The organophosphorus pesticide chlorpyrifos (CPF) is widely utilized in agriculture to protect crops from pests and diseases. Concerns regarding its extensive use have emerged due to the substance's persistence, bioaccumulation, endocrine disruption, and associated toxicity, which may lead to various adverse reactions. In this study, 32 male C57BL/6 J mice were orally administered varying doses of CPF over a period of two weeks. Metabolic perturbations resulting from subacute exposure to CPF were assessed using LC-MS/MS-based untargeted metabolomics, alongside biochemical analysis and histopathological techniques. The 16S rRNA gene sequencing method was employed to evaluate changes in the gut microbial community within the cecal contents of mice exposed to CPF. In vivo studies have shown that CPF exposure induced dose-dependent damage and dysregulation of the intestinal microbiota in mouse colonic tissues. This was characterized by significant alterations in the gut microbiota, increased intestinal permeability and elevated levels of lipopolysaccharides. These changes may have compromised intestinal barrier function and facilitated the transfer of intestinal microbial metabolites and endotoxins to the liver, subsequently leading to liver injury. Collectively, this study elucidates a potential mechanism by which CPF triggers liver injury through alterations in the intestinal microbial community and increased intestinal permeability. These findings not only enhance our understanding of the toxicological effects of CPF but also contribute to the assessment of health risks associated with CPF exposure.

The human gut hosts a diverse microbial community, essential for maintaining overall health. However, antibiotics, commonly prescribed for infections, can disrupt this delicate balance, leading to antibiotic-associated diarrhea, inflammatory bowel disease, obesity, and even neurological disorders. Recognizing this, probiotics have emerged as a promising strategy to counteract these adverse effects.

This review aims to offer a comprehensive overview of the latest evidence concerning the utilization of probiotics in managing antibiotic-associated side effects.

Probiotics play a crucial role in preserving gut homeostasis, regulating intestinal function and metabolism, and modulating the host immune system. These mechanisms serve to effectively alleviate antibiotic-associated adverse effects and enhance overall well-being.

Shigella is a significant cause of diarrhea, predominantly affecting children in low- and middle-income countries, as well as international travelers. Not all individuals exposed to Shigella or other enteropathogens have symptomatic responses, and investigating the differences between symptomatic and asymptomatic individuals can further our understanding of enteropathogen proliferation and symptomatic responses. Here, we profiled the fecal microbiomes of 45 individuals infected with Shigella sonnei strain 53G through 16S rRNA sequencing in a controlled human infection model before and during infection, after antibiotic treatment, and after clinical recovery. This model allowed for a detailed exploration of microbiome temporal dynamics during infection, as well as a comparative analysis between those with shigellosis (defined as severe symptoms caused by Shigella infection, including severe diarrhea, fever, and/or abdominal pain) and those without shigellosis. Alpha diversity decreased to a greater degree in individuals with shigellosis. Perturbations in microbial composition during infection and antibiotic treatment were significantly larger in individuals diagnosed with shigellosis than in those who were not. Participants with shigellosis had persistent changes to their microbiomes after recovery, while those without shigellosis recovered to a composition resembling their pre-infection microbiomes. These persistent changes included taxa associated with gut inflammation, such as a decrease in Faecalibacterium and an increase in Ruminococcus gnavus. Furthermore, the initial microbiomes of participants who did not develop shigellosis had a greater abundance of taxa associated with short-chain fatty acid production than participants who did develop shigellosis, including Bifidobacterium, Roseburia, and Faecalibacterium. These data could help prevent Shigella infection or symptoms.IMPORTANCEDiarrheal disease is a major contributor to the global disease burden and can lead to an increased individual risk of chronic sequelae post-infection, such as irritable bowel syndrome, reactive arthritis, and altered gut permeability. Understanding the differential responses of individuals to enteropathogen exposure can elucidate factors that could lead to treatments or preventative measures to reduce the disease burden. Here, we use a controlled human infection model study to directly identify the effects of Shigella sonnei 53G infection on the microbiome. We identified taxa that were more or less abundant in participants who would develop shigellosis during the study, as well as persistent changes after recovery in the microbiomes of participants who developed severe symptoms. Understanding these changes could elucidate ways to prevent Shigella infection or recover altered microbiomes after recovery.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02816346.

Systemic sclerosis (SSc) is an autoimmune disease with progressive fibrotic disorders in multiple organs. Mesenchymal stem cells (MSCs) have shown great potential in treating SSc, but the exact regulatory mechanism is not fully understood. In this study, we used human umbilical cord-derived MSCs (hUC-MSCs) to treat SSc mice induced by bleomycin. The gut microbiota composition and predicted functions were analyzed using 2bRAD sequencing of fecal samples from control, SSc, and MSCs-treated mice. Treatment with MSCs improved the bleomycin-induced SSc mice, characterized by significantly reduced collagen deposition and dermal thickness. The gut microbiota of SSc mice exhibited lower species evenness and was clearly separated from the control mice based on beta diversity. MSC treatment led to a significant reduction of conditionally pathogenic bacteria enriched in SSc, including Akkermansia muciniphila and Parasutterella excrementihominis. Conversely, the relative abundance of butyrate-producing bacteria, such as Roseburia, Butyricicoccus porcorum, and Gemmiger formicilis, was notably increased in MSCs-treated SSc mice. Additionally, the functional analysis revealed that MSCs intervention effectively enhanced sulfur metabolism, tryptophan metabolism, citrate cycle, RNA polymerase, and beta-lactam resistance. In summary, the findings in the present study have suggested the close association between gut microbiota and metabolic dysbiosis in mice with SSc. The administration of MSCs has been shown to regulate the disrupted metabolic pathways in SSc mice, thus restoring the normal function of the gut microbiota. This study provides valuable insights into the specific gut microbiota and metabolic pathways involved in the efficacy of MSC treatment, thereby proposing a novel therapeutic strategy for SSc.

Human umbilical cord-derived mesenchymal stem cells (HUC‑MSCs) demonstrate efficacy in alleviating skin thickening and collagen deposition in systemic sclerosis (SSc) mice, which also regulate the gut microbiota composition and function. Specifically, MSC intervention leads to a notable increase in butyrate-producing bacteria, a decrease in Akkermansia muciniphila and Parasutterella excrementihominis, and a reversal of the dysregulated microbial function in SSc mice. These findings underscore the potential significance of gut microbiota in the therapeutic effects of MSCs in SSc.

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

The gut microbiome and diet are important factors in the pathogenesis and management of Crohn's disease (CD). However, the role of the gut phageome under dietary influences is unknown.

We aim to explore the effect of diet on the gut phageome-bacteriome interaction linking to CD protection.

We recruited CD patients and healthy subjects (n=140) and conducted a multiomics investigation, including paired ileal mucosa phageome and bacteriome profiling, dietary survey and phenome interrogation. We screened for the effect of diet on the gut phageome and bacteriome, as well as its epidemiological association with CD risks. The underlying mechanisms were explored in target phage-bacteria monocultures and cocultures in vitro and in two mouse models in vivo.

On dietary screening in humans, whey protein (WP) consumption was found to profoundly impact the gut phageome and bacteriome (more pronounced on the phageome) and was associated with a lower CD risk. Indeed, the WP reshaped gut phageome can causally attenuate intestinal inflammation, as shown by faecal phageome versus bacteriome transplantation from WP-consuming versus WP-non-consuming mice to recipient mice. Mechanistically, WP induced phage (a newly isolated phage AkkZT003P herein) lysis of the mucin-foraging bacterium Akkermansia muciniphila, which unleashed the symbiotic bacterium Streptococcus thermophilus to counteract intestinal inflammation.

Our study charted the importance of cross-kingdom interaction between gut phage and bacteria in mediating the dietary effect on CD protection. Importantly, we uncovered a beneficial dietary WP, a keystone phage AkkZT003P, and a probiotic S. thermophilus that can be used in CD management in the future.

Epidemiological studies reveal that inflammatory bowel disease (IBD) is associated with an increased risk of Parkinson's disease (PD). Gut dysbiosis has been documented in both PD and IBD, however it is currently unknown whether gut dysbiosis underlies the epidemiological association between both diseases. To identify shared and distinct features of the PD and IBD microbiome, we recruited 54 PD, 26 IBD, and 16 healthy control individuals and performed the first joint analysis of gut metagenomes. Larger, publicly available PD and IBD metagenomic datasets were also analyzed to validate and extend our findings. Depletions in short-chain fatty acid (SCFA)-producing bacteria, including Roseburia intestinalis, Faecalibacterium prausnitzii, Anaerostipes hadrus, and Eubacterium rectale, as well depletion in SCFA-synthesis pathways were detected across PD and IBD datasets, suggesting that depletion of these microbes in IBD may influence the risk for PD development.

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.

Host immunity and commensal bacteria synergistically maintain intestinal homeostasis and mediate colonization resistance against pathogens. However, the molecular and cellular mechanisms remain unclear. Here, with a mouse infection model of Citrobacter rodentium, a natural mouse intestinal pathogen that mimics human enteropathogenic Escherichia coli and enterohaemorrhagic Escherichia coli, we find that group 3 innate lymphoid cells (ILC3s) can protect the host from infection by regulating gut microbiota. Mechanistically, ILC3s can control gut dysbiosis through IL-22-dependent regulation of intestinal galactosylation in mice. ILC3 deficiency led to an increase in intestinal galactosylation and the expansion of commensal Akkermansia muciniphila in colonic mucus. The increased A. muciniphila and A. muciniphila-derived metabolic product succinate further promoted the expression of pathogen virulence factors tir and ler, resulting in increased susceptibility to C. rodentium infection. Together, our data reveal a mechanism for ILC3s in protecting against pathogen infection through the regulation of intestinal glycosylation and gut microbiota metabolism.

Methamphetamine is a widely abused drug associated with significant neuroinflammation and neurodegeneration, mainly through the activation of glial cells and neurons in the central nervous system. This study investigates the role of the astrocyte-specific NOD-like receptor family pyrin domain-containing protein 6 (NLRP6) inflammasome in methamphetamine-induced astrocytic pyroptosis and neuroinflammation. Our findings demonstrate that methamphetamine exposure induces NLRP6-dependent pyroptosis, astrocyte activation, and the release of proinflammatory cytokines in mouse primary astrocytes. Gene silencing of NLRP6 reduces methamphetamine-induced pyroptosis and proinflammatory cytokines release. We also identified miR-152 as a critical upstream regulator of NLRP6, which is downregulated in methamphetamine-exposed astrocytes. Overexpression of miR-152 decreases NLRP6 expression, mitigating methamphetamine-induced pyroptosis and inflammation. In vivo and ex vivo studies in methamphetamine-exposed mice confirmed these results and showed that methamphetamine induces anxiety-like, cognitive impairment, and depression-like behavior, further linking astrocyte-specific NLRP6 signaling to methamphetamine-induced neuroinflammation. This study highlights the potential of targeting the NLRP6 inflammasome in astrocytes as a therapeutic approach to alleviate methamphetamine-induced central nervous system pathology. Further research is warranted to explore clinical applications and identify therapeutic targets for methamphetamine-related neurological disorders.

Ulcerative colitis (UC) is often characterized by dysbiosis of the colonic microbiota and metabolic disturbances, which can lead to liver damage. Patchoulene epoxide (PAO), a tricyclic sesquiterpene derived from the aged essential oil of Pogostemonis Herba, is known for its anti-inflammatory and ulcer-healing properties. However, its dual protective role against UC and liver injury remains largely unexplored. This study aims to elucidate the protective effect and underlying mechanism of PAO against dextran sulfate sodium (DSS)-induced UC and liver injury in mice.

Colitis and liver injury in mice were induced by adding 3% DSS to their drinking water continuously for 7 days, and PAO at the doses of 20 and 40 mg/kg was administered orally to mice daily from the first day until the experimental endpoint. Stool consistency scores, blood stool scores, and body weights were recorded weekly. Disease activity index (DAI) was determined before necropsy, where colon and liver tissues were collected for biochemical analyses. Additionally, the fecal microbiome and its metabolites of treated mice were characterized using 16S rRNA amplicon sequencing and metabolomics.

PAO significantly reduced the disease activity index and mitigated colonic atrophy in UC mice. It also improved colonic and hepatic pathological changes by safeguarding tight and adherens junctions, and suppressing the generation of pro-inflammatory cytokines and lipopolysaccharide. These beneficial effects were attributed to PAO's capability to regulate the colonic microbiota and metabolic processes. PAO was found to enhance the diversity of the colonic microbiota and to shift the microbial balance in UC mice. Specifically, it restored the microbiota from an Akkermansia-dominated state, characteristic of UC, to a healthier Muribaculaceae-dominated composition. Furthermore, PAO corrected the colon metabolic disturbance in UC mice by modulating the purine metabolism, notably increasing the abundance of deoxyadenosine, adenosine and guanine in UC mice.

The therapeutic effect of PAO on UC and liver injury was mainly attributed to its regulation of colonic microbiota and purine metabolism. These insights emphasize the overall therapeutic benefits of PAO in treating UC and liver injury.

The modern livestock industry faces significant challenges due to the extension of production cycles and a growing shortage of feed resources. Low-protein (LP) diets offer potential environmental advantages whereas damage intestinal integrity and increase pro-inflammatory cytokines. Bile acids (BAs), metabolic products of cholesterol in the liver, possess strong antioxidative and immune properties. This study evaluated the effects of dietary porcine BA supplementation at different protein levels on the antioxidant status, immune function, and gut microbiota of late-laying hens. A 2 × 2 factorial design was employed with 198 Hy-Line Brown laying hens (62 weeks old), randomly divided into one of four treatment groups with 8 replicates for each treatment. Diets included normal (16.42%) or low-protein (15.35%) levels, with porcine BAs supplemented at 0 or 120 mg/kg (62-69 weeks) and 0 or 200 mg/kg (70-75 weeks) over 14 weeks. Dietary protein levels and bile acids had no effect on organ development in laying hens. Low-protein diets increased serum anti-inflammatory cytokines IL-4 and IL-10 but elevated pro-inflammatory cytokines IL-1β (p < 0.05), corroborated by higher IL-10 gene expression in the ileum mucosa (p < 0.05). The supplementation of bile acids improved immune function by increasing serum IL-4 and TGF-β while decreasing IL-6 levels (p < 0.05). Moreover, bile acids treatments upregulated IL-10, TGF-β and ZO-1 gene expression in the ileum mucosa (p < 0.05) and alleviated oxidative stress by enhancing serum GSH-Px activity (p < 0.05). Additionally, both low-protein diets and bile acids enriched beneficial cecal bacteria, including Hungatella and Blautia, primarily linked to immune function. These findings demonstrate that porcine bile acids administration improve antioxidant capacity, immune function and gut microbiota dysbiosis. These beneficial effects were associated with Hungatella and Blautia levels, which may be responsible for the porcine bile acids efficacy in poultry nutrition.

Polysaccharides have been suggested to ameliorate metabolic diseases. However, their differential colitis-mitigating effects in mouse models with different colony structures remain poorly understood. Therefore, this study investigated the effects of polysaccharides from Lycium barbarum (LBP), sunflower (SP), and yam (YP) on colitis in C57BL/6 J (B6) mice born via vaginal delivery (VD) and in both caesarean section (CS)- and VD-born Institute of Cancer Research (ICR) mice. LBP was mainly composed of glucose (30.2 %), galactose (27.5 %), and arabinose (26.9 %). The main components of SP and YP were galacturonic acid (75.8 %) and glucose (98.1 %), respectively. Interestingly, LBP effectively alleviated body weight loss, reduced inflammatory cytokine levels, and restored intestinal barrier function in all three mouse models. Moreover, LBP decreased the abundance of norank_f__norank_o__Clostridia_UCG-014, Coriobacteriaceae_UCG-002, and norank_f_Eubacterium_coprostanoligenes_group in B6 mice, and the abundance of these genera positively correlated with pro-inflammatory cytokine levels. LBP increased the abundance of Lactobacillus, which was positively correlated with the levels of the protective factor, IL-10, in CS-born ICR mice. Collectively, our study suggests the potential application of LBP in the treatment of ulcerative colitis. We also provide an alternative method for restoring intestinal homeostasis in CS-born offspring.

Evidence-based dietary recommendations for individuals with inflammatory bowel diseases (IBD) are limited. Red meat consumption is associated with increased IBD incidence and relapse in patients, suggesting that switching to a plant-based diet may limit gut inflammation. However, the mechanisms underlying the differential effects of these diets remain poorly understood. Feeding diets containing plant- or animal-derived proteins to murine colitis models revealed that mice given a beef protein (BP) diet exhibited the most severe colitis, while mice fed pea protein (PP) developed mild inflammation. The colitis-promoting effects of BP were microbially-mediated as determined by bacterial elimination or depletion and microbiota transplant studies. In the absence of colitis, BP-feeding reduced abundance of Lactobacillus johnsonii and Turicibacter sanguinis and expanded Akkermansia muciniphila, which localized to the mucus in association with decreased mucus thickness and quality. BP-fed mice had elevated primary and conjugated fecal bile acids (BAs), and taurocholic acid administration to PP-fed mice worsened colitis. Dietary psyllium protected against BP-mediated inflammation, restored BA-modulating commensals and normalized BA ratios. Collectively, these data suggest that the protein component of red meat may be responsible, in part, for the colitis-promoting effects of this food source and provide insight into dietary factors that may influence IBD severity.

The gut microbiota play crucial roles in the digestion and degradation of nutrients, synthesis of biological agents, development of the immune system, and maintenance of gastrointestinal integrity. Gut dysbiosis is thought to be associated with type 2 diabetes mellitus (T2DM), one of the world's fastest growing diseases. The aim of this systematic review is to identify differences in the composition and diversity of the gut microbiota in individuals with T2DM.

A systematic search was conducted to identify studies reporting on the difference in gut microbiota composition between individuals with T2DM and healthy controls. Relevant studies were evaluated, and their characteristics and results were extracted using a standardized data extraction form. The studies were assessed for risk of bias and their findings were reported narratively.

58 observational studies published between 2010 and 2024 were included. Beta diversity was commonly reported to be different between individuals with T2DM and healthy individuals. Genera Lactobacillus, Escherichia-Shigella, Enterococcus, Subdoligranulum and Fusobacteria were found to be positively associated; while Akkermansia, Bifidobacterium, Bacteroides, Roseburia, Faecalibacteirum and Prevotella were found to be negatively associated with T2DM.

This systematic review demonstrates a strong association between T2DM and gut dysbiosis, as evidenced by differential microbial abundances and altered diversity indices. Among these taxa, Escherichia-Shigella is consistently associated with T2DM, whereas Faecalibacterium prausnitzii appears to offer a protective effect against T2DM. However, the heterogeneity and observational nature of these studies preclude the establishment of causative relationships. Future research should incorporate age, diet and medication-matched controls, and include functional analysis of these gut microbes.

https://www.crd.york.ac.uk/prospero/, identifier CRD42023459937.

Dysbiosis of gut microbiota plays a crucial role in acute radiation-induced intestinal injury. However, studies on the influence of gut microbiota on acute radiation-induced intestinal injury are inconsistent. In this study, we established an acute radiation-induced intestinal injury mouse model and performed fecal microbiota transplantation to explore the role of the gut microbiota in acute radiation-induced intestinal injury. We observed a significant increase in Akkermansia muciniphila following irradiation, whereas fecal microbiota transplantation effectively reduced A. muciniphila levels. Contrary to expectations, A. muciniphila supplementation increased acute radiation-induced intestinal injury and mortality. Mechanistically, postradiation A. muciniphila upregulates mucin metabolism genes and consumes mucin, thinning the mucosal barrier and promoting the adhesion and translocation of potential pathogens to epithelial cells, thus exacerbating acute radiation-induced intestinal injury. This enables A. muciniphila to use mucin as an energy source. Additionally, A. muciniphila increases the inflammatory macrophage changes and secretion of inflammatory cytokines, leading to a decrease in epithelial stem cell density and inhibition of goblet cell differentiation, further exacerbating acute radiation-induced intestinal injury. Our findings suggest that in certain intestinal environments, the addition of A. muciniphila may worsen radiation-induced intestinal damage; thus, alternative approaches to reverse the dysbiosis associated with radiotherapy should be explored.

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.

Akkermansia muciniphila, a Gram-negative anaerobic bacterium colonizing the intestinal mucus layer, is regarded as a promising "next-generation probiotic". There is mounting evidence that diabetes and its complications are associated with disorders of A. muciniphila abundance. Thus, A. muciniphil and its components, including the outer membrane protein Amuc_1100, A. muciniphila-derived extracellular vesicles (AmEVs), and the secreted proteins P9 and Amuc_1409, are systematically summarized with respect to mechanisms of action in diabetes mellitus. Diabetes treatments that rely on altering changes in A. muciniphila abundance are also reviewed, including the identification of A. muciniphila active ingredients, and dietary and pharmacological interventions for A. mucinihila abundance. The potential and challenges of using A. muciniphila are also highlighted, and it is anticipated that this work will serve as a reference for more in-depth studies on A. muciniphila and diabetes development, as well as the creation of new therapeutic targets by colleagues domestically and internationally.

The present investigation explores into the influence of dietary nutrients, particularly alpha-linolenic acid (ALA), a plant-derived omega-3 fatty acid abundant in perilla seed oil (PSO), on the development of colitis-associated colorectal cancer (CRC). The study employs a mouse model to scrutinize the effects of ALA-rich PSO in the context of inflammation-driven CRC. Perilla seeds were subjected to oil extraction, and the nutritional composition of the obtained oil was analysed. Male ICR mice, initiated at four weeks of age, were subjected to diets comprising 5%, 10%, or 20% PSO, 10% fish oil, or 5% soybean oil. All groups, with the exception of the control group (5% soybean oil), underwent induction with azoxymethane (AOM) and dextran sulphate sodium (DSS) to instigate CRC. Disease development, colon samples, preneoplastic lesions, dysplasia, and biomarkers were meticulously evaluated. Furthermore, gut microbiota composition was elucidated through 16S rRNA sequencing. The analysis revealed that PSO contained 61.32% ALA and 783.90 mg/kg tocopherols. Mice subjected to diets comprising 5% soybean or 10% fish oil exhibited higher tumour incidence, burden, multiplicity, and aberrant crypt counts. Remarkably, these parameters were significantly reduced in mice fed a 5% PSO diet. Additionally, 5% PSO-fed mice displayed reduced proliferative and pro-inflammatory markers in colon tissues, coupled with an alleviation of AOM/DSS-induced gut dysbiosis. Notably, PSO demonstrated inhibitory effects on colitis-associated CRC in the AOM/DSS mice model, achieved through the suppression of proliferative and pro-inflammatory protein levels, and mitigation of gut dysbiosis, with discernible efficacy observed at a 5% dietary concentration.

The microbiome greatly affects health and wellbeing. Evolutionarily, it is doubtful that a host would rely on chance alone to pass on microbial colonization to its offspring. However, the literature currently offers only limited evidence regarding two alternative hypotheses: active microbial shaping by host genetic factors or transmission of a microbial maternal legacy.

To further dissect the influence of host genetics and maternal inheritance, we collected two-cell stage embryos from two representative wild types, C57BL6/J and BALB/c, and transferred a mixture of both genotype embryos into hybrid recipient mice to be inoculated by an identical microbiome at birth.

Observing the offspring for six generations unequivocally emphasizes the impact of host genetic factors over maternal legacy in constant environments, akin to murine laboratory experiments. Interestingly, maternal legacy solely controlled the microbiome in the first offspring generation. However, current evidence supporting maternal legacy has not extended beyond this initial generation, resolving the aforementioned debate. Video Abstract.

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

Vanillic acid (VA) is a natural phenolic acid compound that is widely found in various foods and medicinal plants, with a remarkable antifibrotic effect observed in animal studies, but its exact antifibrotic mechanism remains unclear. Herein, hepatic function, fibrotic index, and histopathological, microbiome, and metabolomic methods were used to investigate the potential mechanisms behind the improvement effect of vanillic acid against thioacetamide (TAA)-induced liver fibrosis in mice. Our results showed that VA reversed TAA-induced liver fibrosis manifested a decrease in collagen fiber deposition, serum transaminase, serum hepatic fibrotic index, and liver inflammation indicator levels. When analyzed, TAA injection mainly increased the abundance of Akkermansia and Roseburia and significantly reduced the abundance of Anaerotruncus. VA reversed these changes back to normal levels to varying degrees. Metabolomic profiling demonstrated that VA treatment was efficacious in modulating several key liver metabolites involved in neuroactive ligand-receptor interaction, prolactin signaling pathway, estrogen signaling pathway, and glutathione metabolism. Conclusively, VA may ameliorate liver damage and suppress the fibrogenesis caused by thioacetamide by correcting intestinal microbiota disorders and promoting normal hepatic metabolism. This research provides a novel perspective on vanillic acid as a dietary supplement for hepatic fibrosis improvement.

Acute alcoholic liver injury (AALI) is a widespread disease that can develop into hepatitis, liver fibrosis, and cirrhosis. In severe cases, it can be life-threatening, while drug treatment presents various side effects. This study characterized the structure of natural lentinan (LNT) from the Qinba Mountain area and investigated the protective mechanism of different LNT doses (100 mg kg-1, 200 mg kg-1, and 400 mg kg-1) on AALI. The results showed that LNT was a glucose-dominated pyran polysaccharide with a triple-helical structure and a molecular weight (Mw) of 7.56 × 106 Da. An AALI mouse model showed that all the LNT doses protected liver function, reduced hepatic steatosis, alleviated oxidative stress and inflammatory response, and stimulated probiotic proliferation. Low-dose LNT increased anti-oxidant-associated beneficial bacteria, medium-dose LNT improved liver swelling and promoted anti-oxidant-associated probiotics, and high-dose LNT increased the probiotics that helped protect liver function and anti-oxidant and anti-inflammatory properties. All the LNT doses inhibited pathogenic growth, including Oscillospiraceae, Weeksellaceae, Streptococcaceae, Akkermansiaceae, Morganellaceae, and Proteus. These results indicated that the protective effect of LNT against AALI was mediated by the proliferation of various intestinal probiotics and was related to the consumption doses. These findings offer new strategies for comprehensively utilizing Lentinula edodes from the Qinba Mountain area and preventing AALI using natural food-based substances.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) marked by persistent inflammation of the mucosal lining of the large intestine, leading to debilitating symptoms and reduced quality of life. Emerging evidence suggests that an imbalance of the gut microbiota plays a crucial role in UC pathogenesis, and various signaling pathways are implicated in the dysregulated immune response. Probiotics are live microorganisms that confer health benefits to the host, have attracted significant attention for their potential to restore gut microbial balance and ameliorate inflammation in UC. Recent studies have elucidated the mechanisms by which probiotics modulate these signaling pathways, often by producing anti-inflammatory molecules and promoting regulatory immune cell function. For example, probiotics can inhibit the nuclear factor-κB (NF-κB) pathway by stabilizing Inhibitor of kappa B alpha (IκBα), dampening the production of proinflammatory cytokines. Similarly, probiotics can modulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, suppressing the activation of STAT1 and STAT3 and thus reducing the inflammatory response. A better understanding of the underlying mechanisms of probiotics in modulating pathogenic signaling pathways in UC will pave the way for developing more effective probiotic-based therapies. In this review, we explore the mechanistic role of probiotics in the attenuation of pathogenic signaling pathways, including NF-κB, JAK/STAT, mitogen-activated protein kinases (MAPKs), Wnt/β-catenin, the nucleotide-binding domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, Toll-like receptors (TLRs), interleukin-23 (IL-23)/IL-17 signaling pathway in UC.

Intestinal homeostasis is essential for maintaining human health, and its dysfunction is related to the onset and progression of various diseases, including immune and metabolic disorders, and even tumorigenesis. Intestinal microbiota plays a critical role in intestinal homeostasis, with Akkermansia muciniphila (A. muciniphila) emerging as a key commensal bacterium utilizing mucin as its sole carbon and nitrogen source. A. muciniphila has been recognized in both experimental and clinical studies for its beneficial role in managing intestinal inflammation, tumors, functional gastrointestinal disorders, and secondary conditions such as liver and metabolic diseases. This review provides a comprehensive overview of the research history and current understanding of A. muciniphila, its association with various intestinal-related diseases, and the potential mechanisms behind its effects. This paper also explores the possibilities of leveraging the probiotic enzyme such as the active ingredients of A. muciniphila for the innovative clinical treatment of intestinal-related diseases.

The intestinal mucus barrier is an important line of defense against gut pathogens. Damage to this barrier brings bacteria into close contact with the epithelium, leading to intestinal inflammation. Therefore, its restoration is a promising strategy for alleviating intestinal inflammation. This study showed that Abelmoschus manihot polysaccharide (AMP) fortifies the intestinal mucus barrier by increasing mucus production, which plays a crucial role in the AMP-mediated amelioration of colitis. IL-10-deficient mouse models demonstrated that the effect of AMP on mucus production is dependent on IL-10. Moreover, bacterial depletion and replenishment confirmed that the effects of AMP on IL-10 secretion and mucus production were mediated by Akkermansia muciniphila. These findings suggest that plant polysaccharides fortify the intestinal mucus barrier by maintaining homeostasis in the gut microbiota. This demonstrates that targeting mucus barrier is a promising strategy for treating intestinal inflammation.

Symbiotic interactions between humans and our communities of resident gut microbes (microbiota) play many roles in health and disease. Some gut bacteria utilize mucus as a nutrient source and can under certain conditions damage the protective barrier it forms, increasing disease susceptibility. We investigated how Ruminococcus torques-a known mucin degrader that has been implicated in inflammatory bowel diseases (IBDs)-degrades mucin glycoproteins or their component O-linked glycans to understand its effects on the availability of mucin-derived nutrients for other bacteria. We found that R. torques utilizes both mucin glycoproteins and released oligosaccharides from gastric and colonic mucins, degrading these substrates with a panoply of mostly constitutively expressed, secreted enzymes. Investigation of mucin oligosaccharide degradation by R. torques revealed strong α-L-fucosidase, sialidase and β1,4-galactosidase activities. There was a lack of detectable sulfatase and weak β1,3-galactosidase degradation, resulting in accumulation of glycans containing these structures on mucin polypeptides. While the Gram-negative symbiont, Bacteroides thetaiotaomicron grows poorly on mucin glycoproteins, we demonstrate a clear ability of R. torques to liberate products from mucins, making them accessible to B. thetaiotaomicron. This work underscores the diversity of mucin-degrading mechanisms in different bacterial species and the probability that some species are contingent on others for the ability to more fully access mucin-derived nutrients. The ability of R. torques to directly degrade a variety of mucin and mucin glycan structures and unlock released glycans for other species suggests that it is a keystone mucin degrader, which might contribute to its association with IBD.IMPORTANCEAn important facet of maintaining healthy symbiosis between host and intestinal microbes is the mucus layer, the first defense protecting the epithelium from lumenal bacteria. Some gut bacteria degrade the various components of intestinal mucins, but detailed mechanisms used by different species are still emerging. It is imperative to understand these mechanisms as they likely dictate interspecies interactions and may illuminate species associated with bacterial mucus damage and subsequent disease susceptibility. Ruminococcus torques is positively associated with IBD in multiple studies. We identified mucin glycan-degrading enzymes in R. torques and found that it shares mucin degradation products with another species of gut bacteria, Bacteroides thetaiotaomicron. Our findings underscore the importance of understanding mucin degradation mechanisms in different gut bacteria and their consequences on interspecies interactions, which may identify keystone bacteria that disproportionately affect mucus damage and could therefore be key players in effects that result from reductions in mucus integrity.

Due to its physiological benefits from in vitro and in vivo points of view, Akkermansia muciniphila, a common colonizer in the human gut mucous layer, has consistently been identified as an option for the next-generation probiotic. A. muciniphila is a significant bacterium that promotes host physiology. However, it also has a great deal of potential to become a probiotic due to its physiological advantages in a variety of therapeutic circumstances. Therefore, it can be established that the abundance of A. muciniphila in the gut environment, which is controlled by many genetic and dietary variables, is related to the biological behaviors of the intestinal microbiota and gut dysbiosis/eubiosis circumstances. Before A. muciniphila is widely utilized as a next-generation probiotic, regulatory obstacles, the necessity for significant clinical trials, and the sustainability of manufacturing must be eliminated. In this review, the outcomes of recent experimental and clinical reports are comprehensively reviewed, and common colonization patterns, main factors involved in the colonization of A. muciniphila in the gut milieu, their functional mechanisms in establishing homeostasis in the metabolic and energy pathways, the promising delivery role of microencapsulation, potential genetic engineering strategies, and eventually safety issues of A. muciniphila have been discussed.

NLRP6 plays a crucial role in maintaining intestinal homeostasis by regulating the interaction between the intestinal mucosa and the microbiota. However, the impact of NLRP6 deficiency on intestinal damage following hematopoietic stem cell transplantation (HSCT) remains poorly understood. In this study, we established a syngeneic HSCT mouse model using C57BL/6 mice as donors and NLRP6-/- or C57BL/6 mice as recipients. Our findings revealed that NLRP6 deficiency had minimal influence on peripheral blood cell counts and splenic immune cell proportions in transplanted mice. However, it exacerbated pathological changes in the small intestine on day 14 post-transplantation, accompanied by increased proportions of macrophages, dendritic cells, and neutrophils. Furthermore, the NLRP6 deficiency resulted in elevated expression of MPO and CD11b, while reducing the levels mature caspase-1 and mature IL-1β in the intestine. Moreover, the NLRP6 deficiency disturbed the expression of apoptosis-related molecules and decreased the tight junction protein occludin. Notably, recipient mice with NLRP6 deficiency exhibited lower mRNA expression levels of antimicrobial genes, such as Reg3γ and Pla2g2a. The short-term increase in inflammatory cell infiltration caused by NLRP6 deficiency was associated with intestinal damage, increased apoptosis, reduced expression of antimicrobial peptides, and impaired intestinal repair. Taken together, our findings demonstrate that the loss of NLRP6 exacerbates post-transplantation intestinal damage in recipient mice.

Proper and functional immune response requires a complex interaction between innate and adaptive immune cells, which dendritic cells (DCs) are the primary actors in this coordination as professional antigen-presenting cells. DCs are armed with numerous pattern recognition receptors (PRRs) such as nucleotide-binding and oligomerization domain-like receptors (NLRs) like NLRP3, which influence the development of their activation state upon sensation of ligands. NLRP3 is a crucial component of the immune system for protection against tumors and infectious agents, because its activation leads to the assembly of inflammasomes that cause the formation of active caspase-1 and stimulate the maturation and release of proinflammatory cytokines. But, when NLRP3 becomes overactivated, it plays a pathogenic role in the progression of several autoimmune disorders. So, NLRP3 activation is strictly regulated by diverse signaling pathways that are mentioned in detail in this review. Furthermore, the role of NLRP3 in all of the diverse immune cells' subsets is briefly mentioned in this study because NLRP3 plays a pivotal role in modulating other immune cells which are accompanied by DCs' responses and subsequently influence differentiation of T cells to diverse T helper subsets and even impact on cytotoxic CD8+ T cells' responses. This review sheds light on the functional and therapeutic role of NLRP3 in DCs and its contribution to the occurrence and progression of autoimmune disorders, prevention of diverse tumors' development, and recognition and annihilation of various infectious agents. Furthermore, we highlight NLRP3 targeting potential for improving DC-based immunotherapeutic approaches, to be used for the benefit of patients suffering from these disorders.

Postpartum depression (PPD) is a severe mental disorder that affects approximately 10---20% of women after childbirth. The precise mechanism underlying PPD pathogenesis remains elusive, thus limiting the development of therapeutics. Gut microbiota dysbiosis is considered to contribute to major depressive disorder. However, the associations between gut microbiota and PPD remain unanswered. Here, we established a mouse PPD model by sudden ovarian steroid withdrawal after hormone-simulated pseudopregnancy-human (HSP-H) in ovariectomy (OVX) mouse. Ovarian hormone withdrawal induced depression-like and anxiety-like behaviors and an altered gut microbiota composition. Fecal microbiota transplantation (FMT) from PPD mice to antibiotic cocktail-treated mice induced depression-like and anxiety-like behaviors and neuropathological changes in the hippocampus of the recipient mice. FMT from healthy mice to PPD mice attenuated the depression-like and anxiety-like behaviors as well as the inflammation mediated by the NOD-like receptor protein (NLRP)-3/caspase-1 signaling pathway both in the gut and the hippocampus, increased fecal short-chain fatty acids (SCFAs) levels and alleviated gut dysbiosis with increased SCFA-producing bacteria and reduced Akkermansia in the PPD mice. Also, downregulation of NLRP3 in the hippocampus mitigated depression-like behaviors in PPD mice and overexpression of NLRP3 in the hippocampal dentate gyrus induced depression-like behaviors in naïve female mice. Intriguingly, FMT from healthy mice failed to alleviate depression-like behaviors in PPD mice with NLRP3 overexpression in the hippocampus. Our results highlighted the NLRP3 inflammasome as a key component within the microbiota-gut-brain axis, suggesting that targeting the gut microbiota may be a therapeutic strategy for PPD.

To identify the gut bacteria associated with chemotherapeutic outcomes, t characterized the gut microbiota in patients with esophageal squamous cell carcinoma (ESCC) in this prospective study.

Thirty-one patients with ESCC were enrolled. Chemotherapy was performed with paclitaxel and cisplatin (TP). Fecal samples were collected before and after treatment and analyzed using 16S rRNA sequencing.

The species with differences in baseline abundance between partial response (PR) and non-PR groups was identified as Bacteroides plebeius (P = 0.043). The baseline abundance of B. plebeius was higher in the responder (R, PR + stable disease (SD)) group (P = 0.045) than in the non-responder (NR). The abundance of B. ovatus was identified as a predictor for distinguishing patients with PR from those without PR (sensitivity, 83.3 %; specificity, 69.6 %). The abundance of B. plebeius was positively associated with the response to PR + SD (R) in predicting responders in the receiver operating characteristic (ROC) curve analysis (area under the ROC curve = 0.865, P = 0.041). The abundance of B. plebeius and B.uniform was a predictor of grade (G) 3-4 chemotherapy toxicities. The sensitivity and specificity of the established multi-analyte microbial predictive model demonstrated a better predictive ability than a single parameter (B. uniform or B. plebeius).

The abundance of gut microbiota B. plebeius and B. ovatus are associated with the efficacy of TP chemotherapy in patients with ESCC. The abundance of B. plebeius and B.uniform may related to the toxicity of TP chemotherapy.

Probiotics are increasingly used to manage gut dysbiosis-related conditions due to their robust ability to manipulate the gut microbial community. However, few studies have reported that probiotics can specifically modulate individual gut microbes. This study demonstrated that administering the probiotic, Lactiplantibacillus fermentum F6, could ameliorate dextran sulfate sodium-induced colitis in a rat model, evidenced by the decreases in the disease activity index score, histopathology grading, and serum pro-inflammatory cytokine levels, as well as the increase in the serum anti-inflammatory cytokine levels. Shotgun metagenomics revealed that the fecal metagenomic of colitis rats receiving the probiotic intervention contained substantially fewer Akkermansia muciniphila than the dextran sulfate sodium group. Thus, the probiotic mechanism might be exerted by reducing specific gut microbial species associated with disease pathogenesis. A new paradigm for designing probiotics that manage diseases through direct and precise manipulation of gut microbes has been provided through this study.