The intestinal barrier serves as a boundary between the mucosal immune system in the lamina propria and the external environment of the intestinal lumen, which contains a diverse array of microorganisms and ingested environmental factors, including pathogens, food antigens, toxins, and other foreign substances. This barrier has a central role in regulating the controlled interaction between luminal factors and the intestinal immune system. Disruptions of intestinal epithelial cells, which serve as a physical barrier, or the antimicrobial peptides and mucins they produce, which act as a chemical barrier, can lead to a leaky gut. In this state, the intestinal wall is unable to efficiently separate the intestinal flora and luminal contents from the intestinal immune system. The subsequent activation of the immune system has an important role in the pathogenesis of inflammatory bowel disease, as well as in metabolic dysfunction-associated steatohepatitis, primary sclerosing cholangitis, and colorectal cancer. Dysregulated intestinal barrier integrity has also been described in patients with chronic inflammatory diseases outside the gastrointestinal tract, including rheumatoid arthritis and neurodegenerative disorders. Mechanistic studies of barrier dysfunction have revealed that the subsequent local activation and systemic circulation of activated immune cells and the cytokines they secrete, as well as extracellular vesicles, promote proinflammatory processes within and outside the gastrointestinal tract. In this Review, we summarise these findings and highlight several new therapeutic concepts currently being developed that attempt to control inflammatory processes via direct or indirect modulation of intestinal barrier function.

Dietary fiber plays a crucial role in maintaining gastrointestinal health. However, its protective effects on the intestinal health of calves remain to be fully elucidated. This study aimed to investigate the impact of dietary fiber supplementation on the intestinal microbiota of pre-weaned calves and its potential role in modulating microbial metabolic pathways.

A randomized controlled trial was conducted, enrolling 135 calves that were randomly assigned into three groups: (1) inulin supplementation, (2) psyllium husk powder (PHP) supplementation, and (3) a control group receiving no dietary fiber. Fecal microbiota samples were collected from calves without diarrhea at five time points (0, 7, 14, 28, and 56 days of age). Metagenomic sequencing was performed to analyze microbial composition and functional pathways. Additionally, a differential analysis of carbohydrate-active enzymes (CAZymes) was performed to evaluate the effect of dietary fiber on carbohydrate metabolism enzyme activity within the intestinal microbiota.

Calves supplemented with dietary fiber exhibited a significant increase in the abundance of Bifidobacterium and Prevotella compared to the control group. These bacterial genera contributed to intestinal protection by modulating secondary bile acid metabolism and flavonoid metabolism pathways. CAZymes differential analysis revealed an increased abundance of carbohydrate metabolism enzymes in response to dietary fiber supplementation, with distinct microbial community compositions observed among different fiber treatments. Notably, at 56 days of age, calves fed PHP harbored intergeneric symbiotic clusters comprising Clostridium, Prevotella, and Bacteroides, suggesting a cooperative microbial network that may contribute to intestinal homeostasis.

The findings of this study highlight the beneficial effects of dietary fiber on calf intestinal microbiota, particularly in enhancing microbial diversity and enzymatic activity related to carbohydrate metabolism. The observed microbial symbiosis in PHP-fed calves suggests a potential role in maintaining intestinal homeostasis. These insights provide a theoretical foundation for optimizing dietary interventions to promote gut health in calves during the transition period. Further research is warranted to explore the mechanistic interactions between dietary fiber, gut microbiota, and host health outcomes.

The human microbiome, an intricate ecosystem of trillions of microbes residing across various body sites, significantly influences cancer, a leading cause of morbidity and mortality worldwide. Recent studies have illuminated the microbiome's pivotal role in cancer development, either through direct cellular interactions or by secreting bioactive compounds such as metabolites. Microbial metabolites contribute to cancer initiation through mechanisms such as DNA damage, epithelial barrier dysfunction, and chronic inflammation. Furthermore, microbial metabolites exert dual roles on cancer progression and response to therapy by modulating cellular metabolism, gene expression, and signaling pathways. Understanding these complex interactions is vital for devising new therapeutic strategies. This review highlights microbial metabolites as promising targets for cancer prevention and treatment, emphasizing their impact on therapy responses and underscoring the need for further research into their roles in metastasis and therapy resistance.

Acute-on-chronic liver failure (ACLF) is a severe condition in patients with decompensated liver cirrhosis, marked by high short-term mortality. Recent experimental and clinical evidence has linked intestinal dysfunction to both the initiation of ACLF as well as disease outcome. This review discusses the significant role of the gut-liver axis in ACLF pathogenesis, highlighting recent advances. Gut mucosal barrier disruption, gut dysbiosis, and bacterial translocation emerge as key factors contributing to systemic inflammation in ACLF. Different approaches of therapeutically targeting the gut-liver axis via farnesoid X receptor agonists, nonselective beta receptor blockers, antibiotics, and probiotics are discussed as potential strategies mitigating ACLF progression. The importance of understanding the distinct pathophysiology of ACLF compared with other stages of liver cirrhosis is highlighted. In conclusion, research findings suggest that disruption of intestinal integrity may be an integral component of ACLF pathogenesis, paving the way for novel diagnostic and therapeutic approaches to manage this syndrome more effectively.

Consumption of a high-fat, high-carbohydrate Western-style diet (WD) associated with obesity and inflammation in humans has not been investigated in dogs.

To determine the effects of WD on inflammatory indices, microbiome, and fecal bile acids (BAs) in dogs.

Ten adult clinically healthy dogs.

A dietary trial compared the effects of two home-prepared diets: a high-fiber, low-fat control diet (CD) to a diet containing the macronutrient composition of WD (low-fiber, high fat). Dietary treatments were given sequentially for three feeding periods, each lasting 1 month. Outcome measures included molecular/microbiologic testing of colonic biopsies, histopathology, inflammatory biomarkers, and quantification of fecal BA following each feeding period.

Cell markers of apoptosis (TUNEL-positive cells: CD1, 0.36% ± 0.2%; WD, 0.79% ± 0.5%; CD2, 0.42% ± 0.3%; 95% CI) and inflammation (NF-ĸB area: CD1, 8.09% ± 3.3%; WD, 11.58% ± 3.4%; CD2 7.25% ± 3.8%; 95% CI), as well as serum high-sensitivity C-reactive protein (CD1, 2.0 ± 0.4 ng/mL; WD, 2.76 ± 0.23 ng/mL; CD2, 2.29 ± 0.25 ng/mL; 95% CI), were increased (p < 0.05) in dogs fed WD versus CD. Other perturbations seen with WD ingestion included altered (p < 0.05) colonic mucosal bacteria (bacterial counts: CD1, 301.5 ± 188.5; WD, 769.8 ± 431.9; CD2, 542.1 ± 273.9; 95% CI) and increased (p < 0.05) fecal cholic acid (median and interquartile range/IQR: CD1, 9505 [2384-33 788] peak heights; WD, 34 131 [10 113-175 909] peak heights) and serum myeloperoxidase (CD1, 46.98 ± 16.6 ng/mL; WD, 82.93 ± 33.6 ng/mL; CD2, 63.52 ± 29.5 ng/mL; 95% CI).

WD fed to clinically healthy dogs promotes colonic dysbiosis, altered fecal BA, and low-grade inflammation independent of obesity.

Background: This study explores the potential of the Pleurotus eryngii mushroom fermentation supernatant (FS-PEWS) as an intervention for mitigating sodium deoxycholate (SDC)-induced intestinal barrier dysfunction and inflammation. Methods: FS-PEWS was assessed for its protective effects against SDC-induced barrier dysfunction and inflammation using an in vitro Caco-2 cell model and ex vivo colonic biopsies from healthy adult donors, where barrier integrity, permeability, immunomodulation and receptor-mediated pathways were evaluated. Results: In Caco-2 cells, SDC exposure downregulated ZO-1, occludin, and claudin-1 expression, with FS-PEWS restoring ZO-1 and claudin-1 levels while maintaining cell viability. In colonic biopsies from healthy adults, FS-PEWS maintained tissue integrity and selectively mitigated transcellular permeability without affecting paracellular permeability when combined with the stressor. Additionally, FS-PEWS exhibited potent anti-inflammatory effects, reducing pro-inflammatory cytokines, e.g., TNF-α, IL-6, and IL-1β and modulating receptor-mediated pathways, i.e., TLR-4, dectin-1. Conclusions: These results demonstrate the potential of FS-PEWS to sustain intestinal barrier function and modulate immune responses under stress, highlighting its therapeutic potential for managing gut barrier dysfunction and inflammation associated with microbial metabolite-induced disruptions.

Microbial metabolism of bile acids (BAs) is crucial for maintaining homeostasis in vertebrate hosts and environments. Although certain organisms involved in bile acid metabolism have been identified, a global, comprehensive elucidation of the microbes, metabolic enzymes, and bile acid remains incomplete. To bridge this gap, we employed hidden Markov models to systematically search in a large-scale and high-quality search library comprising 28,813 RefSeq multi-kingdom microbial complete genomes, enabling us to construct a secondary bile acid production gene catalog. This catalog greatly expanded the distribution of secondary bile acid production genes across 11 phyla, encompassing bacteria, archaea, and fungi, and extended to 14 habitats spanning hosts and environmental contexts. Furthermore, we highlighted the associations between secondary bile acids (SBAs) and gastrointestinal and hepatic disorders, including inflammatory bowel disease (IBD), colorectal cancer (CRC), and nonalcoholic fatty liver disease (NAFLD), further elucidating disease-specific alterations in secondary bile acid production genes. Additionally, we proposed the pig as a particularly suitable animal model for investigating secondary bile acid production in humans, given its closely aligned secondary bile acid production gene composition. This gene catalog provides a comprehensive and reliable foundation for future studies on microbial bile acid metabolism, offering new insights into the microbial contributions to health and disease.

Bile acid metabolism is an important function in both host and environmental microorganisms. The existing functional annotations from single source pose limitations on cross-habitat analysis. Our construction of a systematic secondary bile acid production gene catalog encompassing numerous high-quality reference sequences propelled research on bile acid metabolism in the global microbiome, holding significance for the concept of One Health. We further highlighted the potential of the microbiota-secondary bile acid axis as a target for the treatment of hepatic and intestinal diseases, as well as the varying feasibility of using animal models for studying human bile acid metabolism. This gene catalog offers a solid groundwork for investigating microbial bile acid metabolism across different compartments, including humans, animals, plants, and environments, shedding light on the contributions of microorganisms to One Health.

Numerous studies have revealed that a long-term high-fat diet can raise intestinal deoxycholate acid concentration, which can harm intestinal mucosal barrier function in several ways. This study aims to verify the protective effect of GYY4137, as a slow-releasing H2S donor, on microbiome disturbance and the chronic injury of the intestinal mucosal barrier function caused by sodium deoxycholate.

Caco-2 monolayer and mouse models were treated with a relatively high concentration of sodium deoxycholate (1.0 mM and 0.2%, respectively) for longer periods (32 h and 12 weeks, respectively) to understand the effects of GYY4137 on sodium deoxycholate-induced chronic intestinal barrier dysfunction and its fundamental mechanisms.

A relatively long period of sodium deoxycholate treatment can remarkably increase the intestinal barrier permeability, alter the distribution and expression of tight junction proteins and generate the production of pro-inflammatory cytokines (TNF-α and IL-1β) in the Caco-2 monolayers and mouse models. Moreover, it can activate the MLCK-P-MLC2 pathway in the Caco-2 monolayers, which was further confirmed using RNA sequencing. The body weight, intestinal barrier histological score, and TUNEL index of sodium deoxycholate-treated mice worsened. In addition, an induced microbiome imbalance was observed in these mice. The above variations can be reversed with the administration of GYY4137.

This study demonstrates that GYY4137 ameliorates sodium deoxycholate-induced chronic intestinal barrier injury by restricting the MLCK-P-MLC2 pathway while elevating the expression level of tight junction proteins, anti-apoptosis and maintaining the microbiome's homeostasis.

Excess body fat elevates colorectal cancer risk. While bariatric surgery (BRS) induces significant weight loss, its effects on the fecal stream and colon biology are poorly understood. Specifically, limited data exist on the impact of bariatric surgery (BRS) on fecal secondary bile acids (BA), including lithocholic acid (LCA), a putative promotor of colorectal carcinogenesis.

This cross-sectional case-control study included 44 patients with obesity; 15 pre-BRS (controls) vs. 29 at a median of 24.1 months post-BRS. We examined the fecal concentrations of 11 BA by liquid chromatography and gene abundance of BA-metabolizing bacterial enzymes through fecal metagenomic sequencing. Differences were quantified using non-parametric tests for BA levels and linear discriminant analysis (LDA) effect size (LEfSe) for genes encoding BA-metabolizing enzymes.

Total fecal secondary BA concentrations trended towards lower levels post- vs. pre-BRS controls (p = 0.07). Individually, fecal LCA concentrations were significantly lower post- vs. pre-BRS (8477.0 vs. 11,914.0 uM/mg, p < 0.008). Consistent with this finding, fecal bacterial genes encoding BA-metabolizing enzymes, specifically 3-betahydroxycholanate-3-dehydrogenase (EC 1.1.1.391) and 3-alpha-hydroxycholanate dehydrogenase (EC 1.1.1.52), were also lower post- vs. pre-BRS controls (LDA of - 3.32 and - 2.64, respectively, adjusted p < 0.0001). Post-BRS fecal BA concentrations showed significant inverse correlations with weight loss, a healthy diet quality, and increased physical activity.

Concentrations of LCA, a secondary BA, and bacterial genes needed for BA metabolism are lower post-BRS. These changes can impact health and modulate the colorectal cancer cascade. Further research is warranted to examine how surgical alterations and the associated dietary changes impact bile acid metabolism.

Bile acids (BAs) play a crucial role in the human body's defense against infections caused by bacteria, fungi, and viruses. BAs counteract infections not only through interactions with intestinal bacteria exhibiting bile salt hydrolase (BSH) activity but they also directly combat infections. Building upon our research group's previous discoveries highlighting the role of BAs in combating infections, we have initiated an in-depth investigation into the interactions between BAs and intestinal microbiota. Leveraging the existing literature, we offer a comprehensive analysis of the relationships between BAs and 16 key microbiota. This investigation encompasses bacteria (e.g., Clostridioides difficile (C. difficile), Staphylococcus aureus (S. aureus), Escherichia coli, Enterococcus, Pseudomonas aeruginosa, Mycobacterium tuberculosis (M. tuberculosis), Bacteroides, Clostridium scindens (C. scindens), Streptococcus thermophilus, Clostridium butyricum (C. butyricum), and lactic acid bacteria), fungi (e.g., Candida albicans (C. albicans) and Saccharomyces boulardii), and viruses (e.g., coronavirus SARS-CoV-2, influenza virus, and norovirus). Our research found that Bacteroides, C. scindens, Streptococcus thermophilus, Saccharomyces boulardii, C. butyricum, and lactic acid bacteria can regulate the metabolism and function of BSHs and 7α-dehydroxylase. BSHs and 7α-dehydroxylase play crucial roles in the conversion of primary bile acid (PBA) to secondary bile acid (SBA). It is important to note that PBAs generally promote infections, while SBAs often exhibit distinct anti-infection roles. In the antimicrobial action of BAs, SBAs demonstrate antagonistic properties against a wide range of microbiota, with the exception of norovirus. Given the intricate interplay between BAs and intestinal microbiota, and their regulatory effects on infections, we assert that BAs hold significant potential as a novel approach for preventing and treating microbial infections.

The impact of dietary nutrients on body growth performance and the composition of gut microbes and metabolites is well-established. In this study, we aimed to determine whether dietary protein can regulate the physiological indexes and changes the intestinal tissue morphology in rats, and if dietary protein was a crucial regulatory factor for the composition, function, and metabolic pathways of the gut microbiota.

A total of thirty male Sprague Dawley (SD) rats (inbred strain, weighted 110 ± 10 g) were randomly assigned to receive diets containing animal-based protein (whey protein, WP), plant-based protein (soybean protein, SP), or a blended protein (soybean-whey proteins, S-WP) for a duration of 8 weeks. To investigate the effects of various protein supplement sources on gut microbiota and metabolites, we performed a high throughput 16S rDNA sequencing association study and fecal metabolomics profiling on the SD rats. Additionally, we performed analyses of growth indexes, serum biochemical indexes, and intestinal morphology.

The rats in S-WP and WP group exhibited a significantly higher body weight and digestibility of dietary protein compared to the SP group (P < 0.05). The serum total protein content of rats in the WP and S-WP groups was significantly higher (P < 0.05) than that in SP group, and the SP group exhibited significantly lower (P < 0.05) serum blood glucose levels compared to the other two groups. The morphological data showed the rats in the S-WP group exhibited significantly longer villus height and shallower crypt depth (P < 0.05) than the SP group. The gut microbial diversity of the SP and S-WP groups exhibited a higher level than that of the WP group, and the microbiomes of the WP and S-WP groups are more similar compared to those of the SP group. The Arachidonic acid metabolism pathway is the most significant KEGG pathway when comparing the WP group and the SP group, as well as when comparing the SP group and the S-WP group.

The type of dietary proteins exerted a significant impact on the physiological indices of SD rats. Intake of S-WP diet can enhance energy provision, improve the body's digestion and absorption of nutrients, as well as promote intestinal tissue morphology. In addition, dietary protein plays a crucial role in modulating fecal metabolites by regulating the composition of the gut microbiota. Metabolomics analysis revealed that the changes in the levels of arachidonic acid metabolites and secondary bile acid metabolite induced by Clostridium_sensu_stricto_1 and [Eubacterium]_coprostanoligenes_group maybe the primarily causes of intestinal morphological differences.

The potential involvement of the gut microbiota in metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis has garnered increasing attention. In this study, we elucidated the link between high-fat/cholesterol/cholate-based (iHFC)#2 diet-induced MASH progression and gut microbiota in C57BL/6 mice using antibiotic treatments. Treatment with vancomycin (VCM), which targets gram-positive bacteria, exacerbated the progression of liver damage, steatosis, and fibrosis in iHFC#2-fed C57BL/6 mice. The expression levels of inflammation- and fibrosis-related genes in the liver significantly increased after VCM treatment for 8 weeks. F4/80+ macrophage abundance increased in the livers of VCM-treated mice. These changes were rarely observed in the iHFC#2-fed C57BL/6 mice treated with metronidazole, which targets anaerobic bacteria. A16S rRNA sequence analysis revealed a significant decrease in α-diversity in VCM-treated mice compared with that in placebo-treated mice, with Bacteroidetes and Firmicutes significantly decreased, while Proteobacteria and Verrucomicrobia increased markedly. Finally, VCM treatment dramatically altered the level and balance of bile acid (BA) composition in iHFC#2-fed C57BL/6 mice. Thus, the VCM-mediated exacerbation of MASH progression depends on the interaction between the gut microbiota, BA metabolism, and inflammatory responses in the livers of iHFC#2-fed C57BL/6 mice.

Tsumura-Suzuki non-obese (TSNO) mice exhibit a severe form of metabolic dysfunction-associated steatohepatitis (MASH) with advanced liver fibrosis upon feeding a high-fat/cholesterol/cholate-based (iHFC) diet. Another ddY strain, Tsumura-Suzuki diabetes obese (TSOD) mice, are impaired in the progression of iHFC diet-induced MASH.

To elucidate the underlying mechanisms contributing to the differences in MASH progression between TSNO and TSOD mice.

We analyzed differences in the immune system, gut microbiota, and bile acid metabolism in TSNO and TSOD mice fed with a normal diet (ND) or an iHFC diet.

TSOD mice had more anti-inflammatory macrophages in the liver than TSNO mice under ND feeding, and were impaired in the iHFC diet-induced accumulation of fibrosis-associated macrophages and formation of histological hepatic crown-like structures in the liver. The gut microbiota of TSOD mice also exhibited a distinct community composition with lower diversity and higher abundance of Akkermansia muciniphila compared with that in TSNO mice. Finally, TSOD mice had lower levels of bile acids linked to intestinal barrier disruption under iHFC feeding.

The dynamics of liver macrophage subsets, and the compositions of the gut microbiota and bile acids at steady state and post-onset of MASH, had major impacts on MASH development.

Inflammasomes are a central component of innate immunity and play a vital role in regulating innate immune response. Activation of inflammasomes is also indispensable for adaptive immunity, modulating the development and response of adaptive immunity. Recently, increasing studies have shown that metabolic alterations and adaptations strongly influence and regulate the differentiation and function of the immune system. In this review, we will take a holistic view of how inflammasomes bridge innate and adaptive (especially T cell) immunity and how inflammasomes crosstalk with metabolic signals during the immune responses. And, special attention will be paid to the metabolic control of inflammasome-mediated interactions between innate and adaptive immunity in disease. Understanding the metabolic regulatory functions of inflammasomes would provide new insights into future research directions in this area and may help to identify potential targets for inflammasome-associated diseases and broaden therapeutic avenues.

Aim: The cell matrix of plant foods has received little attention in prebiotic fiber research. We aimed to understand the impact of the plant cell matrix in dried chicory root on its breakdown in the human gut to explain its reported beneficial effects on gut and metabolic health. Methods: We applied in vitro digestion and fermentation models together with an ex vivo gut barrier integrity model. Plant cell matrix intactness in the upper gastrointestinal tract was investigated by scanning electron microscopy. Colonic breakdown of inulin, and chicory root cubes and powder was assessed by gut microbiota analysis using 16S rRNA gene amplicon sequencing and determining the kinetics of changes in pH, gas, and short-chain fatty acid (SCFA) production. Finally, effects on gut barrier integrity were explored by exposing colonic biopsies to fermentation supernatants in an Ussing chamber model. Results: The plant cell matrix of dried chicory root cubes remained intact throughout upper gastrointestinal transit. Dried chicory root fermentation resulted in higher final relative abundances of pectin-degrading Monoglobus and butyrate-producing Roseburia spp. compared to inulin and a seven-fold increase in Bifidobacterium spp. in donors where these species were present. Dried chicory root cubes yielded similar total SCFAs but higher final butyrate levels than chicory root powder or isolated inulin with less gas produced. No uniform but donor-specific effects of fermentation supernatants on the maintenance of gut barrier integrity were detected. Conclusion: The intact plant cell matrix of dried chicory root affected its colonic breakdown kinetics and microbiota, underpinning its beneficial effect in vivo.

Crosstalk between gut and brain has long been appreciated in health and disease, and the gut microbiota is a key player in communication between these two distant organs. Yet, the mechanisms through which the microbiota influences development and function of the gut-brain axis remain largely unknown. Barriers present in the gut and brain are specialized cellular interfaces that maintain strict homeostasis of different compartments across this axis. These barriers include the gut epithelial barrier, the blood-brain barrier and the blood-cerebrospinal fluid barrier. Barriers are ideally positioned to receive and communicate gut microbial signals constituting a gateway for gut-microbiota-brain communication. In this Review, we focus on how modulation of these barriers by the gut microbiota can constitute an important channel of communication across the gut-brain axis. Moreover, barrier malfunction upon alterations in gut microbial composition could form the basis of various conditions, including often comorbid neurological and gastrointestinal disorders. Thus, we should focus on unravelling the molecular and cellular basis of this communication and move from simplistic framing as 'leaky gut'. A mechanistic understanding of gut microbiota modulation of barriers, especially during critical windows of development, could be key to understanding the aetiology of gastrointestinal and neurological disorders.

The limited tolerance of crustacean tissue physiology to a high-fat diet has captured the attention of researchers. Yet, investigations into the physiological response mechanisms of the crustacean intestinal barrier system to a high-fat diet are progressing slowly. Elucidating potential physiological mechanisms and determining the precise regulatory targets would be of great physiological and nutritional significance. This study established a high-fat diet-induced intestinal barrier damage model in Macrobrachium rosenbergii, and systematically investigated the functions of gut microbiota and its functional metabolites. The study achieved this by monitoring phenotypic indicators, conducting 16S rDNA sequencing, targeted metabolomics, and in vitro anaerobic fermentation of intestinal contents. Feeding prawns with control and high-fat diets for 8 weeks, the lipid level of 7 % in the CON diet and 12 % in the HF diet. Results showed that high-fat intake impaired the intestinal epithelial cells, intestinal barrier structure, and permeability of M. rosenbergii, activated the tight junction signaling pathway inhibiting factor NF-κB transcription factor Relish/myosin light chain kinase (MLCK), and suppressed the expression of downstream tight junction proteins zona occludens protein 1 (ZO-1) and Claudin. High-fat intake resulted in a significant increase in abundance of Aeromonas, Enterobacter, and Clostridium sensu stricto 3 genera, while Lactobacillus, Lactococcus, Bacteroides, and Ruminococcaceae UCG-010 genera were significantly decreased. Targeted metabolomics results of bile acids and short-chain fatty acids in intestinal contents and in vitro anaerobic fermentation products showed a marked rise in the abundance of DCA, 12-KetoLCA, 7,12-diketoLCA, and Isovaleric acid, and a significant reduction in the abundance of HDCA, CDCA, and Acetate in the HF group. Pearson correlation analysis revealed a substantial correlation between various genera (Clostridium sensu stricto 3, Lactobacillus, Bacteroides) and secondary metabolites (DCA, HDCA, 12-KetoLCA, Acetate), and the latter was significantly correlated with intestinal barrier function related genes (Relish, ZO-1, MLCK, vitamin D receptor, and ecdysone receptor). These findings indicate that gut microorganisms and their specific bile acids and short-chain fatty acid secondary metabolites play a crucial role in the process of high-fat-induced intestinal barrier damage of M. rosenbergii. Moreover, identifying and targeting these factors could facilitate precise regulation of high-fat nutrition for crustaceans.

Trichinella spiralis is recognized for its ability to regulate host immune responses. The serine protease inhibitor of T. spiralis (Ts-SPI) participates in T. spiralis-mediated immunoregulatory effects. Studies have shown that helminth therapy exhibits therapeutic effects on metabolic diseases. In addition, we previously found that T. spiralis-derived crude antigens could alleviate diet-induced obesity. Thus, Ts-SPI was hypothesized to alleviate non-alcoholic fatty liver disease (NAFLD). Herein, recombinant Ts-SPI (rTs-SPI) was prepared from the muscle larvae T. spiralis. The relative molecular mass of rTs-SPI was approximately 35,000 Da, and western blot analysis indicated good immunoreactivity. rTs-SPI ameliorated hepatic steatosis, inflammation, and pyroptosis in NAFLD mice, which validated the hypothesis. rTs-SPI also reduced macrophage infiltration, significantly expanded Foxp3+ Treg population, and inactivated TLR4/NF-κB/NLRP3 signaling in the liver. Furthermore, rTs-SPI treatment significantly shifted the gut microbiome structure, with a remarkable increase in beneficial bacteria and reduction in harmful bacteria to improve gut barrier integrity. Finally, Abx-treated mice and FMT confirmed that gut-liver crosstalk contributed to NAFLD improvement after rTs-SPI treatment. Taken together, Taken together, these findings suggest that rTs-SPI exerts therapeutic effects in NAFLD via anti-inflammatory activity and gut-liver crosstalk.

It is well-known that different populations and animals, even experimental animals with the same rearing conditions, differ in their susceptibility to obesity. The disparity in gut microbiota could potentially account for the variation in susceptibility to obesity. However, the precise impact of gut microbiota on gut metabolites and its subsequent influence on susceptibility to obesity remains uncertain.

In this study, we established obesity-prone (OP) and obesity-resistant (OR) mouse models by High Fat Diet (HFD). Fecal contents of cecum were examined using 16S rDNA sequencing and untargeted metabolomics. Correlation analysis and MIMOSA2 analysis were used to explore the association between gut microbiota and intestinal metabolites.

After a HFD, gut microbiota and gut metabolic profiles were significantly different between OP and OR mice. Gut microbiota after a HFD may lead to changes in eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), a variety of branched fatty acid esters of hydroxy fatty acids (FAHFAs) and a variety of phospholipids to promote obesity. The bacteria g_Akkermansia (Greengene ID: 175696) may contribute to the difference in obesity susceptibility through the synthesis of glycerophosphoryl diester phosphodiesterase (glpQ) to promote choline production and the synthesis of valyl-tRNA synthetase (VARS) which promotes L-Valine degradation. In addition, gut microbiota may affect obesity and obesity susceptibility through histidine metabolism, linoleic acid metabolism and protein digestion and absorption pathways.

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Evidence indicates that bile acid homeostasis is disrupted during NEC: ileal bile acid levels are elevated in animals with experimental NEC, as is expression of the apical sodium-dependent bile acid transporter (Asbt). In addition, bile acids, which are synthesized in the liver, are extensively modified by the gut microbiome, including via the conversion of primary bile acids to more cytotoxic secondary forms. We hypothesized that the addition of bile acid-modifying bacteria would increase susceptibility to NEC in a neonatal rat model of the disease. The secondary bile acid-producing species Clostridium scindens exacerbated both incidence and severity of NEC. C. scindens upregulated the bile acid transporter Asbt and increased levels of intraenterocyte bile acids. Treatment with C. scindens also altered bile acid profiles and increased hydrophobicity of the ileal intracellular bile acid pool. The ability of C. scindens to enhance NEC requires bile acids, as pharmacological sequestration of ileal bile acids protects animals from developing disease. These findings indicate that bile acid-modifying bacteria can contribute to NEC pathology and provide additional evidence for the role of bile acids in the pathophysiology of experimental NEC.NEW & NOTEWORTHY Necrotizing enterocolitis (NEC), a life-threatening gastrointestinal emergency in premature infants, is characterized by dysregulation of bile acid homeostasis. We demonstrate that administering the secondary bile acid-producing bacterium Clostridium scindens enhances NEC in a neonatal rat model of the disease. C. scindens-enhanced NEC is dependent on bile acids and driven by upregulation of the ileal bile acid transporter Asbt. This is the first report of bile acid-modifying bacteria exacerbating experimental NEC pathology.

The main purpose of the current study was to investigate the ameliorative effects of bovine milk osteopontin (bmOPN) on the gut dysfunction of pregnant rats fed a high-fat diet (HFD). Bovine milk osteopontin was supplemented at a dose of 6 mg/kg body weight. Bovine milk osteopontin supplementation during pregnancy reduced colonic inflammation of HFD dams, and it also increased the colonic expression of ZO-1 and claudin-4 of HFD dams. Bovine milk osteopontin significantly enriched the relative abundance of Bacteroidetes, whereas it decreased Proteobacteria, Helicobacteraceae, and Desulfovibrionaceae in feces of HFD dams. The levels of isobutyric acid and pentanoic acid in the HFD + bmOPN group were higher than that of the HFD group. Functional predication analysis of microbial genomes revealed that bmOPN supplementation to HFD pregnancies changed 4 Kyoto Encyclopedia of Genes and Genomes pathways including bile acid biosynthesis. Further, bmOPN enriched hepatic taurochenodeoxycholic acid and tauroursodeoxycholic acid plus taurohyodeoxycholic acid in the gut of HFD maternal rats. Our findings suggested that bmOPN improved the gut health of HFD pregnant rats partially through modulating bile acid biosynthesis.

Necrotizing enterocolitis (NEC) is one of the most common acute gastrointestinal diseases in preterm infants. Recent studies have found that NEC is not only caused by changes in the intestinal environment but also by the failure of multiple systems and organs, including the liver. The accumulation of bile acids (BAs) in the ileum and the disorder of ileal BA transporters are related to the ileum injury of NEC. Inflammatory factors such as tumor necrosis factor (TNF)-α and interleukin (IL)-18 secreted by NEC also play an important role in regulating intrahepatic BA transporters. As an important link connecting the liver and intestinal circulation, the bile acid metabolic pathway plays an important role in the regulation of intestinal microbiota, cell proliferation, and barrier protection. In this review, we focus on how bile acids explore the dynamic changes of bile acid metabolism in necrotizing enterocolitis and the potential therapeutic value of targeting the bile acid signaling pathways.

Excessive predominance of pathological species in the gut microbiota could increase the production of inflammatory mediators at the gut level and, via modification of the gut-blood barrier, at the systemic level. This pro-inflammatory state could, in turn, increase biological aging that is generally proxied by telomere shortening. In this study, we present findings from a secondary interaction analysis of gut microbiota, aging, and inflammatory marker data from a cohort of patients with different diagnoses of severe mental disorders. We analyzed 15 controls, 35 patients with schizophrenia (SCZ), and 31 patients with major depressive disorder (MDD) recruited among those attending a community mental health center (50 males and 31 females, mean and median age 46.8 and 46.3 years, respectively). We performed 16S rRNA sequencing as well as measurement of telomere length via quantitative fluorescence in situ hybridization and high-sensitivity C-reactive protein. We applied statistical modeling with logistic regression to test for interaction between gut microbiota and these markers. Our results showed statistically significant interactions between telomere length and gut microbiota pointing to the genus Lachnostridium, which remained significantly associated with a reduced likelihood of MDD even after adjustment for a series of covariates. Although exploratory, these findings show that specific gut microbiota signatures overexpressing Lachnoclostridium and interacting with biological aging could modulate the liability for MDD.

Bile acids (BA) are amphipathic molecules originating from cholesterol in the liver and from microbiota-driven biotransformation in the colon. In the gut, BA play a key role in fat digestion and absorption and act as potent signaling molecules on the nuclear farnesoid X receptor (FXR) and membrane-associated G protein-coupled BA receptor-1 (GPBAR-1). BA are, therefore, involved in the maintenance of gut barrier integrity, gene expression, metabolic homeostasis, and microbiota profile and function. Disturbed BA homeostasis can activate pro-inflammatory pathways in the gut, while inflammatory bowel diseases (IBD) can induce gut dysbiosis and qualitative and/or quantitative changes of the BA pool. These factors contribute to impaired repair capacity of the mucosal barrier, due to chronic inflammation. A better understanding of BA-dependent mechanisms paves the way to innovative therapeutic tools by administering hydrophilic BA and FXR agonists and manipulating gut microbiota with probiotics and prebiotics. We discuss the translational value of pathophysiological and therapeutic evidence linking BA homeostasis to gut inflammation in IBD.

Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status.

Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC).

We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model.

Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.

Progressive up-regulation of β-catenin signaling is very common in the transformation of colorectal epithelium to colorectal cancer (CRC). Practical measures for opposing such signaling hence have potential for preventing or slowing such transformation. cAMP/PKA activity in colon epithelium, as stimulated by COX-2-generated prostaglandins and β2-adrenergic signaling, boosts β-catenin activity, whereas cGMP/PKG signaling has the opposite effect. Bacterial generation of short-chain fatty acids (as supported by unrefined high-carbohydrate diets, berberine, and probiotics), dietary calcium, daily aspirin, antioxidants opposing cox-2 induction, and nicotine avoidance, can suppress cAMP production in colonic epithelium, whereas cGMP can be boosted via linaclotides, PDE5 inhibitors such as sildenafil or icariin, and likely high-dose biotin. Selective activation of estrogen receptor-β by soy isoflavones, support of adequate vitamin D receptor activity with UV exposure or supplemental vitamin D, and inhibition of CK2 activity with flavanols such as quercetin, can also oppose β-catenin signaling in colorectal epithelium. Secondary bile acids, the colonic production of which can be diminished by low-fat diets and berberine, can up-regulate β-catenin activity by down-regulating farnesoid X receptor expression. Stimulation of PI3K/Akt via insulin, IGF-I, TLR4, and EGFR receptors boosts β-catenin levels via inhibition of glycogen synthase-3β; plant-based diets can down-regulate insulin and IGF-I levels, exercise training and leanness can keep insulin low, anthocyanins and their key metabolite ferulic acid have potential for opposing TLR4 signaling, and silibinin is a direct antagonist for EGFR. Partially hydrolyzed phytate can oppose growth factor-mediated down-regulation of β-catenin by inhibiting Akt activation. Multifactorial strategies for safely opposing β-catenin signaling can be complemented with measures that diminish colonic mutagenesis and DNA hypomethylation - such as avoidance of heme-rich meat and charred or processed meats, consumption of phase II-inductive foods and nutraceuticals (e.g., Crucifera), and assurance of adequate folate status.

Fructose is a common ingredient of food industry in the form of sucrose and high fructose corn sirup (HFCS). Due to its unique metabolic properties, excessive intake of fructose has been linked to various diseases, including obesity, nonalcoholic fatty liver disease (NAFLD), cardiovascular disease (CVD), chronic renal insufficiency, and even increase the risk of death. Interestingly, although high fructose intake may induce gout, it does not cause hyperuricemia, and the underlying molecular mechanisms remain debated. While previous studies focused on the liver as the primary site of fructose metabolism, recent evidence has suggested a crucial role for the intestine-hepatic axis in fructose metabolism. Low dose fructose is mainly metabolized in the small intestine. Only when the intake exceeds the intestine's metabolic capacity fructose spills over to be metabolized in the liver. High fructose diets also have a significant impact on the diversity of the gut microbiota, leading to alterations in the metabolic byproducts produced by these gut bacteria and thereby inducing endotoxemia. This paper provides a comprehensive review of the epidemiological and pathological studies conducted in recent years, describing the metabolic differences between fructose and glucose and the possible mechanisms underlying the link between excessive fructose intake and chronic metabolic diseases.

Healthy host-microbial mutualism with our intestinal microbiota relies to a large degree on compartmentalization and careful regulation of adaptive mucosal and systemic anti-microbial immune responses. However, commensal intestinal bacteria are never exclusively or permanently restricted to the intestinal lumen and regularly reach the systemic circulation. This results in various degrees of commensal bacteremia that needs to be appropriately dealt with by the systemic immune system. While most intestinal commensal bacteria, except for pathobionts or opportunistic pathogen, have evolved to be non-pathogenic, this does not mean that they are non-immunogenic. Mucosal immune adaptation is carefully controlled and regulated to avoid an inflammatory response, but the systemic immune system usually responds differently and more vigorously to systemic bacteremia. Here we show that germ-free mice have increased systemic immune sensitivity and display anti-commensal hyperreactivity in response to the addition of a single defined T helper cell epitope to the outer membrane porin C (OmpC) of a commensal Escherichia coli strain demonstrated by increased E. coli-specific T cell-dependent IgG responses following systemic priming. This increased systemic immune sensitivity was not observed in mice colonized with a defined microbiota at birth indicating that intestinal commensal colonization also regulates systemic, and not only mucosal, anti-commensal responses. The observed increased immunogenicity of the E. coli strain with the modified OmpC protein was not due to a loss of function and associated metabolic changes as a control E. coli strain without OmpC did not display increased immunogenicity.

Despite advances in preventive measures and treatment options, cardiovascular disease (CVD) remains the number one cause of death globally. Recent research has challenged the traditional risk factor profile and highlights the potential contribution of non-traditional factors in CVD, such as the gut microbiota and its metabolites. Disturbances in the gut microbiota have been repeatedly associated with CVD, including atherosclerosis and hypertension. Mechanistic studies support a causal role of microbiota-derived metabolites in disease development, such as short-chain fatty acids, trimethylamine-N-oxide, and bile acids, with the latter being elaborately discussed in this review. Bile acids represent a class of cholesterol derivatives that is essential for intestinal absorption of lipids and fat-soluble vitamins, plays an important role in cholesterol turnover and, as more recently discovered, acts as a group of signaling molecules that exerts hormonal functions throughout the body. Studies have shown mediating roles of bile acids in the control of lipid metabolism, immunity, and heart function. Consequently, a picture has emerged of bile acids acting as integrators and modulators of cardiometabolic pathways, highlighting their potential as therapeutic targets in CVD. In this review, we provide an overview of alterations in the gut microbiota and bile acid metabolism found in CVD patients, describe the molecular mechanisms through which bile acids may modulate CVD risk, and discuss potential bile-acid-based treatment strategies in relation to CVD.

Autoimmune liver diseases (AILD) are a group of immune-mediated liver inflammatory diseases with three major forms including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Interaction of both genetic and environmental factors leads to the breakdown of self-tolerance, hence resulting in hyper-responsive of autoantibodies and aggressive autoreactive immune cells. Genetic studies have identified dozens of risk loci associated with initiation and development of AILD. However, the role of exogenous factors remains unclear. Recently, both infectious and inflammatory diseases have been associated with microbiota, which colonizes multiple mucosal surfaces and participates in human physiological process and function in immune system, particularly influencing liver, and biliary system via gut-liver axis. Emerging evidence on the role of gut microbiota has expanded our knowledge of AILD in both pathogenesis and potential therapeutic targets, along with putative diagnosis biomarkers. Herein we review the relationship between host and gut microbiota, discuss their potential roles in disease onset and progression, and summarize the compositional and functional alterations of the microbiota in AILD. We also highlighted the microbiota-based therapeutics such as antibiotics and fecal microbiota transplantation (FMT).

The potential roles of the gut microbiota in the pathogenesis of non-alcoholic fatty liver disease, including non-alcoholic steatohepatitis (NASH), have attracted increased interest. We have investigated the links between gut microbiota and NASH development in Tsumura-Suzuki non-obese mice fed a high-fat/cholesterol/cholate-based (iHFC) diet that exhibit advanced liver fibrosis using antibiotic treatments. The administration of vancomycin, which targets Gram-positive organisms, exacerbated the progression of liver damage, steatohepatitis, and fibrosis in iHFC-fed mice, but not in mice fed a normal diet. F4/80⁺-recruited macrophages were more abundant in the liver of vancomycin-treated iHFC-fed mice. The infiltration of CD11c⁺-recruited macrophages into the liver, forming hepatic crown-like structures, was enhanced by vancomycin treatment. The co-localization of this macrophage subset with collagen was greatly augmented in the liver of vancomycin-treated iHFC-fed mice. These changes were rarely seen with the administration of metronidazole, which targets anaerobic organisms, in iHFC-fed mice. Finally, the vancomycin treatment dramatically modulated the level and composition of bile acid in iHFC-fed mice. Thus, our data demonstrate that changes in inflammation and fibrosis in the liver by the iHFC diet can be modified by antibiotic-induced changes in gut microbiota and shed light on their roles in the pathogenesis of advanced liver fibrosis.

Inflammatory bowel disease (IBD) is a chronic disorder thought to be caused by enteric inflammation in a genetically susceptible host. Although the pathogenesis of IBD is largely unknown, it is widely accepted that dietary components play an important role. Human and animal-based studies have explored the role of various dietary components such as meat, artificial sweeteners and food additives in causing enteric inflammation. Several diets have also been studied in patients with IBD, specifically their role in the induction or maintenance of remission. The most well-studied of these include exclusive enteral nutrition and specific carbohydrate diet. A diet low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols), typically prescribed for patients with irritable bowel syndrome, has also been studied in a specific subgroup of patients with IBD. In this review, we describe the current evidence on how various dietary components can induce enteric and colonic inflammation, and the clinical-epidemiological evidence exploring their role in predisposing to or protecting against the development of IBD. We also discuss several special diets and how they affect clinical outcomes in IBD patients. Based on the available evidence, we provide guidance for patients and clinicians managing IBD regarding the best practice in dietary modifications.

The gut-liver axis has emerged as a key player in the progression of non-alcoholic fatty liver disease (NAFLD). Sulforaphane (SFN) is a bioactive compound found in cruciferous vegetables; however, it has not been reported whether SFN improves NAFLD via the gut-liver axis. C57BL/6 mice were fed a high-fat and high-fructose (HFHFr) diet, with or without SFN gavage at doses of 15 and 30 mg·kg^-1 body weight for 12 weeks. The results showed that SFN reduced weight gain, hepatic inflammation, and steatosis in HFHFr mice. SFN altered the composition of gut microbes. Moreover, SFN enhanced the intestinal tight junction protein ZO-1, reduced serum LPS, and inhibited LPS/TLR4 and ERS pathways to reduce intestinal inflammation. As a result, SFN protected the intestinal integrity and declined the gut-derived LPS translocations to the liver in HFHFr diet-induced mice. SFN decreased the liver LPS levels and inhibited the LPS/TLR4 pathway activations, thus inhibiting the pro-inflammatory cytokines. Notably, Spearman correlation analysis showed that the protective effect of SFN on intestinal barrier integrity and its anti-inflammatory effect on the liver was associated with improved intestinal dysbiosis. Above all, dietary intervention with SFN attenuates NAFLD through the gut-liver axis.

High-fat diet (HFD) has been recognized as a primary factor in the risk of chronic disease. Obesity, diabetes, gastrointestinal diseases, neurodegenerative diseases, and cardiovascular diseases have long been known as chronic diseases with high worldwide incidence. In this review, the influences of gut microbiota and their corresponding bacterial metabolites on the mechanisms of HFD-induced chronic diseases are systematically summarized. Gut microbiota imbalance is also known to increase susceptibility to diseases. Several studies have proven that HFD has a negative impact on gut microbiota, also exacerbating the course of many chronic diseases through increased populations of Erysipelotrichaceae, facultative anaerobic bacteria, and opportunistic pathogens. Since bile acids, lipopolysaccharide, short-chain fatty acids, and trimethylamine N-oxide have long been known as common features of bacterial metabolites, we will explore the possibility of synergistic mechanisms among those metabolites and gut microbiota in the context of HFD-induced chronic diseases. Recent literature concerning the mechanistic actions of HFD-mediated gut microbiota have been collected from PubMed, Google Scholar, and Scopus. The aim of this review is to provide new insights into those mechanisms and to point out the potential biomarkers of HFD-mediated gut microbiota.

Bile acids are critical for the digestion and absorption of lipids and fat-soluble vitamins; however, evidence continues to emerge supporting additional roles for bile acids as signaling molecules. After they are synthesized from cholesterol in the liver, primary bile acids are modified into secondary bile acids by gut flora contributing to a diverse pool and making the composition of bile acids highly sensitive to alterations in gut microbiota. Disturbances in bile acid homeostasis have been observed in patients with Inflammatory Bowel Diseases (IBD). In fact, a decrease in secondary bile acids was shown to occur because of IBD-associated dysbiosis. Further, the increase in luminal bile acids due to malabsorption in Crohn's ileitis and ileal resection has been implicated in the induction of diarrhea and the exacerbation of inflammation. A causal link between bile acid signaling and intestinal inflammation has been recently suggested. With respect to potential mechanisms related to bile acids and IBD, several studies have provided strong evidence for direct effects of bile acids on intestinal permeability in porcine and rodent models as well as in humans. Interestingly, different bile acids were shown to exert distinct effects on the inflammatory response and intestinal permeability that require careful consideration. Such findings revealed a potential effect for changes in the relative abundance of different bile acids on the induction of inflammation by bile acids and the development of IBD. This review summarizes current knowledge about the roles for bile acids as inflammatory mediators and modulators of intestinal permeability mainly in the context of inflammatory bowel diseases.