Deviations in the diversity and composition of the gut microbiota are called "gut dysbiosis". They have been linked to various chronic diseases including cancers and resistance to immunotherapy. Stool shotgun based-metagenomics informs on the ecological composition of the gut microbiota and the prevalence of homeostatic bacteria such as Akkermansia muciniphila (Akk), while determination of the serum addressin MAdCAM-1 instructs on endothelial gut barrier dysfunction. Here we examined patient survival during chemo-immuno-therapy in 955 cancer patients across four independent cohorts of non-small cell lung (NSCLC), genitourinary (GU) and colorectal (CRC) cancers, according to hallmarks of gut dysbiosis. We show that Akk prevalence represents a stable and favorable phenotype in NSCLC and CRC cancer patients. Over-dominance of Akk above the healthy threshold was observed in dismal prognosis in NSCLC and GU and mirrored an immunosuppressive gut ecosystem and excessive intestinal epithelial exfoliation in NSCLC. In CRC, the combination of a lack of Akk and low sMAdCAM-1 levels identified a subset comprising 28% of patients with reduced survival, independent of the immunoscore. We conclude that gut dysbiosis hallmarks deserve integration within the diagnosis toolbox in oncological practice.

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.

Alpha-defensin 1 is a small antimicrobial peptide that acts as the first line of defense against pathogens. It is induced following microbial cues and inflammatory signals in neutrophils and Paneth cells in the small intestine, which suggests that it plays a role in microbial homeostasis in the gut. The gut microbial products also serve as ligands for the aryl hydrocarbon receptor (AhR), an environmental sensor. In the current study, we investigated if there is any crosstalk between AhR and alpha-defensin 1. Interestingly, we found a positive correlation between AhR and alpha-defensin 1 protein levels in ileal tissues from active Crohn's' (CD) patients and epithelial cells (IECs) from multiple models of murine colitis. In vitro downregulation of AhR led to inhibition of α-defensin 1, while activation of AhR induced α-defensin 1 in IECs. AhR directly targeted the dioxin response element 3 (DRE3) region on the α-defensin 1 promoter in IECs. AhR-mediated induction of α-defensin 1 in colitis mice reversed the gut microbial dysbiosis and alleviated colitis. Our data identify a novel signaling pathway in which AhR acts as a transcription factor for α-defensin 1, leading to regulation of homeostasis between gut microbiota, intestinal mucosa, and mucosal immunity.

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 intestinal barrier is a critical defense against external pathogens and plays a central role in immune regulation and nutrient absorption. Oxidative stress and chronic inflammation in high-altitude environments can exacerbate the damage to the intestinal barrier in Baimei ternary pigs. Anthocyanin extract of Lycium ruthenicum Murray (AEL), has garnered widespread attention due to its rich anthocyanin flavonoid content, which exhibits antioxidant and anti-inflammatory properties. These properties help alleviate inflammation and oxidative stress, thereby enhancing gut function in animals. Based on this, the study employed Bamei ternary pigs and supplemented their basic diet with varying concentrations of AEL to investigate its impact on gut barrier function. The results demonstrated that AEL inhibited key factors of the intestinal Toll-like receptor pathway, including Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated protein 6 (TRAF6), and nuclear factor kappa B (NF-κB), affecting gene transcription and protein expression levels. This led to a reduction in pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), an increase in anti-inflammatory IL-10 production, and improved antioxidant capacity by enhancing total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activity, while decreasing malondialdehyde (MDA) production. Additionally, AEL improved intestinal morphology and facilitated the transcription and expression of tight junction proteins, including zonula occludens-1 (ZO-1), claudin-1 (CLDN-1), and occludin (OCLN). AEL also elevated the transcription levels of mucin 1 (MUC1) and mucin 2 (MUC2), as well as the secretion levels of polymeric immunoglobulin receptor (pIgR) and secretory immunoglobulin A (SIgA), while increased the number of intestinal goblet cells. Furthermore, dietary supplementation with AEL altered the structure of the intestinal microbiota, enhancing the abundance of beneficial bacterial genera such as Verrucomicrobiaceae, Rikenellaceae, Butyricicoccaceae, UCG-005、Rikenellaceae_RC9_gut_group、norank_f_Ruminococcaceae、Eubacterium_oxidoreducens_group, thereby promoting the production of intestinal short-chain fatty acids (SCFAs). In conclusion, AEL inhibits the Toll-like receptor pathway, reduces the production of inflammatory factors, enhances antioxidant levels, improves intestinal morphology and microbiota structure,, thereby reinforcing intestinal barrier function.

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.

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.

The disruption of the intestinal mucosal barrier is strongly associated with the onset of various diseases, including inflammatory bowel disease. Exopolysaccharides (EPS) support the functionality of the intestinal barrier. Weissella Cibaria (W. cibaria), belonging to the lactic acid bacteria, exhibits a significant capacity for EPS production. However, the specific mechanisms by which the EPS produced by W. cibaria confers intestinal barrier protection remain unexplored. Here, we characterized the polysaccharide, EPS-2, produced by W. cibaria isolated from the feces of healthy infants. EPS-2 was a novel dextran composed of α-(1 → 6) and α-(1 → 3,6) glycosidic linkages with a molecular weight of 845 kDa. EPS-2 alleviates intestinal mucosal barrier dysfunction in a mouse model of colitis, via a mechanism specifically reliant on the gut microbiota and their metabolic products, which is different from the well-known direct protective effects of other EPS on the intestinal barrier. EPS-2 reversed colitis-induced reductions in Muribaculaceae and propionate levels, thereby enhancing colonic goblet cell function and mucin content. Additionally, EPS-2 decreased the number of LPS-producing bacteria, such as Escherichia_Shigella. EPS-2 alleviated dextran sulfate sodium-induced intestinal inflammation and barrier damage. Therefore, EPS-2 shows promise as a postbiotic treatment for diseases associated with intestinal barrier dysfunction.

Numerous studies demonstrate that intestinal microbiota contribute to colorectal cancer (CRC), which is often associated with dysbiosis. Most of the data were obtained from studies on CRC patients, making it challenging to determine whether alterations in microbiota are a consequence of the pathology or whether they actively drive its progression. Several studies using laboratory animals suggest that gut microbiota may be involved in both the onset and progression of CRC. In the present study we utilized the azoxymethane-dextran sulfate sodium (AOM/DSS) mouse model of CRC to investigate the contribution of healthy-state microbiota to inflammation-associated tumorigenesis. Two cohorts of C57BL/6 mice harboring different intestinal microbiota demonstrated different susceptibility to AOM/DSS treatment. Sequencing of 16S rRNA bacterial DNA from fecal samples revealed Akkermansia muciniphila and Bacteroides acidifaciens as marker features in the healthy-state microbiota (before AOM/DSS administration), which showed a strong positive correlation with tumor incidence. Moreover, the healthy-state abundance of these markers, considered beneficial bacteria, was strongly positively correlated with the sulfate-reducing bacteria Desulfovibrio fairfieldensis identified as a marker of chronic colitis-associated microbiota. Furthermore, the abundances of these marker features, associated with CRC outcome, correlated with the expression of interferon gamma and nitric oxide synthase 2 genes in colon tissue during the early stage of DSS-induced intestinal inflammation. In contrast to multiple studies demonstrating the anti-inflammatory properties of A. muciniphila and B. acidifaciens, our results point out their potential adverse effect under specific conditions of genotoxicity and inflammation in the intestine. Taken together, our findings suggest a complex, context-dependent role of commensal microbiota in inflammation-associated dysbiosis and CRC.

Colorectal cancer (CRC) is one of the most prevalent and lethal cancers worldwide, ranking third in incidence and second in mortality. While immunotherapy has shown promise in patients with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H), its effectiveness in proficient mismatch repair (pMMR) or microsatellite stable (MSS) CRC remains limited. Recent advances highlight the gut microbiota as a potential modulator of anti-tumor immunity. The gut microbiome can significantly influence the efficacy of immune checkpoint inhibitors (ICIs), especially in pMMR/MSS CRC, by modulating immune responses and systemic inflammation. This review explores the role of the gut microbiota in pMMR/MSS CRC, the mechanisms by which it may enhance immunotherapy, and current strategies for microbiota modulation. We discuss the potential benefits of combining microbiota-targeting interventions with immunotherapy to improve treatment outcomes for pMMR/MSS CRC patients.

Ulcerative colitis (UC) pathogenesis is strongly linked to gut microbiota dysbiosis and compromised intestinal barrier integrity. Emerging evidence suggests that targeted dietary interventions may restore microbial homeostasis and ameliorate colitis progression. In this study, we evaluated the therapeutic potential of Fu Brick tea (FBT) using a dextran sulfate sodium (DSS)-induced murine colitis model. The results indicated that oral administration of FBT extract significantly improved the disease index, reduced inflammatory response, protected intestinal barrier protein (e.g., ZO-1), and maintained intestinal structure integrity. Furthermore, FBT intake increased the diversity of gut microbiota, promoted the growth of beneficial bacteria (e.g., Akkermansia), inhibited the proliferation of harmful bacteria (e.g., Desulfovibrioceae, Escherichia, and Helicobacter), restored intestinal homeostasis, and alleviated colitis symptoms including diarrhea. These findings position FBT as a promising nutraceutical candidate for UC management via multi-target modulation of mucosal immunity and microbial ecology.

Earlier studies have implicated a crucial link between diabetic nephropathy (DN) and the gut microbiota (GM) by considering the gut-kidney axis; however, the specific cause-and-effect connections between these processes remain unclear.

To compare changes in the GM between DN patients and control subjects, a review of observational studies was performed. The examination focused on the phylum, family, genus, and species/genus categories. To delve deeper into the cause-effect relationship, instrumental variables for 211 GM taxa (9 phyla, 16 classes, 20 orders, 35 families, and 131 genera), which were eligible for the mbQTL (microbial quantitative trait locus) mapping analysis, were collected from the Genome Wide Association Study (GWAS). A Mendelian randomization investigation was then conducted to gauge their impact on DN susceptibility using data from the European Bioinformatics Institute (EBI) and the FinnGen consortium. The European Bioinformatics Institute data included 1032 DN patients and 451,248 controls, while the FinnGen consortium data consisted of 3283 DN patients and 210,463 controls. Two-sample Mendelian randomization (TSMR) was utilized to determine the link between the GM and DN. The primary method for analysis was the inverse variance weighted (IVW) approach. Moreover, a reverse Mendelian randomization analysis was carried out, and the findings were validated through sensitivity assessments.

This review examined 11 observational studies that satisfied the inclusion and exclusion criteria. There was a significant difference in the abundance of 144 GM taxa between DN patients and controls. By employing the MR technique, 13 bacteria were pinpointed as having a causal link to DN (including 3 unknown GM taxa). Even after Bonferroni correction, the protective impact of the phylum Proteobacteria and genus Dialister (Sequeira et al. Nat Microbiol. 5:304-313, 2020; Liu et al. EBioMedicine. 90:104527, 2023) and the harmful impact of the genus Akkermansia, family Verrucomicrobiaceae, order Verrucomicrobia and class Verrucomicrobiae on DN remained significant. No noticeable heterogeneity or horizontal pleiotropy was detected in the instrumental variables (IVs). However, reverse MR investigations have failed to reveal any substantial causal relationship between DN and the GM.

Differences in the GM among DN patients and healthy controls are explored in observational studies. We verified the possible connection between certain genetically modified genera and DN, thereby emphasizing the connection between the "gut-kidney" axis and new insights into the GM's role in DN pathogenesis underlying DN. Investigations into this association are necessary, and novel biomarkers for the development of targeted preventive strategies against DN are needed.

Notch signaling is an evolutionarily conserved, multifunctional pathway involved in cell fate determination and immune modulation and contributes to the pathogenesis of autoinflammatory diseases. Emerging evidence reveals a bidirectional interaction between Notch and the gut microbiota (GM), whereby GM composition is capable of modulating Notch signaling through the binding of microbial elements to Notch receptors, leading to immune modulation. Furthermore, Notch regulates the GM by promoting SCFA-producing bacteria while suppressing proinflammatory strains. Beneficial microbes, such as Lactobacillus and Akkermansia muciniphila, modulate Notch and reduce proinflammatory cytokine production (such as IL-6 and TNF-α). The interaction between GM and Notch can either amplify or attenuate inflammatory pathways in inflammatory bowel diseases (IBDs), Behçet's disease, and PAPA syndrome. Together, these findings provide novel therapeutic perspectives for autoinflammatory diseases by targeting the GM via probiotics or inhibiting Notch signaling. This review focuses on Notch-GM crosstalk and how GM-based and/or Notch-targeted approaches may modulate immune responses and promote better clinical outcomes.

Recent studies indicate that the gut microbiota controls the host's immune system. Probiotics use different signaling pathways to regulate intestinal permeability, barrier integrity, and energy balance.

This research examined how Akkermansia muciniphila and its extracellular vesicles (EVs) impact inflammation and genes related to the endocannabinoid system in the STC-1 cell line through RT-PCR and ELISA assays.

The study's results indicated that EVs had a significant impact on GLP-1 expression compared to the multiplicity of infections (MOI) ratio. Notably, there was a substantial increase in the expression of PYY and GLP-1 genes across all treatments (p < 0.05). Conversely, the expression of CB-1, CB-2, and FAAH genes notably decreased in the STC-1 cell line when treated with MOI 50 of A. muciniphila and an EV concentration of 100 μg/mL (p < 0.05). Both MOI 50 of A. muciniphila and an EV concentration of 100 μg/mL significantly enhanced the expression of the TLR-2 gene. In contrast, EVs at a concentration of 100 μg/mL substantially reduced TLR-4 gene expression. A. muciniphila-derived EVs notably decreased the levels of inflammatory cytokines (TNF-α and IL-6), while increasing IL-10 expression at MOI 100 and an EV concentration of 100 μg/mL. These findings suggest that A. muciniphila and its EVs could regulate the expression of specific genes, serving as targets for maintaining host energy balance.

In summary, this study illustrates that A. muciniphila-derived EVs exhibit anti-inflammatory properties and have the potential to modulate gene expression in cases of obesity and gastrointestinal tract inflammation.

Pullorum disease (PD) caused by Salmonella Pullorum (SP) results in high mortality in chicks and potential carriers in adult chickens, negatively affecting growth and egg production. This study identified SP infection in 100-day-old White Plymouth Rock hens by serum plate agglutination and fecal and anal swab polymerase chain reaction. SP-infected broilers were classified into positive (P) and negative (N) groups using hematoxylin-and-eosin staining, metabolome sequencing, and 16S rDNA to investigate the effects of SP infection on the metabolites and microorganisms in the cecum of broilers. Groups had different degrees of inflammatory cell infiltration in the cecum, spleen, liver, and lung tissues. The diversity of bacterial flora in the cecum of Groups P and N differed significantly (P < 0.05). o__Lactobacillales and o__Verrucomicrobiota were significantly higher in Group P than in Group N (P < 0.05). At the genus level, g__Akkermansia was significantly higher in Group N (P < 0.05). Metabolome sequencing of cecum contents in Groups P and N screened 77 differential metabolites at the secondary metabolite level. 11 metabolites, including 2,4-dimethylbenzaldehyde, 3a,6b,7b,12a-tetrahydroxy-5b-cholanoic acid, and LysoPG 19:1, were differentially expressed in Group P (P < 0.05). A combined analysis of 16S rDNA sequencing and cecal content metabolomics identified 28 genera significantly associated with 38 metabolites in the cecum (P < 0.05). Specific bacterial genera such as Corynebacterium and Roseobacter have particularly prominent effects on metabolites. These findings highlight the significant alterations in gut microbial composition and metabolic functions due to SP infection. The differential metabolites and bacterial taxa identified in this study may provide insights into the underlying mechanisms of PD pathogenesis and potential biomarkers for disease management.

Akkermansia muciniphila (A. muciniphila), a critical bacterium within the gut microbiota, plays a key role in human health and immunomodulation. Since its identification in 2004, A. muciniphila has emerged as a significant agent in treating metabolic diseases, gastroenterological diseases, and tumor immunotherapy. Its rapid ascent in scientific translation underscores its importance in gut microbiome research. However, there has been a lack of visualization and analysis of the rapidly occurring commercialization in this field, which has critically hindered insights into the current knowledge structure and understanding of the cutting-edge of the discipline. This study employs the Web of Science Core Collection (WOSCC) and Innography platforms to provide the first comprehensive analysis of A. muciniphila's academic progresses and commercialization over the past two decades, highlighting its growing prominence in global health research. Our analysis delineates that, following the academic trajectory, the evolution of A. muciniphila patents from foundational research through to application development and maturity, with particular emphasis on its expansive potential in emerging fields, including gastroenterological disorders, non-alcoholic fatty liver disease, cancer immunotherapy, stress management, and neurodegenerative disease treatment. Concluding, A. muciniphila presents as a next-generation probiotic with vast implications for human health. Our findings provide essential insights for future research and product development, contributing to the advancement of this burgeoning field.

Chronic gut inflammation and dysbiosis contribute significantly to colorectal cancer (CRC) development. Shaoyao decoction (SYD) is a well-established Chinese medicine prescription. Besides ameliorating CRC via anti-inflammatory effects, SYD modulates gut microbiota (GM) to improve inflammatory responses in ulcerative colitis (UC). However, whether and how SYD suppresses CRC by regulating GM remains largely unknown.

SD rats were orally administered SYD for 7 days to obtain medicated serum. We utilized liquid chromatography-mass spectrometry (LC-MS) analysis, GeneCards, DisGeNET, and SwissTargetPrediction databases to analyze blank and SYD-medicated rat serum, comparing the findings with those of SYD aqueous extract in previous studies to identify SYD circulating compounds/components with predictable target genes. Using network pharmacology, the potential active compounds and corresponding hub genes associated with modulating GM to suppress CRC were selected for molecular docking. In vivo experiments, a CRC transplantation tumor model was established in BALB/c mice using CT26 cells, with SYD gavage for 14 days. To investigate the mechanism of SYD-regulated GM against CRC, HE and IHC staining, Western blotting, and 16S rRNA sequencing were employed.

LC-MS identified 26 SYD compounds with computationally predicted target genes. Network pharmacology prioritized 13 compounds targeting 8 inflammation/immunity-related genes (IL-17/TNF pathways), validated by molecular docking. In vivo experiments, SYD dose-dependently suppressed tumor growth (p < 0.05, medium/high doses), as confirmed by HE staining and IHC analysis of Ki-67. Notably, SYD potentially delayed CRC liver metastasis and alleviated hepatic injury in tumor-bearing mice. Western blotting demonstrated SYD's inhibition of the IL-17/TNF/NF-κB axis, aligning with computational predictions. 16S rRNA sequencing revealed SYD-enriched Akkermansia and GM structural shifts, mechanistically linking microbiota remodeling to anti-tumor efficacy.

SYD combats CRC via dual modulation of IL-17/TNF/NF-κB signaling and GM ecosystems (e.g., Akkermansia enrichment). This microbiota-immune crosstalk positions SYD as a potential adjunct to conventional therapies, particularly for CRC patients with dysbiosis.

The gut microbiota is closely associated with inflammatory bowel disease (IBD) and colorectal cancer (CRC). Probiotics such as Clostridium butyricum (CB) or Akkermansia muciniphila (AKK) have the potential to treat inflammatory bowel disease (IBD) or colorectal cancer (CRC). However, research on the combined therapeutic effects and immunomodulatory mechanisms of CB and AKK in treating IBD or CRC has never been studied. This study evaluates the potential of co-administration of CB and AKK in treating DSS/AOM-induced IBD and colitis-associated CRC. Our results indicate that compared to mono-administration, the co-administration of CB and AKK not only significantly alleviates symptoms such as weight loss, colon shortening, and increased Disease Activity Index in IBD mice but also regulates the gut microbiota composition and effectively suppresses colonic inflammatory responses. In the colitis-associated CRC mice model, a combination of CB and AKK significantly alleviates weight loss and markedly reduces inflammatory infiltration of macrophages and cytotoxic T lymphocytes (CTLs) in the colon, thereby regulating anti-tumor immunity and inhibiting the occurrence of inflammation-induced CRC. In addition, we found that the combined probiotic therapy of CB and AKK can enhance the sensitivity of colitis-associated CRC mice to the immune checkpoint inhibitor anti-mouse PD-L1 (aPD-L1), significantly improving the anti-tumor efficacy of immunotherapy and the survival rate of colitis-associated CRC mice. Furthermore, fecal microbiota transplantation therapy showed that transplanting feces from CRC mice treated with the co-administration of CB and AKK into other CRC mice alleviated the tumor loads in the colon and significantly extended their survival rate. Our study suggests that the combined use of two probiotics, CB and AKK, can not only alleviate chronic intestinal inflammation but also inhibit the progression to CRC. This may be a natural and relatively safe method to support the gut microbiota and enhance the host's immunity against cancer.

Our study suggests that the combined administration of CB and AKK probiotics, as opposed to a single probiotic strain, holds considerable promise in preventing the advancement of IBD to CRC. This synergistic effect is attributed to the ability of this probiotic combination to more effectively modulate the gut microbiota, curb inflammatory reactions, bolster the efficacy of immunotherapeutic approaches, and optimize treatment results via fecal microbiota transplantation.

As the largest mucosal surface, the gut has built a physical, chemical, microbial, and immune barrier to protect the body against pathogen invasion. The disturbance of gut microbiota aggravates pathogenic bacteria invasion and gut barrier injury. Fecal microbiota transplantation (FMT) is a promising treatment for microbiome-related disorders, where beneficial strain engraftment is a significant factor influencing FMT outcomes. The aim of this research was to explore the effect of FMT on antibiotic-induced microbiome-disordered (AIMD) models infected with enterotoxigenic Escherichia coli (ETEC). We used piglet, mouse, and intestinal organoid models to explore the protective effects and mechanisms of FMT on ETEC infection. The results showed that FMT regulated gut microbiota and enhanced the protection of AIMD piglets against ETEC K88 challenge, as demonstrated by reduced intestinal pathogen colonization and alleviated gut barrier injury. Akkermansia muciniphila (A. muciniphila) and Bacteroides fragilis (B. fragilis) were identified as two strains that may play key roles in FMT. We further investigated the alleviatory effects of these two strains on ETEC infection in the AIMD mice model, which revealed that A. muciniphila and B. fragilis relieved ETEC-induced intestinal inflammation by maintaining the proportion of Treg/Th17 cells and epithelial damage by moderately activating the Wnt/β-catenin signaling pathway, while the effect of A. muciniphila was better than B. fragilis. We, therefore, identified whether A. muciniphila protected against ETEC infection using basal-out and apical-out intestinal organoid models. A. muciniphila did protect the intestinal stem cells and stimulate the proliferation and differentiation of intestinal epithelium, and the protective effects of A. muciniphila were reversed by Wnt inhibitor. FMT alleviated ETEC-induced gut barrier injury and intestinal inflammation in the AIMD model. A. muciniphila was identified as a key strain in FMT to promote the proliferation and differentiation of intestinal stem cells by mediating the Wnt/β-catenin signaling pathway.

Akkermansia muciniphila, as a probiotic, is negatively linked to IBD, obesity, and T2DM. The aim of this study was to comprehensively assess the research status of Akkermansia muciniphila over the past decade and explore the relationships between this bacterium and various health-related aspects.

Tools VOSviewer, Bibliometrix, and CiteSpace were used to analyze various aspects including publication metrics, contributors, institutions, geography, journals, funding, and keywords.

Over the past decade, research on Akkermansia muciniphila has demonstrated a consistent annual growth in the number of publications, with a notable peak in 2021. China led in the number of publications, totaling 151, whereas the United States exhibited a higher centrality value. Among the 820 institutions involved in the research, the University of California (from the United States) and the Chinese Academy of Sciences (from China) occupied central positions. Willem M. De Vos ranked at the top, with 12 publications and 1,108 citations. The journal GUT, which had 5,125 citations and an Impact Factor of 23.0 in 2024, was the most highly cited. The most cited articles deepened the understanding of the bacterium's impact on human health, spanning from basic research to translational medicine. Thirty-nine high-frequency keywords were grouped into five clusters, illustrating Akkermansia muciniphila's associations with metabolic diseases, chronic kidney disease, the gut-brain axis, intestinal inflammation, and Bacteroidetes-Firmicutes shifts.

Given Akkermansia muciniphila's anti-inflammatory and gut-barrier-strengthening properties, it holds promise as a therapeutic for obesity, metabolic disorders, and inflammatory conditions. Therefore, future research should explore its potential further by conducting clinical trials, elucidating its mechanisms of action, and investigating its efficacy and safety in diverse patient populations.

Polyacylated anthocyanins are known for their enhanced stability and immunosuppressive properties. Although peonidin-3-O-(3,6-O-dimalonyl-β-D-glucoside) (P3GdM) from black corncobs has demonstrated notable antibacterial and stress-resistance effects in plants, its regulatory role in inflammatory bowel disease (IBD) remains unexplored. In this study, P3GdM was isolated from black corncobs, and its potential as a treatment for dextran sulfate sodium (DSS)-induced colitis in mice was evaluated. The findings revealed that P3GdM significantly mitigated clinical symptoms, reduced the disease activity index (DAI), suppressed the production of pro-inflammatory cytokines and endotoxins, and repaired the intestinal barrier. Furthermore, P3GdM markedly improved DSS-induced gut microbiota dysbiosis, significantly increasing microbial diversity and enhancing the relative abundance of critical bacterial species such as Akkermansia muciniphila and Lactobacillus reuteri, while also stimulating the production of short-chain fatty acids (SCFAs) and lactic acid. Correlation analyses further revealed strong associations between key microbial taxa, pro-inflammatory factors, clinical symptoms, tight junction proteins, and SCFAs. These findings provide support for the potential of P3GdM as an adjunct therapy for intestinal disorders, particularly colitis.

Resistant starch (RS) has been shown to modulate intestinal microbiota in animal models in ways that could reduce the effects of dysbiosis-related diseases. However, the mechanism of how this is achieved is not understood. The present study aimed to reveal the mechanism of how RS mitigates dextran sulfate sodium (DSS)-induced colitis in mice by using a starch-lipid complex (RS type 5), with an RS type 2 from high-amylose maize starch as a comparison. Both RS5 and RS2 induced changes in the diversity and composition of the gut bacteria, leading to the alleviation of the induced colitis symptoms including decreasing the loss in body weight, disease activity index score, and colonic shortening. The levels of inflammatory cytokines were modulated and accompanied by an increase in goblet cell numbers and thickening of the intestinal mucus layer. RS5 was more effective, compared to RS2, in alleviating all of the colitis symptoms, mainly through improving the gut microflora dysbiosis and stimulating the generation of short-chain fatty acids (SCFAs). Our study shows that RS5 could effectively alleviate the symptoms of colitis, highlighting a potential use for RS5, particularly in relieving inflammatory bowel disease.

Ulcerative colitis (UC) remains an intractable and relapsing disease featured by intestinal inflammation. The anti-UC activity of Akkermansia muciniphila (AKK), an intestinal microorganism, has been widely investigated. The current work is to explore the impacts of AKK on UC and its possible reaction mechanism. In vivo UC model was induced by dextran sulfate sodium (DSS) and phorbol-12-myristate-13-acetate (PMA)-induced THP-1-M0 and raw264.7 macrophages were treated by lipopolysaccharide (LPS). H&E staining evaluated tissue damage. Inflammatory and oxidative stress levels were assessed by relevant kits. The high-throughput analysis of fatty acids was performed by the LC/MS method. RT-qPCR and Western blot detected related gene expression. Flow cytometry measured cell apoptosis and macrophage polarization. Energy metabolism was detected by ELISA, related assay kits, JC-1 staining, and Western blot. AKK reduced the pathological damage of mice colon tissues, alleviated oxidative stress and inflammatory response, upregulated the expression of Occludin-1 and SCFAs receptors, and stimulated M1 to M2 macrophage polarization in vivo. After FFAR2 was silenced, the promoting role of AKK in the viability and M1 to M2 macrophage polarization and the inhibitory role in oxidative stress, inflammation, apoptosis, energy metabolism disorder, necroptosis, and pyroptosis were both reverted. Conclusively, AKK might mediate SCFAs-SLC52A2/FFAR2 pathways to exert protective activities against intestinal inflammatory response in UC, suggesting that AKK might represent a novel and promising candidate for UC therapy.

A. muciniphila (AKK) has attracted extensive research interest as a potential next-generation probiotics, but its role in intestinal pathology is remains unclear. Herein, this study was conducted to investigate the effects of A. muciniphila DSM 22,959 on growth performance, intestinal barrier function, microecology and inflammatory response of weaned piglets stimulated by dextran sulfate sodium salt (DSS).

Twenty-four Duroc × Landrace × Yorkshire (DLY) weaned piglets used for a 2 × 2 factorial arrangement of treatments were divided into four groups with six piglets in each group. From 1 to 15 d, the CA and DA groups were orally fed with 1.0 × 1011 colony-forming units A. muciniphila per day, while the CON and DCON groups were received gastric infusion of anaerobic sterile saline per day. The pigs were orally challenged (DCON, DA) or not (CON, CA) with DSS from day 9 to the end of the experiment and slaughtered on day 16.

Presence of A. muciniphila in DSS-challenged weaned pigs resulted in numerically increased diarrhea rate, blood neutrophilic granulocyte, serum C-reactive protein and immunoglobulin M levels, and numerically reduced final weight, average daily feed intake and average daily gain. The decrease in intestinal villus height, villous height: crypt depth ratio and digestibility was accompanied by lower expression of ZO1, ZO2, Claudin1, DMT1, CAT1, SGLT1 and PBD114 genes, as well as decreased enzyme activities of intestinal alkaline phosphatase, lactase, sucrase and maltase of piglets in DA group compared to piglets in DCON group. The abundance of Bifdobacterium, Lactobacillus, A. muciniphila, Ruminococcus gnavus was numerically higher in digesta of pigs in DA group than those in DCON group. The inflammatory responses of piglets were dramatically changed by the simultaneous presence of A. muciniphila and DSS: expression level of IL17A, IL17F, IL23, RORγt, Stat3 was elevated in DA pigs compared to the other pig groups.

Our result showed that the oral A. muciniphila aggravates DSS-induced health damage of weaned piglet, which may attribute to the deteriorating intestinal morphology, dysbiosis of microbiota and inflammatory response disorders.

The acute pulmonary infectious disease caused by influenza viruses is known as influenza virus pneumonia (IVP). In recent years, Gegen Qinlian Decoction (GQD) has been widely used to treat pulmonary inflammation; however, the underlying mechanism of action of GQD in IVP remains unclear. This study aimed to elucidate the molecular mechanism through which GQD improved IVP.

The efficacy of GQD was evaluated using classical pharmacodynamic indicators in a murine model of H1N1-induced IVP. Network pharmacology predicted the material basis of GQD in improving IVP, while metabonomics and 16 s rDNA sequencing assessed its regulation on small molecule metabolites and intestinal flora. Additionally, molecular biology techniques were used to investigate the molecular mechanism underlying the improvement of IVP by GQD.

The study results demonstrated that GQD exhibited a significant ameliorative effect on the inflammatory response in lung tissue of IVP mice. The potential pharmacological substances of GQD for improving IVP were identified by network pharmacology combined with ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) analysis, including puerarin, baicalin, berberine, and glycyrrhizin. Further analysis of biological processes and mechanisms of action predicted that GQD could improve IVP by inhibiting activation of inflammasomes, regulating the body's immune system, and intestinal microecology. Metabolomics and microbiomics findings revealed that GQD could bi-directionally regulate lipid and amino acid metabolites by increasing the abundance of beneficial bacteria like Akkermansia and Acetobacter, thereby maintaining host metabolic balance and immune homeostasis. RT-qPCR and immunohistochemistry results indicated that GQD improved IVP by inhibiting the complement C3/NLRP3 inflammasome pathway.

The findings of this study confirmed that GQD effectively inhibited IVP by modulating the "gut microbiota-metabolomics-immune/inflammation" axis in the host, thereby establishing a solid immunological foundation for the clinical application of GQD.

Isoflavone components extracted from red clover have anti-inflammatory, antioxidant and immune boosting effects. We hypothesize that red clover isoflavones (RCIs) achieve health-promoting effects via altering the gut microbiota. A total of 48 mice (20 ± 2 g) were randomly divided into a control group, low-dose group (0.05% RCIs in feed), middle-dose group (0.1% RCIs in feed), and high-dose group (0.2% RCIs in feed) with 12 mice per group. The feeding period was 20 d. The results showed that RCIs can increase the daily gain and decrease the ratio of feed to gain in mice. The organ indexes and blood biochemical indexes of the mice in each RCI group were in the normal range, indicating that RCIs do not damage liver or kidney function. RCI supplementation increased serum immunity and altered the microbial community structure in the cecum of the mice. RCIs can increase the diversity of beneficial bacteria such as Bacteroidaceae, Muribaculaceae, and Akkermansiaceae, and reduced the pathogenic Staphylococcaceae. Therefore, supplementing the diet with RCIs results in improved growth performance and notable alterations in the cecal microbiota in mice, and has potential applications as a feed additive to improve livestock production.

Alzheimer's disease (AD) is a prevalent and progressive neurodegenerative disorder that is the leading cause of dementia. The underlying mechanisms of AD have not yet been completely explored. Neuroinflammation, an inflammatory response mediated by certain mediators, has been exhibited to play a crucial role in the pathogenesis of AD. Additionally, disruption of the gut microbiota has been found to be associated with AD, and fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach. However, the precise mechanism of FMT in the treatment of AD remains elusive. In this study, FMT was performed by transplanting fecal microbiota from healthy wild-type mice into APP/PS1 mice (APPswe, PSEN1dE9) to assess the effectiveness of FMT in mitigating AD-associated inflammation and to reveal its precise mechanism of action. The results demonstrated that FMT treatment improved cognitive function and reduced the expression levels of inflammatory factors by regulating the TLR4/MyD88/NF-κB signaling pathway in mice, which was accompanied by the restoration of gut microbial dysbiosis. These findings suggest that FMT has the potential to ameliorate AD symptoms and delay the disease progression in APP/PS1 mice.

The interplay between gut microbiota and immune responses is crucial in ulcerative colitis (UC). Though Akkermansia muciniphila (Akk) shows therapeutic potential, the mechanisms remain unclear. This study sought to investigate differences in therapeutic efficacy among different forms or strains of Akk and elucidate the underlying mechanisms.

Employing a dextran sulfate sodium (DSS)-induced colitis mouse model, we assessed Akk's impact on colitis using cellular cytokine analysis, immune phenotyping, proteomics, and biochemical methods. Our results suggest that treatment with live Akk effectively reduced colitis in the DSS-induced model, whereas heat-inactivated Akk did not yield the same results. Notably, Akk exhibited protective properties by promoting the secretion of IL-22 by Group 3 innate lymphoid cells (ILC3s), as evidenced by the absence of protection in IL-22 knockout mice. Additionally, Akk augmented the population of CD103+CD11b- dendritic cells (DCs) and enhanced their retinoic acid (RA) synthesis through the modulation of RALDH2, a crucial enzyme in RA metabolism. The depletion of RALDH2 in DCs diminished Akk's protective properties and impaired IL-22-mediated mucosal healing. Mechanistically, Akk activated RA production in DCs by enhancing the JAK2-STAT3 signaling pathway. Additionally, various strains of Akk may exhibit differing abilities to alleviate colitis, with the novel strain Am06 derived from breast milk showing consistent efficacy similar to the reference strain.

In summary, our findings indicate that certain strains of Akk may mitigate colitis through the promotion of RA synthesis and IL-22 secretion, underscoring the potential efficacy of Akk as a therapeutic intervention for the management of UC. Video Abstract.

The gut microbiota (GM) may be associated with uveitis. However, the causal relationship between the GM and uveitis and whether blood metabolites act as mediators of the GM remain unclear. We extracted the GM, blood metabolites, and uveitis data from genome-wide association study (GWAS) summary data. We used Mendelian randomization (MR) to investigate the causal relationships among GM, blood metabolites, and uveitis. The primary statistical method used was the inverse variance weighted (IVW) method. In addition, we used 2-sample MR, bidirectional MR, 2-step method and multiple MR to explore whether blood metabolites were mediators of the association between the GM and uveitis. After removing confounding factors, the abundances of the order Bacillales and the genus Holdemanella are risk factors for uveitis, and the abundances of Peptococcus and Ruminococcaceae UCG010 are protective factors. The inverse analysis revealed that uveitis affected 6 GM taxa - 4 positively and 2 negatively. In addition, N-methyl proline and 2-hydroxy sebacate were identified as risk factors for uveitis, and N-formy1 phenylalanine, 1-ribosyl-imidazole acetate, 1-palmitoyl-2-arachidonoyl-GPE (16:0/20:4) and alpha-ketoglutarate/pyruvate were identified as protective factors for uveitis. Finally, there was a causal association between 3 GM taxa and 6 blood metabolites, with 6 positive and 2 negative effects. N-methylproline possessed the greatest mediated effect (9.41%) between Ruminococcaceae UCG010 and uveitis. These results provide new insights into the pathogenesis of uveitis and offer a new approach to uveitis prevention and treatment from GM and blood metabolites perspective.