights into disease states and treatment efficacy. Looking forward, this review underscores the challenges and opportunities in translating BEV research to clinical practice, promoting the need of standardized methods in BEV characterization and scaling up production. The diverse abilities of BEVs, ranging from contributing to pathogen virulence to driving therapeutic innovation, highlight their potential as a cornerstone in the future of biomedical advancements. STATEMENT OF SIGNIFICANCE: Bacterial extracellular vesicles (BEVs) are emerging as pivotal players in both pathogenesis and therapeutic innovation. This review explores their dual nature as agents of disease and as promising biomaterials for biomedical applications, and provides a comprehensive survey on their involvement in disease mechanisms and microbial ecology, and their potential in biomedical applications such as vaccine development, targeted drug delivery, cancer therapy, and diagnosis. It highlights the complex interactions of BEVs within bacterial communities and between bacteria and hosts. This review also addresses current advancements, challenges, and opportunities in translating BEV research into clinical practice. The insights presented here position BEVs as a cornerstone in the future of biomedical advancements, advocating for standardized methods in BEV characterization and scalable production techniques.

Inflammatory bowel disease (IBD) is an inflammatory disease of the intestine whose primary pathological presentation is the destruction of the intestinal epithelium. The intestinal epithelium, located between the lumen and lamina propria, transmits luminal microbial signals to the immune cells in the lamina propria, which also modulate the intestinal epithelium. In IBD patients, intestinal epithelial cells (IECs) die dysfunction and the mucosal barrier is disrupted, leading to the recruitment of immune cells and the release of cytokines. In this review, we describe the structure and functions of the intestinal epithelium and mucosal barrier in the physiological state and under IBD conditions, as well as the patterns of epithelial cell death and how immune cells modulate the intestinal epithelium providing a reference for clinical research and drug development of IBD. In addition, according to the targeting of epithelial apoptosis and necroptotic pathways and the regulation of immune cells, we summarized some new methods for the treatment of IBD, such as necroptosis inhibitors, microbiome regulation, which provide potential ideas for the treatment of IBD. This review also describes the potential for integrating AI-driven approaches into innovation in IBD treatments.

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.

Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a major global health concern that affects about a quarter of the global population. Recently, host-gut microbiota metabolic interactions have emerged as key mechanistic pathways in MASH development. Oryzanol (ORY), a rice bran bioactive compound, exhibits antioxidant, anti-inflammatory, hypolipidemic, and hypoglycemic properties. Here, we investigated the potential of ORY in alleviating MASH and its association with gut microbiota and MASH progression. Male C57BL/6J mice were fed normal chow diet or methionine-choline-deficient diet and received ORY supplementation at 300 mg/kg/day via gavage for 4 wk. Liver injury, inflammation, lipid accumulation, and TLR4/NF-κB signaling protein levels were assessed. In addition, changes in gut microbiota diversity and abundance across groups were evaluated using 16S rDNA sequencing. Our results demonstrated that ORY significantly reduced lipid accumulation and liver enzymes, ameliorated liver and ileum damage, and restored intestinal barrier function in MASH mice. Furthermore, ORY decreased plasma lipopolysaccharide levels, and inflammatory cytokines and downregulated TLR4, MyD88, and NF-κB protein levels in the liver. ORY enhanced tight junction protein level (ZO-1, occludin) in the gut. Microbial analysis revealed that ORY positively impacted Firmicutes and Bacteroidetes abundance, promoted beneficial bacteria like Lactobacillus and Lachnospiraceae_NK4A136_group, and inhibited harmful bacteria such as Mucispirillum, Bacteroides, and Colidextribacter. Notably, ORY increased Akkermansia abundance, potentially modulating metabolic and inflammatory pathways. ORY exerted restorative and reversible effects on the pathophysiological damage within the gut-liver axis in MASH mice. The therapeutic mechanism may be related to the modulation of the gut microbiota and TLR4/NF-κB signaling pathway.NEW & NOTEWORTHY This study demonstrates that oryzanol (ORY), a bioactive rice bran compound, alleviates metabolic dysfunction-associated steatohepatitis (MASH) in mice by reducing lipid accumulation and inflammation. ORY beneficial effects are associated to the modulation of gut microbiota, enhancing gut barrier integrity, and lowering endotoxemia and TLR4/NF-κB signaling pathway. These findings suggest ORY potential in MASH prevention and treatment, highlighting its influence on gut-liver axis dynamics.

Probiotics have been established to exert a positive impact on the treatment of various diseases. Indeed, these active microorganisms have garnered significant attention in recent years for their potential to prevent and treat illnesses. Their beneficial effects have been hypothesized to be linked to their released extracellular vesicles. These nanoscale structures, secreted during the growth and metabolism of probiotics, possess favorable biocompatibility and targeting properties, thereby promoting intercellular material transport and signaling. This article aimed to review the bioactive components and functions of these probiotics vesicles, highlighting their role in the treatment of various diseases and discussing their potential future applications. By exploring the mechanisms of probiotic extracellular vesicles in disease development, this review aimed to provide a theoretical reference for further research on their therapeutic potential. © 2025 Society of Chemical Industry.

Both the flower of Citrus aurantium L. var. amara (CAVA) and rhizome of Zingiber officinale Roscoe (ginger) are food and medicinal homologous plants that have been used in China for aiding gastric digestion and preventing obesity. However, the combinatorial use of the two plants on obesity remains elusive. Our endeavor aimed to identify the optimal synergistic ratio between CAVA and ginger and to explore the underlying mechanism of their anti-obesity effects. Aqueous CAVA and ginger extracts were prepared separately and then combined into nine different ratios. The constituents of CAVA and ginger were unambiguously characterized by employing LC-MS. High-fat diet (HFD)-induced obese C57BL/6J mice were established and then administered with the nine combinations of CAVA-G extracts for 6 weeks. The trajectory of mice's body weights was analyzed. Besides, hematoxylin and eosin (HE) staining of the liver and oil red O staining of adipose tissue were performed. ELISA assay was employed to measure serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Moreover, serum metabolic profiling was conducted through UPLC-Q-TOF/MS analysis. Gut microbiota analysis was performed via 16S rRNA gene sequencing. Pattern recognition and Pearson correlation analysis were used to pinpoint the key endogenous metabolites and microbiota. Two groups of CAVA-G combination treatment (C3 and A1) significantly prevented the increase of weight in mice. According to our analysis, the best anti-obesity effect was achieved when the ratio between CAVA and ginger was 37:63. The levels of TC and LDL-C were dramatically decreased in the C3 group, whereas the level of TG was significantly reduced in the A1 group. Interestingly, HDL-C level was increased dramatically in the C3 group. Compared with the model group, a total of 16 and 25 biomarkers were identified for groups C3 and A1, respectively. These biomarkers are mainly implicated in lipid metabolism and primary bile acid biosynthesis. Interestingly, the abnormal diversity of gut microbiota was induced by HFD feeding. Treatment with C3 or A1 significantly increased the relative abundance of Akkermansia and Novosphingobium, while reducing the relative abundance of Dorea, Bacteroides and Roseburia. Of note, this is the first report that Novosphingobium is involved in preventing obesity. These findings will layer a foundation for the usage of CAVA-G for preventing obesity.

Lactobacillus fermentum has been shown to improve intestinal health and treat colitis; however, its precise efficacy and mechanisms in inflammatory bowel disease remain unclear.

This study aimed to evaluate whether L fermentum and its metabolites, extracellular vesicles, and other components could modulate intestinal barrier function and gut microbiota to alleviate dextran sulfate sodium (DSS)-induced colitis in mice.

Forty-eight mice were randomly assigned to 6 groups: control, DSS, L fermentum+DSS group (LF+DSS), heat-inactivated L fermentum+DSS group (LHF+DSS), L fermentum supernatant solution+DSS group (LSF+DSS), and L fermentum extracellular vesicles+DSS group (LEV+DSS). After a 1-wk acclimation, mice were gavaged daily for 3 wk. Fresh cultures, including live (LF+DSS), heat-inactivated (LHF+DSS), supernatant (LSF+DSS), and extracellular vesicles (LEV+DSS), were prepared daily. During the final 7 d, the control group received normal water, and the other groups received 3% DSS. Data were collected daily, followed by sample collection from the mice.

In this study, significant reductions (P < 0.05) in body weight changes, disease activity index, intestinal damage, and histology scores were observed in the treatment groups, especially LEV+DSS and LF+DSS. Additionally, compared with the DSS group, colonic mucus secretion, as well as claudin-1 and occludin expression, increased significantly (P < 0.05) in the LEV+DSS and LF+DSS groups, whereas proinflammatory cytokines IL-1β and TNF-α decreased (P < 0.05) and IL-10 increased (P < 0.05) in the LEV+DSS group. L fermentum and its components significantly regulated gut microbiota α-diversity and β-diversity, affecting overall composition. Linear discriminant analysis effect size analysis revealed an enrichment of beneficial bacteria including Prevotellaceae_UCG-001, Romboutsia, and Ruminococcus species in the LF+DSS group and Akkermansia, Odoribacter, and Marvinbryantia species in the LEV+DSS group. Both L fermentum and its extracellular vesicles significantly downregulated the gene expression of TNF-α and IL-1β, whereas the expression of IL-10 was upregulated, thereby contributing to the alleviation of colitis symptoms.

This study reveals that L fermentum alleviates colitis through modulation of the gut microbiota and reinforcement of the intestinal mucosal barrier, with its extracellular vesicles potentially playing a key role in this regulatory process.

This study investigated the effects of astaxanthin (AST) supplementation in drinking water on the growth performance, intestinal barrier function, and cecal microbiota of broilers challenged with Salmonella Enteritidis. During the 20-day experiment, two hundred and forty 1-day-old male Arbor Acres birds were randomly assigned into a 2 × 2 factorial design with four groups: a non-challenged control (CON), an S. Enteritidis-challenged group (SA), a group receiving AST treatment (AST), and an S. Enteritidis-challenged group receiving AST treatment (SA+AST). Each treatment comprised six replicate groups, and challenged groups were inoculated with S. Enteritidis from day 2 to day 4. The results indicated that S. Enteritidis infection significantly reduced the average daily feed intake (ADFI) in broilers and adversely affected average daily gain (ADG) and feed conversion ratio (FCR) by day 20. AST supplementation significantly improved FCR. While S. Enteritidis infection did not significantly affect ileal mucosa antioxidation, it significantly decreased villus height and the villus height-to-crypt depth ratio (VCR), and significantly downregulated mRNA expression of ZO-1 and Occludin. However, AST supplementation significantly enhanced antioxidant capacity (T-AOC), increased villus height and VCR in the ileum, and notably upregulated ZO-1 and MUC2 expression levels, particularly mitigating the adverse effects of S. Enteritidis infection on ileal crypt depth. Furthermore, S. Enteritidis infection significantly affected both the α- and β-diversity of cecal microbiota. Infection with S. Enteritidis was associated with changes at the phylum level, including significant increases in Alistipes, unclassified_f__Lachnospiraceae, and bacteria of the Clostridia UCG-014 grouping, alongside notable decreases in Bacteroides, Akkermansia, Blautia, and Butyricicoccus. AST supplementation significantly decreased the abundance of norank_f__Ruminococcaceae and increased the abundance of Lachnoclostridium and unclassified_f__Lachnospiraceae in the challenged group. In conclusion, AST supplementation in drinking water could improve growth performance and intestinal health in broilers challenged with S. Enteritidis.

While studies of various carcinomas have reported aberrant metal metabolism, much remains unknown regarding their spatial accumulation and regulatory impacts in tumors. Here, elevated copper levels are detected in breast cancer tumors from patients and animal models, specifically exhibiting a zonate spatial pattern. Spatially resolved multiomics analyses reveal that copper zonation drives a tumor metabolic preference for oxidative phosphorylation (OXPHOS) over glycolysis and promotes tumor metastatic and immune-desert phenotypes. Then, a copper-depleting nanoagent is developed based on copper chelator tetrathiomolybdate (TM)-loaded hybridized bacterial outer membrane vesicles (hOMVs) from both Akkermansia muciniphila bacteria and CD326-targeting peptide-engineered Escherichia coli (TM@CD326hOMV). Systemic administration of TM@CD326hOMV reduces the labile copper level in tumors and inhibits both tumor growth and metastatic phenotypes, specifically through metabolic reprograming of OXPHOS toward glycolysis and restoration of antitumor immunity responses involving natural killer cells, CD4+ T cells, and cytotoxic CD8+ T cells in tumors. Assessing survival in murine breast cancer models, a combination of TM@CD326hOMV and a checkpoint blockade agent outperforms monotherapies. Notably, a copper-rich diet undermines the therapeutic efficacy of TM@CD326hOMV. Beyond demonstrating an effective nanoagent for treating breast cancer, this study deepens the understanding of how the pattern of copper accumulation in tumors affects pathophysiology and immunity.

SUMMARYRecent advances in therapeutic probiotics have shown promising results across various health conditions, reflecting a growing understanding of the human microbiome's role in health and disease. However, comprehensive reviews integrating the diverse therapeutic effects of probiotics in human subjects have been limited. By analyzing randomized controlled trials (RCTs) and meta-analyses, this review provides a comprehensive overview of key developments in probiotic interventions targeting gut, liver, skin, vaginal, mental, and oral health. Emerging evidence supports the efficacy of specific probiotic strains and combinations in treating a wide range of disorders, from gastrointestinal (GI) and liver diseases to dermatological conditions, bacterial vaginosis, mental disorders, and oral diseases. We discuss the expanding understanding of microbiome-organ connections underlying probiotic mechanisms of action. While many clinical trials demonstrate significant benefits, we acknowledge areas requiring further large-scale studies to establish definitive efficacy and optimal treatment protocols. The review addresses challenges in standardizing probiotic research methodologies and emphasizes the importance of considering individual variations in microbiome composition and host genetics. Additionally, we explore emerging concepts such as the oral-gut-brain axis and future directions, including high-resolution microbiome profiling, host-microbe interaction studies, organoid models, and artificial intelligence applications in probiotic research. Overall, this review offers a comprehensive update on the current state of therapeutic probiotics across multiple domains of human health, providing insights into future directions and the potential for probiotics to revolutionize preventive and therapeutic medicine.

Biogenic selenium nanoparticles (SeNPs) have emerged as novel promising modulators of biological reactions such as redox and immune responses due to their multiple bioactivities and unique physicochemical properties.

The research objective of this investigation is to explore the mechanism of uptake and metabolism of SeNPs by intestinal epithelial cells and its protective effect on intestinal barrier function with gut-on-a-chip.

We designed a gut-on-a-chip to replicate key structural and environmental features of the intestinal tract to investigate the effects of oxidative stress on the intestinal barrier function and immune homeostasis of the intestinal epithelial cells as well as the regulatory role of SeNPs, and verified it through mice and piglet models.

Biogenic SeNPs can be effectively taken up by IPEC-J2 cells via clathrin- and caveolae-mediated endocytosis and further metabolized into selenocystine and trace amounts of selenite within cells, which are then incorporated into the synthesis of antioxidant selenoenzymes. A gut-on-a-chip model confirmed that Diquat-induced oxidative stress significantly impaired intestinal epithelial barrier integrity and damaged villi-like structures. In addition, the oxidative stress in IPEC-J2 cells induced activation of intestinal mucosal mast cells (MCs) to release IL-1β and TNF-α, further exacerbating oxidative stress in IPEC-J2 cells and leading to excessive ROS generation. However, SeNPs treatment increased cellular selenium content and antioxidant selenoenzyme activities, modulated AMPK/NLRP3/Nrf2 pathways, effectively alleviated oxidative stress, maintained mitochondrial homeostasis, inhibited pro-inflammatory factors expression. The mice and early-weaned piglet models further confirmed that SeNPs can increase the selenoproteins expression in the jejunum, reduce MCs activation, inhibited cell pyroptosis, and eventually exhibit an effective protective effect against intestinal barrier oxidative damage.

These results indicated that biogenic SeNPs reinforced antioxidant enzyme defenses, maintained mitochondrial homeostasis, inhibited crosstalk between inflammatory cells and intestinal epithelial cells, thereby protecting the intestinal epithelial barrier against oxidative stress damage.

Akkermansia muciniphila (A. muciniphila) is an emerging probiotic with potential impact on human health, and there is a growing interest in this area, but an overall analysis of research trends is lacking. This study conducted a detailed bibliometric analysis and visualization of A. muciniphila research to examine the current research status, hotspots, and trends, aiming to inform future research directions.

This study utilized the Web of Science database to search research on A. muciniphila from 2010 to 2024. Bibliometric analysis was conducted using CiteSpace and VOSviewer software to generate yearly publication trends, contributions by countries, institutions, and distinguished researchers, as well as key themes and influential researches. This analysis aimed to visualize and explore the literature over the past 15 years, guiding future researches and identifying gaps in the field of intestinal flora in A. muciniphila.

We searched a total of 4,423 related publications. Wei Chen, Willem de Vos and Patrice D. Cani are the primary contributors to A. muciniphila 's research. The top contributing countries and institutions are China, the United States, South Korea, Spain, and Italy, with research centers such as the Chinese Academy of Sciences, Zhejiang University, the University of Copenhagen, and the University of Helsinki being the main contributors. Current research hotspots focus on the molecular biology of A. muciniphila, such as its role in intestinal barrier maintenance, immune response, and its potential for regulating and treating digestive and metabolic diseases, such as cancer, fatty liver disease, inflammatory bowel disease, etc., through bile acid metabolism, extracellular vesicles, and insulin resistance.

Our study synthesizes current research on A. muciniphila in various disease areas and suggests enhancing collaboration among countries, institutions, and authors to advance A. muciniphila-related clinical and basic research, explore its efficacy in a variety of diseases and the effects of commonly used clinical medications on A. muciniphila, to fill the research gaps in the current field, and to provide valid evidence for the development of A. muciniphila as a novel probiotic supplement.

The high prevalence and disability rate of type 2 diabetes (T2D) caused a huge social burden to the world. Currently, new mechanisms and therapeutic approaches that may affect this disease are being sought. With in-depth research on the pathogenesis of T2D and growing advances in microbiome sequencing technology, the association between T2D and gut microbiota has been confirmed. The gut microbiota participates in the regulation of inflammation, intestinal permeability, short-chain fatty acid metabolism, branched-chain amino acid metabolism and bile acid metabolism, thereby affecting host glucose and lipid metabolism. Interventions focusing on the gut microbiota are gaining traction as a promising approach to T2D management. For example, dietary intervention, prebiotics and probiotics, faecal microbiota transplant and phage therapy. Meticulous experimental design and choice of analytical methods are crucial for obtaining accurate and meaningful results from microbiome studies. How to design gut microbiome research in T2D and choose different machine learning methods for data analysis are extremely critical to achieve personalized precision medicine.

Bacterial extracellular vesicles (BEVs) have emerged as versatile and promising tools for therapeutic interventions across a spectrum of medical applications. Among these, Lactobacillus-derived extracellular vesicles (LDEVs) have garnered significant attention due to their diverse physiological functions and applications in health advancement. These LDEVs modulate host cell signaling pathways through the delivery of bioactive molecules, including nucleic acids and proteins. The immunomodulatory properties of LDEVs are important, as they have been shown to regulate the balance between pro-inflammatory and anti-inflammatory responses in various diseases. These LDEVs play a crucial role in maintaining gut homeostasis by modulating the composition and function of the gut microbiota, which has implications for health conditions, including inflammatory bowel diseases, metabolic disorders, and neurological disorders. Furthermore, LDEVs hold potential to deliver therapeutic payloads to specific tissues or organs. Engineered LDEVs can be loaded with therapeutic agents such as antimicrobial peptides or nucleic acid-based therapies to treat various diseases. By leveraging the unique properties of LDEVs, researchers can develop innovative strategies for disease prevention, treatment, and overall well-being. Thus, this review aims to provide a comprehensive overview of the therapeutic benefits of LDEVs and their implications for promoting overall well-being.

The Porcine Epidemic Diarrhea Virus (PEDV) is one of the major challenges facing the global pig farming industry, and vaccines and treatments have proven difficult in controlling its spread. Faecalibacterium prausnitzii (F.prausnitzii), a key commensal bacterium in the gut, has been recognized as a promising candidate for next-generation probiotics due to its potential wide-ranging health benefits. A decrease in F.prausnitzii abundance has been associated with certain viral infections, suggesting its potential application in preventing intestinal viral infections. In this study, we utilized a piglet model to examine the potential role of F.prausnitzii in PEDV infections.

A piglet model of PEDV infection was established and supplemented with F.prausnitzii, revealing that F.prausnitzii mitigated PEDV infection. Further studies found that outer membrane vesicles (OMVs) are the main functional components of F.prausnitzii, and proteomics, untargeted metabolomics, and small RNA-seq were used to analyze the composition of OMVs. Exhaustion of the gut microbiota demonstrated that the function of Fp. OMVs relies on the presence of the gut microbiota. Additionally, metagenomic analysis indicated that Fp. OMVs altered the gut microbiota composition, enhancing the abundance of Faecalibacterium prausnitzii, Prevotellamassilia timonensis, and Limosilactobacillus reuteri. Untargeted metabolomics analysis showed that Fp. OMVs increased phosphatidylcholine (PC) levels, with PC identified as a key metabolite in alleviating PEDV infection. Single-cell sequencing revealed that PC altered the relative abundance of intestinal cells, increased the number of intestinal epithelial cells, and reduced necroptosis in target cells. PC treatment in infected IPEC-J2 and Vero cells alleviated necroptosis and reduced the activation of the RIPK1-RIPK3-MLKL signaling axis, thereby improving PEDV infection.

F.prausnitzii and its OMVs play a critical role in mitigating PEDV infections. These findings provide a promising strategy to ameliorate PEDV infection in piglets. Video Abstract.

The field of extracellular vesicles (EVs) is advancing rapidly, and this review aims to synthesize the latest research connected to EVs and the gastrointestinal tract. We will address new and emerging roles for EVs derived from internal sources such as the pancreas and immune system and how these miniature messengers alter organismal health or the inflammatory response within the GI tract. We will examine what is known about external EVs from dietary and bacterial sources and the immense anti-inflammatory, immune-modulatory, and proliferative potential within these nano-sized information carriers. EV interactions with the intestinal and colonic epithelium and associated immune cells at homeostatic and disease states, such as necrotizing enterocolitis (NEC) and inflammatory bowel disease (IBD) will also be covered. We will discuss how EVs are being leveraged as therapeutics or for drug delivery and conclude with a series of unanswered questions in the field.

Male osteoporosis is primarily caused by a decrease in testicular testosterone production. Male osteoporosis remains a disease with insufficient diagnosis and treatment, and its consequences are severe, especially in older patients. The gut microbiota plays a crucial role in its occurrence and development. Our study found that the relative abundance of Lactobacillus salivarius in the fecal microbiota of male patients with osteoporosis was significantly lower than that in healthy volunteers. Animal experiments have shown that orchiectomy (ORX) can induce osteoporosis and disrupt the intestinal mucosal barrier, and intestinal microbiota. In addition, we discovered a potential etiological connection between the decreased abundance of the intestinal bacterium L. salivarius and the occurrence of ORX-induced osteoporosis. Cohousing or direct colonization of the intestinal microbiota from healthy rats or direct oral administration of the bacteria alleviated ORX-induced osteoporosis and repaired the intestinal mucosal barrier. Finally, we demonstrated that the extracellular vesicles (EVs) of L. salivarius could be transported to the bones and mitigate ORX-induced osteoporosis in rats. Our results indicate that the gut microbiota participates in protecting bones by secreting and delivering bacterial EVs, and that the reduction of L. salivarius and its EVs is closely related to the development of androgen deficiency-related osteoporosis.

Metabolic-associated fatty liver disease (MAFLD) has become increasingly widespread. The intestine is the primary site of lipid absorption and is important for the homeostasis of lipid metabolism. However, the mechanism underlying the participation of the intestinal tract in the development of MAFLD requires additional investigation. In this study, analysis of the single-cell transcriptome of intestinal tissue from cynomolgus monkeys found that hepatic leukemia factor (HLF) participated in the genetic regulation of intestinal lipid absorption. Results obtained from normal and intestine-specific Hlf-knockout mice confirmed that HLF alleviated intestinal barrier disorders by inhibiting peroxisome proliferator-activated receptor alpha (PPARα) expression. The HLF/PPARα axis alleviated MAFLD by mediating gut microbiota-derived extracellular vesicles (fEVs), thereby inhibiting hepatocyte ferroptosis. Lipidomics and functional experiments verified that taurochenodeoxycholic acid (TCDCA), a conjugated bile acid contained in the fEVs, had a key role in the process. In conclusion, intestinal HLF activity was mediated by fEVs and identified as a novel therapeutic target for MAFLD.

Ischemic stroke (IS) is a cerebrovascular disease that predominantly affects middle-aged and elderly populations, exhibiting high mortality and disability rates. At present, the incidence of IS is increasing annually, with a notable trend towards younger affected individuals. Recent discoveries concerning the "gut-brain axis" have established a connection between the gut and the brain. Numerous studies have revealed that intestinal microbes play a crucial role in the onset, progression, and outcomes of IS. They are involved in the entire pathophysiological process of IS through mechanisms such as chronic inflammation, neural regulation, and metabolic processes. Although numerous studies have explored the relationship between IS and intestinal microbiota, comprehensive analyses of specific microbiota is relatively scarce. Therefore, this paper provides an overview of the typical changes in gut microbiota following IS and investigates the role of specific microorganisms in this context. Additionally, it presents a comprehensive analysis of post-stroke microbiological therapy and the relationship between IS and diet. The aim is to identify potential microbial targets for therapeutic intervention, as well as to highlight the benefits of microbiological therapies and the significance of dietary management. Overall, this paper seeks to provide key strategies for the treatment and management of IS, advocating for healthy diets and health programs for individuals. Meanwhile, it may offer a new perspective on the future interdisciplinary development of neurology, microbiology and nutrition.

Background: Hepatobiliary liver cancers (HBLCs) represent the sixth most common neoplasm in the world. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) constitute the main HBLC types, with alarming epidemiological projections. Methods: In recent decades, alterations in gut microbiota, with mutual implications on the gut-liver axis and gut-biliary axis permeability status, have been massively investigated and proposed as HBLC pathogenetic deus ex machina. Results: In the HCC setting, elevated intestinal levels of Escherichia coli and other Gram-negative bacteria have been demonstrated, resulting in a close association with increased lipopolysaccharide (LPS) serum levels and, consequently, chronic systemic inflammation. In contrast, the intestinal microbiota of HCC individuals feature reduced levels of Lactobacillus spp., Bifidobacterium spp., and Enterococcus spp. In the CC setting, evidence has revealed an increased expression of Lactobacillus spp., with enhanced levels of Actynomices spp. and Alloscardovia spp. Besides impaired strains/species representation, gut-derived metabolites, including bile acids (BAs), short-chain fatty acids (SCFAs), and oxidative-stress-derived products, configure a network severely impacting the progression of HBLC. Conclusions: In the era of Precision Medicine, the clarification of microbiota composition and functioning in HCC and CC settings can contribute to the identification of individual signatures, potentially providing novel diagnostic markers, therapeutic approaches, and prognostic/predictive tools.

Mucin glycoproteins are secreted from epithelial goblet cells to create protective barriers lining the intestines, stomach, lungs, and other body surfaces. MUC2 is the primary glycoprotein secreted in the intestine and is essential for intestinal homeostasis. The D1 segment of the MUC2 N-terminal region was recently shown to bind Cu2+ and Cu+ separately in a unique two-tiered binding site. Copper is an essential metal acquired through diet for cells and enzymes to function properly, but little is known about how it is handled in the digestive tract. With both oxidation states of Cu in the intestine, we asked how the binding of Cu+ to MUC2 D1 impacts the binding of Cu2+ and vice versa. Here, we use a combination of competition titrations, electron paramagnetic spectroscopy, and X-ray absorption spectroscopy to characterize the physical properties of Cu2+ and Cu+ binding to MUC2 D1 at pH values relevant to the intestine. Our data show that simultaneous yet noncooperative binding of Cu2+ and Cu+ is possible and further reveal new insights into the pH dependence and plasticity of the Cu2+ and Cu+ binding sites. These results inspire interesting questions about the functional roles of MUC2 Cu handling in the intestinal tract.

As one of the major challenges to global health, the innovation of prevention and treatment methods for tumors has consistently been a focal point in medical research. In recent years, bacterial membrane vesicles (MVs), particularly outer membrane vesicles (OMVs) secreted by Gram-negative bacteria, have garnered significant attention due to their unique biological characteristics and potential anti-tumor effects. OMVs are bilayer lipid nanocapsules that are actively released by bacteria during their growth, typically ranging in diameter from 20 to 300 nm. They are rich in various biomolecules, including lipids, proteins, nucleic acids, and other small molecules. These components not only reflect the outer membrane structure of bacteria but also contain numerous pathogen-associated molecular patterns (PAMPs) related to bacterial pathogenicity and immunogenicity. Consequently, OMVs play an important role in bacterial resistance, antimicrobial activity, gene transfer, signal transduction, and immune regulation. Research and application of OMVs in anti-tumor therapy have made significant progress. This paper reviews the classification, characteristics, preparation, safety evaluation, biological functions, and specific research advancements of OMVs as antitumor drugs, immunomodulators, and carriers. Additionally, common methods for the preparation and modification of OMVs, including preliminary extraction, purification, characterization, and drug loading, are discussed. This paper also summarizes the challenges faced by OMVs in anti-tumor research and outlines future development directions, aiming to provide a reference for the further application of OMVs in tumor treatment.