The gut mycobiome might have an important influence on the pathogenesis of choledocholithiasis concurrent with cholangitis (CC). The aim of this study was to characterize the fungal mycobiome profiles, explore the correlation and equilibrium of gut interkingdom network among bacteria-fungi-metabolites triangle in CCs.

In a retrospective case-control study, we recruited patients with CC (n = 25) and healthy controls (HCs) (n = 25) respectively to analyze the gut fungal dysbiosis. Metagenomic sequencing was employed to characterize the gut mycobiome profiles, and liquid chromatography/mass spectrometry (LC/MS) analysis was used to quantify the metabolites composition.

The Shannon index displayed a reduction in fungal α-diversity in CCs compared to HCs (p = 0.041), and the overall fungal composition differed significantly between two groups. The dominant 7 fungi species with the remarkable altered abundance were identified (LDA score > 3.0, p < 0.05), including CC-enriched Aspergillus_niger and CC-depleted fungi Saccharomyces_boulardii. In addition, the correlations between CC-related fungi and clinical variables in CCs were analyzed. Moreover, the increased abundance ratio of Basidiomycota-to-Ascomycota and a dense linkage of bacteria-fungi interkingdom network in CCs were demonstrated. Finally, we identified 30 markedly altered metabolites in CCs (VIP > 1.0 and p < 0.05), including low level of acetate and butyrate, and the deeper understanding on the complexity of bacteria-fungi-metabolites triangle involving bile inflammation was verified.

Our investigation demonstrated a distinct gut fungal dysbiosis in CCs and proposed that, beyond bacteria, the more attention should be paid to significantly potential influence of fungi and bacteria-fungi-metabolites triangle interkingdom interactions on pathogenesis of CC.

Probiotic use has increased in preterm infants and may reduce the risk of necrotizing enterocolitis. Probiotic-associated infection is a concern for infants receiving probiotic supplementation in the neonatal intensive care unit, as highlighted by a recent case and subsequent action by the United States Food and Drug Administration. Based on reports to date, invasive infection is an infrequent but known risk of probiotic supplementation. In this article, we discuss the epidemiology and pathophysiology of invasive infection in preterm infants, review the benefits and risks of probiotic as regulations and available products continue to evolve.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic inflammation that affects multiple organs, with its prevalence varying by ethnicity. Intestinal dysbiosis has been observed in both SLE patients and murine models. Additionally, intestinal barrier impairment is thought to contribute to the ability of pathobionts to evade and breach immune defenses, resulting in antigen cross-reactivity, microbial translocation, subsequent immune activation, and, ultimately, multiple organ failure. Since the detailed mechanisms underlying these processes are difficult to examine using human samples, murine models are crucial. Various SLE murine models, including genetically modified spontaneous and inducible murine models, offer insights into pathobionts and how they dysregulate systemic immune systems. Furthermore, since microbial metabolites modulate systemic immune responses, bacteria and their metabolites can be targeted for treatment. Based on human and mouse research insights, this review examines how lupus pathobionts trigger intestinal and systemic immune dysregulation. Therapeutic approaches, such as fecal microbiota transplantation and dietary adjustments, show potential as cost-effective and safe methods for preventing and treating SLE. Understanding the complex interactions between the microbiota, host factors, and immune dysregulation is essential for developing novel, personalized therapies to tackle this multifaceted disease.

The intestinal microbiota plays a vital role in animal growth and development. In this study, we explored the impact of oat grain dietary supplementation on growth performance, intestinal microbiota, short-chain fatty acids (SCFAs), and fatty acids (FAs) in Hu sheep. Thirty-two Hu lambs were randomly assigned to a control group (RC) or an oat grain-supplemented group (RO). After 90 days on their respective diets, rumen digesta were collected from six randomly selected Hu lambs per group to assess microbial diversity, SCFAs, and FAs. The RO diet significantly enhanced growth in Hu sheep (p < 0.01) and increased α-diversity, as indicated by Chao1 and Shannon indices. Core phyla in both groups were Firmicutes and Bacteroidota, with predominant genera including Prevotella, Rikenellaceae_RC9_gut_group, and F082. Oat grain supplementation led to significant shifts in microbial composition, increasing the abundance of Acidobacteriota, Proteobacteria, Chloroflexi, Actinobacteriota, and Subgroup_2, while decreasing Bacteroidota and Oscillospiraceae (p < 0.05). The RO group also exhibited lower levels of isobutyric and citraconic acids but higher levels of azelaic acid (p < 0.05). These results indicate that oat grain supplementation enhances beneficial rumen microbes and optimizes FAs and SCFAs composition, thereby promoting weight gain in Hu sheep.

TF3 is a functional pigment formed during the process of black tea. This study aims to explore the anti-constipation effects of TF3 and compare its efficacy with the anti-constipation drug mosapride. Result showed that both TF3 and mosapride increased fecal water content and promoted gastrointestinal (GI) motility, but TF3 was more effective in restoring excitatory neurotransmitters like gastrin (Gas), motilin (MTL), and substance P (SP). TF3 uniquely altered the gut microbiota profile and restored the bacterial community at the phylum level. TF3 targeted specific bacteria such as Alloprevotella, Bacteroides, and Parabacteroides, while mosapride affected different bacterial groups. Significant changes in Bacteroides and Prevotellaceae UCG-001 were linked to constipation improvement. Importantly, TF3 did not synergize with mosapride in alleviating constipation. These findings highlight TF3's unique role in modulating gut microbiota to relieve constipation and suggest great potential to develop functional foods with anti-constipation properties using tea-derived polyphenols.

Aside from its immediate traumatic effects, spinal cord injury (SCI) presents multiple secondary complications that can be harmful to those who have been affected by SCI. Among these secondary effects, gut dysbiosis (GD) and the activation of the NOD (nucleotide-binding oligomerization domain) like receptor-family pyrin-domain-containing three (NLRP3) inflammasome are of special interest for their roles in impacting mental health. Studies have found that the state of the gut microbiome is thrown into disarray after SCI, providing a chance for GD to occur. Metabolites such as short-chain fatty acids (SCFAs) and a variety of neurotransmitters produced by the gut microbiome are hampered by GD. This disrupts healthy cognitive processes and opens the door for SCI patients to be impacted by mental health disorders. Additionally, some studies have found an increased presence and activation of the NLRP3 inflammasome and its respective parts in SCI patients. Preclinical and clinical studies have shown that NLRP3 inflammasome plays a key role in the maturation of pro-inflammatory cytokines that can initiate and eventually aggravate mental health disorders after SCI. In addition to the mechanisms of GD and the NLRP3 inflammasome in intensifying mental health disorders after SCI, this review article further focuses on three promising treatments: fecal microbiome transplants, phytochemicals, and melatonin. Studies have found these treatments to be effective in combating the pathogenic mechanisms of GD and NLRP3 inflammasome, as well as alleviating the symptoms these complications may have on mental health. Another area of focus of this review article is exploring how artificial intelligence (AI) can be used to support treatments. AI models have already been developed to track changes in the gut microbiome, simulate drug-gut interactions, and design novel anti-NLRP3 inflammasome peptides. While these are promising, further research into the applications of AI for the treatment of mental health disorders in SCI is needed.

Functional constipation (FC) is a common problem in childhood and the first-line therapy is macrogol. The role of FC in the onset of inflammatory bowel disease (IBD) is poorly understood. Our main aim was to investigate the prevalence of FC in children before the diagnosis of IBD.

This is a cross-sectional observational study in pediatric IBD-patients. We collected data on demographics, clinical and endoscopic characteristics at IBD diagnosis, and on the presence of FC and its treatment before IBD diagnosis.

A total of 238 children with IBD, 104 (44%) with Crohn disease (CD), 130 (56%) with ulcerative colitis (UC) and 4 (0.016%) with IBD Unclassified (IBD-U) were enrolled. The mean age was 174 ± 47 months, 56% were male. Forty-seven out of 238 (19.7%) had a FC history before the IBD diagnosis and 31 out of these 47 patients (65%) received macrogol therapy. In the FC group, we found a delay in the diagnosis of IBD compared to the group with no FC [median (interquartile range [IQR]): 5 months (2.5-9.5) and 2 months (0-4), respectively, p ≤ 0.001]. The difference in terms of endoscopic localization was statistically significant in UC patients presenting FC (p = 0.026) with a prevalence of proctitis and left side colitis (30% and 15%, respectively).

In conclusion our study highlighted a prevalence of constipation in pediatric IBD patients at diagnosis of 19.7%, which must be taken into account to avoid diagnostic delay and which is associated with limited extent of disease in UC pediatric patients.

Diatomite is a source of biologically available silicon but in feed industry its insecticide and anti-caking properties have been also widely recognized. The aim of the study was to evaluate the effect of dietary diatomite-bentonite mixture (DBM) supplementation on the quantitative and qualitative composition of the bacterial microbiome of the broiler chicken gut. The trial was carried out on 960 Ross 308 broiler chickens divided into 2 experimental groups throughout the entire rearing period lasting 6 weeks. The birds were fed complete granulated diets without (group C) or with DBM (group E) in an amount of 1% from the 11 day of life. Two nutritionally balanced diets were used, tailored to the age of the broilers: a grower diet (from day 11 to 34) and a finisher diet (from day 35 to 42 of life).

Diatomite used in a mixture with bentonite significantly altered the microbiome. Restricting the description to species that comprise a minimum of 1% of all analyzed sequences, 36 species in group E (with diatomite) and 30 species in group C (without diatomite) were selected. Several bacteria species were identified in intestinal contents of chickens for the first time. Thirteen species occurred only in group E: Agathobaculum butyriciproducens, Anaerobutyricum hallii, Anaerobutyricum soehngenii, Blautia producta ATCC 27,340 = DSM 2950, Gordonibacter pamelaeae 7-10-1-b, Helicobacter pullorum NCTC 12,824, Lactobacillus crispatus, L. helveticus DSM 20,075 = CGMCC 1.1877, Mucispirillum schaedleri, Phascolarctobacterium faecium, Phocaeicola coprocola DSM 17,136, P. massiliensis, and Ruthenibacterium lactatiformans.

The findings highlight the intricate and potentially consequential relationship between diet, specifically diatomite-bentonite mixture supplementation, and gut microbiota composition.

The gut barrier encompasses several interactive, physical, and functional components, such as the gut microbiota, the mucus layer, the epithelial layer and the gut mucosal immunity. All these contribute to homeostasis in a well-regulated manner. Nevertheless, this frail balance might be disrupted for instance by westernized dietary habits, infections, pollution or exposure to antibiotics, thus diminishing protective immunity and leading to the onset of chronic diseases. Several gaps of knowledge still exist as regards this multi-level interaction. In this review we aim to summarize current evidence linking food antigens, microbiota and gut permeability interference in diverse disease conditions such as celiac disease (CeD), non-celiac wheat sensitivity (NCWS), food allergies (FA), eosinophilic gastrointestinal disorder (EOGID) and irritable bowel syndrome (IBS). Specific food elimination diets are recommended for CeD, NCWS, FA and in some cases for EOGID. Undoubtfully, each of these conditions is very different and quite unique, albeit food antigens/compounds, intestinal permeability and specific microbiota signatures orchestrate immune response and decide clinical outcomes for all of them.

Drug safety is a paramount concern in the field of drug development, with researchers increasingly focusing on the bidirectional regulation of gut microbiota in this context. The gut microbiota plays a crucial role in maintaining drug safety. It can influence drug transport processes in the body through various mechanisms, thereby modulating their efficacy and toxicity. The main mechanisms include: (1) The gut microbiota directly interacts with drugs, altering their chemical structure to reduce toxicity and enhance efficacy, thereby impacting drug transport mechanisms, drugs can also change the structure and abundance of gut bacteria; (2) bidirectional regulation of intestinal barrier permeability by gut microbiota, promoting the absorption of nontoxic drugs and inhibiting the absorption of toxic components; (3) bidirectional regulation of the expression and activity of transport proteins by gut microbiota, selectively promoting the absorption of effective components or inhibiting the absorption of toxic components. This bidirectional regulatory role enables the gut microbiota to play a key role in maintaining drug balance in the body and reducing adverse reactions. Understanding these regulatory mechanisms sheds light on novel approaches to minimize toxic side effects, enhance drug efficacy, and ultimately improve drug safety. This review systematically examines the bidirectional regulation of gut microbiota in drug transportation from the aforementioned aspects, emphasizing their significance in ensuring drug safety. Furthermore, it offers a prospective outlook from the standpoint of enhancing therapeutic efficacy and reducing drug toxicity, underscoring the importance of further exploration in this research domain. It aims to provide more effective strategies for drug development and treatment.

Preterm newborns represent a population at risk of developing intestinal dysbiosis as well as being predisposed to sepsis and Necrotizing Enterocolitis. Necrotizing Enterocolitis is a condition burdened by many complications and mortality due to an alteration of the intestinal barrier, an immaturity of the immune system, and intestinal dysbiosis. Low gestational age at birth, low birth weight, and early use of antibiotics are other predisposing factors. Instead, breast milk and probiotics are protective factors in providing intestinal homeostasis and microbiome regulation. In this mini-review, we analysed the protective role of probiotics in the onset of Necrotizing Enterocolitis in preterm populations.

Both nanoplastic (NP) particles and arsenic (As) are widespread in aquatic environments and pose a combined risk of exposure to aquatic organisms. How the gut of aquatic organisms responds to combined risk of exposure is still unclear. In this study, zebrafish (Danio rerio) were subjected to three distinct As stress environments: only As group (10 μg/L), and As combined with different concentrations of polystyrene (PS) NPs (1 mg/L and 10 mg/L) groups for 21 days via semi-static waterborne exposure. The physiological responses to combined stress, the diversity of gut microorganisms, and the metabolomic response of the gut were investigated. The findings indicated that PSNPs were prevalent in the intestines of zebrafish in the co-exposed group. Furthermore, the administration of 1 mg/L and 10 mg/L of PSNPs in the co-exposed group was observed to elevate As levels in the intestines by 24.88% and 76.95%, respectively, in comparison to As treatment alone. Simultaneous exposure of the gut to PSNPs and As resulted in increased contents/activities of MDA, SOD, CAT, and GST, and a decrease in contents/activities of GSH and GPx, when compared to As exposure alone. Additionally, the combined exposure led to an elevated expression of the Cu/Zn-sod, Mn-sod, gpx, and cat genes. The combined treatment with NPs and As resulted in an increase in the abundance of Proteobacteria and Fusobacteriota at the phylum level, as well as a significant increase in the abundance of Cetobacterium, Rhodococcus, and Bacteroides at the genus level. Non-targeted metabolomics analyses suggest that metabolic pathways affected by co-exposure include glycerophospholipid metabolism, glycerolipid metabolism, ABC transporters and autophagy. The findings of this study are of considerable significance for the evaluation of the toxicological impact of co-existing pollutants.

Disorders of gut-brain interaction (DGBI) are common chronic conditions characterized by persistent and recurring gastrointestinal symptoms triggered by several pathophysiological factors, including an altered gut microbiota. The most common DGBI are irritable bowel syndrome (IBS), functional constipation (FC) and functional dyspepsia (FD). Recently, a deep understanding of the role of the gut microbiota in these diseases was possible due to multi-omics methods capable to provide a comprehensive assessment. Most of the therapies recommended for these patients, can modulate the gut microbiota such as diet, prebiotics, probiotics and non-absorbable antibiotics, which were shown to be safe and effective. Since patients complain symptoms after food ingestion, diet represents the first line therapeutic approach. Avoiding dietary fat and fermentable oligosaccharides, disaccharides, monosaccharides, and polyols, and increasing the number of soluble fibers represent the therapeutic choices for FD, IBS and FC respectively. Probiotics, as a category, have been employed with good results in all the abovementioned DGBI. Rifaximin has been shown to be useful in the context of bowel related disorders, although a recent trial showed positive results for FD. Fecal microbiota transplantation has been tested for IBS and FC with promising results. In this review, we will briefly summarize the current understanding on dysbiosis and discuss microbiota modulation strategies to treat patients with DGBI.

Previous observational studies have hinted at a potential correlation between aplastic anemia (AA) and the gut microbiome. However, the precise nature of this bidirectional causal relationship remains uncertain.

We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the potential causal link between the gut microbiome and AA. Statistical analysis of the gut microbiome was based on data from an extensive meta-analysis (genome-wide association study) conducted by the MiBioGen Alliance, involving 18,340 samples. Summary statistical data for AA were obtained from the Integrative Epidemiology Unit database. Single -nucleotide polymorphisms (SNPs) were estimated and summarized using inverse variance weighted (IVW), MR Egger, and weighted median methods in the bidirectional MR analysis. Cochran's Q test, MR Egger intercept test, and sensitivity analysis were employed to assess SNP heterogeneity, horizontal pleiotropy, and stability.

The IVW analysis revealed a significant correlation between AA and 10 bacterial taxa. However, there is currently insufficient evidence to support a causal relationship between AA and the composition of gut microbiome.

This study suggests a causal connection between the prevalence of specific gut microbiome and AA. Further investigation into the interaction between particular bacterial communities and AA could enhance efforts in prevention, monitoring, and treatment of the condition.

Whole-plant corn silage (WPCS) is an important roughage source for livestock, and have critical influences on rumen or intestinal microbiota, thus affecting the growth performance and feed efficiency. Our previous studies showed that adding WPCS to the diet of Hezuo pigs could promote the growth and fiber digestibility. While the aim of this study is to understand the effect of dietary WPCS on the colonic microflora in Hezuo pigs, which is essential for improving the roughage exploitation of pigs.

Thirty-two Hezuo pigs with similar body weight (7.88 ± 0.81) kg were selected and randomly divided into four groups with eight pigs in each group. Pigs in the control group were fed a basal diet, pigs in the experimental groups (Groups I, II, and III) were fed basal diet supplemented with 5%, 10%, and 15% WPCS, respectively, under 120 d experimental period. Six pigs from each group were picked for collecting colonic contents samples. 16S rRNA sequencing was performed to analyze the colonic microbiota of experimental pigs.

The results showed that community richness indexes Chao1 and Observed_species in group III of Hezuo pig were significantly lower than that of the other three groups, community diversity indexes Shannon and Simpson were significantly higher in group I and II in comparison to the control group, and significantly lower in group III in comparison to the control group, group I and II. Adding WPCS to the diet of Hezuo pigs has no influence on the colonic dominant phylum, Clostridium sensu stricto 1 and Rikenellaceae RC9 gut group were most prevalent in the colon of Hezuo pig. When compared with the control group, the relative abundance of Streptococcus was significantly decreased in three experimental groups, while p-251-o5, Parabacteroides, Prevotellaceae UCG-003, Prevotellaceae UCG-001, and F082 exhibited significantly higher relative abundances in at least two experimental groups. Fibrobacter, Rikenellaceae RC9 gut group in group I, UCG-010 in group II, Bacteroides in group III exhibited increased relative abundance as compared with the control group. PICRUSt functional annotation indicated that the functions of cellular process and signaling were significantly increased in all WPCS-rationed groups, cancers, nervous system, immune system and environmental adaptation were all differed from groups I and II; three predominant pathways of translation, nucleotide metabolism and signal were only differed from the group II.

Feeding with 5% and 10% WPCS for Hezuo pigs could improve their colonic microflora diversity, and increase the relative abundance of fiber-digesting bacteria, which may potentially help to improve the fibre digestibility of Hezuo pigs by regulating the microbial function of cellular process and signaling, nucleotide metabolism, translation.

Assessing the bioaccessibility and bioavailability of cadmium (Cd) is crucial for effective evaluation of the exposure risk associated with intake of Cd-contaminated rice. However, limited studies have investigated the influence of gut microbiota on these two significant factors. In this study, we utilized in vitro gastrointestinal simulators, specifically the RIVM-M (with human gut microbial communities) and the RIVM model (without gut microbial communities), to determine the bioaccessibility of Cd in rice. Additionally, we employed the Caco-2 cell model to assess bioavailability. Our findings provide compelling evidence that gut microbiota significantly reduces Cd bioaccessibility and bioavailability (p<0.05). Notably, strong in vivo-in vitro correlations (IVIVC) were observed between the in vitro bioaccessibilities and bioavailabilities, as compared to the results obtained from an in vivo mouse bioassay (R2 = 0.63-0.65 and 0.45-0.70, respectively). Minerals such as copper (Cu) and iron (Fe) in the food matrix were found to be negatively correlated with Cd bioaccessibility in rice. Furthermore, the results obtained from the toxicokinetic (TK) model revealed that the predicted urinary Cd levels in the Chinese population, based on dietary Cd intake adjusted by in vitro bioaccessibility from the RIVM-M model, were consistent with the actual measured levels (p > 0.05). These results indicated that the RIVM-M model represents a potent approach for measuring Cd bioaccessibility and underscore the crucial role of gut microbiota in the digestion and absorption process of Cd. The implementation of these in vitro methods holds promise for reducing uncertainties in dietary exposure assessment.

Enterohemorrhagic Escherichia coli (EHEC) is a foodborne pathogen that infects humans by colonizing the large intestine. Upon reaching the large intestine, EHEC mediates local signal recognition and the transcriptional regulation of virulence genes to promote adherence and colonization in a highly site-specific manner. Two-component systems (TCSs) represent an important strategy used by EHEC to couple external stimuli with the regulation of gene expression, thereby allowing EHEC to rapidly adapt to changing environmental conditions. An increasing number of studies published in recent years have shown that EHEC senses a variety of host- and microbiota-derived signals present in the human intestinal tract and coordinates the expression of virulence genes via multiple TCS-mediated signal transduction pathways to initiate the disease-causing process. Here, we summarize how EHEC detects a wide range of intestinal signals and precisely regulates virulence gene expression through multiple signal transduction pathways during the initial stages of infection, with a particular emphasis on the key roles of TCSs. This review provides valuable insights into the importance of TCSs in EHEC pathogenesis, which has relevant implications for the development of antibacterial therapies against EHEC infection.

Aging is an inevitable life process which is accelerated by lifestyle and environmental factors. It is an irreversible accretion of molecular and cellular damage associated with changes in the body composition and deterioration in physiological functions. Each cell (other than stem cells) reaches the limit of its ability to replicate, known as cellular or replicative senescence, and consequently, the organs lose their physiological functions, resulting in overall impairment. Other factors that promote aging include smoking, alcohol, UV rays, sleep habits, food, stress, sedentary lifestyle, and genetic abnormalities. These stress factors can alter our endogenous clock (the circadian rhythm) and the microbial commensals. As a result of the effect of these stressors, the microorganisms that generally support human physiological processes become baleful. The disturbance of natural physiology instigates many age-related pathologies, such as cardiovascular diseases, chronic obstructive pulmonary disorder, cerebrovascular diseases, opportunistic infections, high blood pressure, cancer, diabetes, kidney diseases, dementia, and Alzheimer's disease. The present review covers the three most essential processes of the circadian clock; the circadian gene mechanism and regulation, the mitotic clock (which plays a vital role in the telomere's attrition) and the gut microbiota and their metabolome that drive aging and lead to age-related pathologies. In conclusion, maintaining a synchronized circadian rhythm, a healthy gut microbiome, and telomere integrity is essential for mitigating the effects of aging and promoting longevity. The interplay among these factors underscores the importance of lifestyle choices in enhancing overall health and lifespan.

The Dobbs decision of the United States Supreme Court and the actions of several state legislatures have made it risky, if not outright dangerous, to teach factual material concerning human embryology. At some state universities, for instance, if a professor's lecture is felt to teach or discuss abortion (as it might when teaching about tubal pregnancies, hydatidiform moles, or eneuploidy), that instructor risks imprisonment for up to 14 years (Gyori, 2023). Some states' new censorship rules have thus caused professors to drop modules on abortion from numerous science and humanities courses. In most states, instructors can still teach about human embryonic development and not risk putting their careers or livelihoods in jeopardy. However, even in many of these institutions, students can bring a professor to a disciplinary hearing by claiming that the instructor failed to provide ample trigger warnings on such issues. This essay attempts to provide some strategies wherein human embryology and the ethical issues surrounding it might be taught and students may be given resources to counter unscientific falsehoods about fertilization and human development. This essay provides evidence for teaching the following propositions. Mis-information about human biology and medicine is rampant on the internet, and there are skills that can be taught to students that will help them determine which sites should trusted. This is a skill that needs to be taught as part of science courses.

Artemisia argyi (AA), a herbal medicine traditionally used in Asian countries, to treat inflammatory conditions such as eczema, dermatitis, arthritis, allergic asthma and colitis. However, the mechanism of action of this plant with regard to hepatitis and other liver-related diseases is still unclear.

This study aimed to investigate the effects of AA ethanol extract on NASH-related fibrosis and gut microbiota in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced mouse model.

Male C57BL/6J mice were fed CDAHFD, with or without AA ethanol extract treatment. Biochemical markers, lipid profiles, hepatic mRNA expression levels of key genes, and the fibrosis area were assessed. In vitro, TGF-β-stimulated human hepatic stellate LX-2 cells and mouse primary hepatic stellate cells (mHSCs) were used to elucidate the effects of AA ethanol extract on fibrosis and steatosis. 16S rRNA sequencing, QIIME2, and PICRUST2 were employed to analyze gut microbial diversity, composition, and functional pathways.

Treatment with the AA ethanol extract improved plasma and liver lipid profiles, modulated hepatic mRNA expression levels of antioxidant, lipolytic, and fibrosis-related genes, and significantly reduced CDAHFD-induced hepatic fibrosis. Gut microbiota analysis revealed a marked decrease in Acetivibrio ethanolgignens abundance upon treatment with the AA ethanol extract, and its functional pathways were significantly correlated with NASH/fibrosis markers. The AA ethanol extract and its active components (jaceosidin, eupatilin, and chlorogenic acid) inhibited fibrosis-related markers in LX-2 and mHSC.

The AA ethanol extract exerted therapeutic effects on CDAHFD-induced liver disease by modulating NASH/fibrosis-related factors and gut microbiota composition. Notably, AA treatment reduced the abundance of the potentially profibrotic bacterium (A. ethanolgignens). These findings suggest that AA is a promising candidate for treating NASH-induced fibrosis.

The mammalian intestine is colonized by trillions of microorganisms that are collectively referred to as the gut microbiota. The majority of symbionts have co-evolved with their host in a mutualistic relationship that benefits both. Under certain conditions, such as in Crohn's disease, a subtype of inflammatory bowel disease, some symbionts bloom to cause disease in genetically susceptible hosts. Although the identity and function of disease-causing microorganisms or pathobionts in Crohn's disease remain largely unknown, mounting evidence from animal models suggests that pathobionts triggering Crohn's disease-like colitis inhabit certain niches and penetrate the intestinal tissue to trigger inflammation. In this Review, we discuss the distinct niches occupied by intestinal symbionts and the evidence that pathobionts triggering Crohn's disease live in the mucus layer or near the intestinal epithelium. We also discuss how Crohn's disease-associated mutations in the host disrupt intestinal homeostasis by promoting the penetration and accumulation of pathobionts in the intestinal tissue. Finally, we discuss the potential role of microbiome-based interventions in precision therapeutic strategies for the treatment of Crohn's disease.

Probiotics, known for regulating gut microbiota, may aid those with overweight or obesity, but their mechanisms require more research. This study involved 75 overweight or obese young adults, randomly assigned to either a Bifidobacterium breve BBr60 (BBr60) group or a placebo group. Both groups received diet guidance and took either BBr60 (1 × 1010 CFU/day) or a placebo for 12 weeks. Researchers analyzed body composition, serum glucose, lipids, liver and kidney function, comprehensive metabolome, and intestinal homeostasis before and after the intervention. After 12 weeks, BBr60 significantly reduced weight and BMI compared to pretreatment levels and outperformed the placebo. The BBr60 group also showed improved blood biochemistry, with notably lower fasting blood glucose (FBG) levels than the placebo group (p < 0.05). Additionally, BBr60 influenced vital serum and fecal metabolites related to three amino acid metabolic pathways and regulated the bacteria Dialister, Klebsiella, and Bacteroides, which correlated strongly with serum metabolites. These findings indicate that BBr60 can safely and effectively regulate BMI, body weight, serum glucose, lipids, and liver function markers, which may involve BBr60's impact on key gut bacteria, which influence metabolites related to the valine, leucine, and isoleucine biosynthesis; glycine, serine, and threonine metabolism; and alanine, aspartate, and glutamate metabolism.

Microbiota and feeding modes influence the susceptibility of premature newborns to necrotizing enterocolitis (NEC) through mechanisms that remain unknown. Here, we show that microbiota colonization facilitated by breastmilk feeding promotes NOD-like receptor family CARD domain containing 5 (Nlrc5) gene expression in mouse intestinal epithelial cells (IECs). Notably, inducible knockout of the Nlrc5 gene in IECs predisposes neonatal mice to NEC-like injury in the small intestine upon viral inflammation in an NK1.1+ cell-dependent manner. By contrast, formula feeding enhances neonatal gut colonization with environment-derived tilivalline-producing Klebsiella spp. Remarkably, tilivalline disrupts microbiota-activated STAT1 signaling that controls Nlrc5 gene expression in IECs through a PPAR-γ-mediated mechanism. Consequently, this dysregulation hinders the resistance of neonatal intestinal epithelium to self-NK1.1+ cell cytotoxicity upon virus infection/colonization, promoting NEC development. Together, we discover the underappreciated role of intestinal microbiota colonization in shaping a disease tolerance program to viral inflammation and elucidate the mechanisms impacting NEC development in neonates.

Progressive oxidative stress easily occurs as a result of a gradual increase in the intensity of maternal metabolism due to rapid foetal development and increased intensity of lactation. However, studies on the effects of processive oxidative stress on nutrient transport in the placenta have received little attention. The present study was conducted on sows at 85 days of gestation to study the effects of pterostilbene (PTE) on maternal oxidative stress status and placental nutrient transport.

PTE increased the antioxidant capacity and immunoglobulin content in mothers' blood and milk, reduced the level of inflammatory factors, and improved the nutrient content of milk. PTE also reduced sow backfat loss and the number of weak sons, and increased piglet weaning weight and total weaning litter weight. We subsequently found that PTE enhanced placental glucose and fatty acid transport and further affected glycolipid metabolism by increasing the expression of LAL, PYGM, and Gbe-1, which activated the PI3K phosphorylation pathway. Moreover, PTE addition altered the relative abundance of the Firmicutes, Proteobacteria, Parabacillus, and Bacteroidetes-like RF16 groups in sow faeces. PTE increased the levels of acetate, propionate, butyrate and isovalerate in the faeces.

These findings reveal that the addition of PTE during pregnancy and lactation mitigates the effects of processive oxidative stress on offspring development by altering maternal microbial and placental nutrient transport capacity.

The gut microbiota exerts a significant influence on human health and disease. While compositional changes in the gut microbiota in specific diseases can easily be determined, we lack a detailed mechanistic understanding of how these changes exert effects at the cellular level. However, the putative local and systemic effects on human physiology that are attributed to the gut microbiota are clearly being mediated through molecular communication. Here, we determined the effects of gut microbiome-derived metabolites l-tryptophan, butyrate, trimethylamine (TMA), 3-methyl-4-(trimethylammonio)butanoate (3,4-TMAB), 4-(trimethylammonio)pentanoate (4-TMAP), ursodeoxycholic acid (UDCA), glycocholic acid (GCA) and benzoate on the first line of defence in the gut. Using in vitro models of intestinal barrier integrity and studying the interaction of macrophages with pathogenic and non-pathogenic bacteria, we could ascertain the influence of these metabolites at the cellular level at physiologically relevant concentrations. Nearly all metabolites exerted positive effects on barrier function, but butyrate prevented a reduction in transepithelial resistance in the presence of the pathogen Escherichia coli, despite inducing increased apoptosis and exerting increased cytotoxicity. Induction of IL-8 was unaffected by all metabolites, but GCA stimulated increased intra-macrophage growth of E. coli and tumour necrosis-alpha (TNF-α) release. Butyrate, 3,4-TMAB and benzoate all increased TNF-α release independent of bacterial replication. These findings reiterate the complexity of understanding microbiome effects on host physiology and underline that microbiome metabolites are crucial mediators of barrier function and the innate response to infection. Understanding these metabolites at the cellular level will allow us to move towards a better mechanistic understanding of microbiome influence over host physiology, a crucial step in advancing microbiome research.

Ulcerative Colitis (UC) is a chronic inflammatory disease of the intestinal tract with unknown definitive etiology. Polysaccharides are among the most important active components of Abelmoschi Corolla, exhibitings various pharmacological activities such as antioxidation and immunomodulation. However, no studies have yet reported the application of Abelmoschi Corolla Polysaccharides (ACP) in treating UC. This study aims to highlight the therapeutic efficacy of ACP in UC and reveal the underlying mechanism. The potential therapeutic effect is initially verified using a dextran sodium sulfate (DSS)-induced colitis model. 16S rRNA sequencing is performed using feces samples and untargeted metabolomics using serum samples to further reveal that ACP reprograms the dysbiosis triggered by UC progression, increases the abundance of Bacteroides spp., Blautia spp., and Parabacteroides spp. at the genus level and enriches the serum concentration of 7-ketodeoxycholic acid (7-KDA). Furthermore, using the FXR-/- mouse model, it is revealed that Farnesoid X Receptor (FXR) is a key target for ACP and the metabolite 7-KDA to block STAT3 phosphorylation by repairing the intestinal barrier to attenuate UC. Taken together, this work highlights the therapeutic potential of ACP against UC, mainly exerting its effects via modulating gut microbiota and regulating the FXR/STAT3 signaling pathway.

Comparative physiologists often compare physiological traits across organisms to understand the selective pressures influencing their evolution in different environments. Traditionally focused on the organisms themselves, comparative physiology has more recently incorporated studies of the microbiome-the communities of microbes living in and on animals that influence host physiology. In this commentary, we describe the utility of applying a comparative framework to study the microbiome, particularly in understanding how hosts vary in their dependence on microbial communities for physiological function, a concept we term the "microbial dependence continuum". This hypothesis suggests that hosts exist on a spectrum ranging from high to low reliance on their microbiota. Certain physiological traits may be highly dependent on microbes for proper function in some species but microbially independent in others. Comparative physiology can elucidate the selective pressures driving species along this continuum. Here, we discuss the microbial dependence continuum in detail and how comparative physiology can be useful to study it. Then, we discuss two example traits, herbivory and flight, where comparative physiology has helped reveal the selective pressures influencing host dependence on microbial communities. Lastly, we discuss useful experimental approaches for studying the microbial dependence continuum in a comparative physiology context.

The human microbiome is a diverse ecosystem of microorganisms that reside in the body and influence various aspects of health and well-being. Recent advances in sequencing technology have brought to light microbial communities in organs and tissues that were previously considered sterile. The gut microbiota plays an important role in host physiology, including metabolic functions and immune modulation. Disruptions in the balance of the microbiome, known as dysbiosis, have been linked to diseases such as cancer, inflammatory bowel disease and metabolic disorders. In addition, the administration of antibiotics can lead to dysbiosis by disrupting the structure and function of the gut microbial community. Targeting strategies are the key to rebalancing the microbiome and fighting disease, including cancer, through interventions such as probiotics, fecal microbiota transplantation (FMT), and bacteria-based therapies. Future research must focus on understanding the complex interactions between diet, the microbiome and cancer in order to optimize personalized interventions. Multidisciplinary collaborations are essential if we are going to translate microbiome research into clinical practice. This will revolutionize approaches to cancer prevention and treatment.

The human digestive system harbors a vast diversity of commensal bacteria and maintains a symbiotic relationship with them. However, imbalances in the gut microbiota accompany various diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancers (CRCs), which significantly impact the well-being of populations globally. Glycosylation of the mucus layer is a crucial factor that plays a critical role in maintaining the homeostatic environment in the gut. This review delves into how the gut microbiota, immune cells, and gut mucus layer work together to establish a balanced gut environment. Specifically, the role of glycosylation in regulating immune cell responses and mucus metabolism in this process is examined.

Improving the number of amino acids and unsaturated fatty acids in the diet is a good way to raise the quality of the meat. Currently, most research on the quality of broiler meat focuses on genetic traits; nevertheless, it is unclear how meat quality is regulated. This experiment was conducted to investigate the effects of different supplemental levels of walnut meal (WM) on growth performance, amino acid and fatty acid composition, microbial composition, and meat quality of white feather broilers. 1 week old white feather broilers (n = 120; Body weight 83.76 ± 2.32 g), were randomly divided into 3 treatments and 4 replicates. Walnut meal of basic diet (CK), 5 %(WM-L) and 10 %(WM-H) were added to the diets of white feather broilers, respectively. The results showed that walnut meal could increase L* 24 h (24 h brightness) of breast muscle of white feathered broilers (p < 0.05). The amount of essential amino acids (e.g., isoleucine, methionine, leucine, tryptophan, and phenylalanine), umami amino taste acids (glutamic acid), and PUFA/SFA (polyunsaturated fatty acid) (n-3PUFA and n-6 PUFA) in breast muscle increased as the dose was increased. Furthermore, walnut meal regulated amino acid flavour metabolism by increasing the relative abundance of Bacteroides, bifidobacterium, and enterococcus faecalis, according to 16S rRNA sequencing and functional prediction analysis. The correlation showed that amino acid and fatty acid composition was one of the key factors affecting pH value, meat color and tenderness of chicken. In conclusion, dietary addition of walnut meal can increase the content of essential amino acids and unsaturated fatty acids and the relative abundance of beneficial bacteria of broilers, which is of great significance for improving meat quality of white feather broilers.

Background: The relationship between gut microbiota and diabetes-related amino acids significantly impacts insulin resistance and obesity. We aimed to quantify two Bacteroidetes species and their correlation with branched-chain amino acids, aromatic amino acids, and glutamate in prediabetes (preDM) and type 2 diabetes mellitus (T2DM). Methods: Fecal samples were collected from 68 participants, including 21 with T2DM, 23 with preDM, and 24 with normal glycemic tolerance (NGT). The abundance of Bacteroides vulgatus and Bacteroides thetaiotaomicron was determined by quantitative real-time polymerase chain reaction. Plasma amino acid measurements were performed using liquid chromatography coupled with tandem mass spectrometry. Results: The quantities of B. vulgatus and B. thetaiotaomicron were reduced in preDM and T2DM than in NGT subjects, but it was not statistically significant. The concentrations of leucine, valine, and tyrosine were significantly higher in preDM and T2DM than in NGT subjects (P < 0.05). A negative correlation was observed between B. thetaiotaomicron abundance and two aromatic amino acids (tyrosine, r = -0.28, P = 0.04; phenylalanine, r = -0.26, P = 0.05). Conclusions: These findings imply that, since gut microbiota varies throughout ethnic groups, further research with many participants will be required to determine the abundance of B. vulgatus and B. thetaiotaomicron in preDM and T2DM and their association with diabetes-related amino acids.

This study investigated the effect of replacing part of the dietary soybean meal with either polymer-coated urea or gelatinized starch urea on the production performance, blood indexes, and ruminal fermentation of Angus heifers. A total of 210 purebred Angus cattle (BW = 314.26 kg) were divided into three groups: the no urea group (CON), the polymer-coated urea group (PCU), and the gelatinized starch urea group (GSU); 20 g/kg polymer-coated urea or 25 g/kg gelatinized starch urea was used to replace part of soybean meal in the concentrate feed, according to the principle of isometabolic energy and isonitrogenous. The result showed that the PCU group had higher ADG and ADF apparent digestibility, while it had a lower feed-weight ratio. On the 86th day, the serum albumin (ALB) content in the PCU group was significantly higher than that in the CON group. In rumen, compared with the CON group, the contents of acetic acid and total volatile fatty acid were significantly higher in the PCU group, whereas butyric acid and propionic acid were significantly higher in the PCU group and GSU group. Ruminal bacterial diversity analysis found that the abundance of Firmicutes was higher in the PCU group at the phylum level, and an inverse result was observed in Bacteroidetes. The abundance of Paraprevotella was higher in the PCU group, whereas higher abundance of Prevotella was found in the GSU group at the genus level. These results indicate that slow-release urea can replace part of soybean meal in the diet, and the amount of substitution in this trial had no diverse effect on the performance of Angus heifers.

Fluorosis is a global public health disease affecting more than 50 countries and 500 million people. Excessive fluoride damages the liver and intestines, yet the mechanisms and therapeutic approaches remain unclear.

To explore the mechanisms by which fluoride-induced intestinal-hepatic damage and vitamin B2 alleviation.

Fluoride and/or vitamin B2-treated IL-17A knockout and wild-type mouse models were established, the morphological and functional changes of liver and gut, total bile acid biosynthesis, metabolism, transport, and regulation of FXR-FGF15 signaling pathways were evaluated, the ileal microbiome was further analyzed by 16S rDNA sequence. Finally, Bifidobacterium supplementation mouse model was designed and re-examined the above indicators.

The results demonstrated that fluoride induced hepatointestinal injury and enterohepatic circulation disorder by altering the synthesis, transporters, and FXR-FGF15 pathway regulation of total bile acid. Importantly, the ileum was found to be the most sensitive and fluoride changed ileal microbiome particularly by reducing abundance of Bifidobacterium. While vitamin B2 supplementation attenuated fluoride-induced enterohepatic circulation dysfunction through IL-17A and ileal microbiome, Bifidobacterium supplementation also reversed fluoride-induced hepatointestinal injury.

Fluoride induces morphological and functional impairment of liver and gut tissues, as well as enterohepatic circulation disorder by altering total bile acid (TBA) synthesis, transporters, and FXR-FGF15 signaling regulation. Vitamin B2 attenuated fluoride-induced enterohepatic circulation disorder through IL-17A knockout and ileal microbiome regulation. The ileum was found to be the most sensitive to fluoride, leading to changes in ileal microbiome, particularly the reduction of Bifidobacterium. Furthermore, Bifidobacterium supplementation reversed fluoride-induced hepatointestinal injury. This study not only elucidates a novel mechanism by which fluoride causes hepatointestinal toxicity, but also provides a new physiological function of vitamin B2, which will be useful in the therapy of fluorosis and other hepatoenterological diseases.

The goal of this study is to investigate the role of microbiota-gut-brain axis involved in the protective effect of pair-housing on post-stroke depression (PSD). PSD model was induced by occluding the middle cerebral artery (MCAO) plus restraint stress for four weeks. At three days after MCAO, the mice were restrained 2 h per day. For pair-housing (PH), each mouse was pair housed with a healthy isosexual cohabitor for four weeks. While in the other PH group, their drinking water was replaced with antibiotic water. On day 35 to day 40, anxiety- and depression-like behaviors (sucrose consumption, open field test, forced swim test, and tail-suspension test) were conducted. Results showed pair-housed mice had better performance on anxiety- and depression-like behaviors than the PSD mice, and the richness and diversity of intestinal flora were also improved. However, drinking antibiotic water reversed the effects of pair-housing. Furthermore, pair-housing had an obvious improvement in gut barrier disorder and inflammation caused by PSD. Particularly, they showed significant decreases in CD8 lymphocytes and mRNA levels of pro-inflammatory cytokines (TNF-a, IL-1β and IL-6), while IL-10 mRNA was upregulated. In addition, pair-housing significantly reduced activated microglia and increased Nissl's body in the hippocampus of PSD mice. However, all these improvements were worse in the pair-housed mice administrated with antibiotic water. We conclude that pair-housing significantly improves PSD in association with enhanced functions of microbiota-gut-brain axis, and homeostasis of gut microbiota is indispensable for the protective effect of pair-housing on PSD.

Constipation is a prevalent gastrointestinal disorder affecting approximately 15% of the global population, leading to significant healthcare burdens. Emerging evidence suggests that gut microbiota plays a pivotal role in the pathogenesis of constipation, although causality remains uncertain due to potential confounding factors in observational studies. This study aims to clarify the causal relationships between gut microbiota and constipation using a bidirectional Mendelian Randomization (MR) approach, which helps to overcome confounding issues and reverse causality.

Utilizing data from genome-wide association studies (GWAS) from the MiBioGen consortium and other sources, we identified genetic variants as instrumental variables (IVs) for 196 bacterial traits and constipation. These IVs were rigorously selected based on their association with the traits and absence of linkage with confounding factors. We applied several MR methods, including Inverse Variance Weighted (IVW), MR Egger, and MR-PRESSO, to examine the causal effects in both directions.

Our analysis revealed a significant causal relationship where specific bacterial taxa such as Coprococcus1 (OR = 0.798, 95%CI: 0.711-0.896, p < 0.001), Coprococcus3 (OR = 0.851, 95%CI: 0.740-0.979, p = 0.024), Desulfovibrio (OR = 0.902, 95%CI: 0.817-0.996, p = 0.041), Flavonifractor (OR = 0.823, 95%CI: 0.708-0.957, p < 0.001), and Lachnospiraceae UCG004, whereas others including Ruminococcaceae UCG005 (OR = 1.127, 95%CI: 1.008-1.261, p = 0.036), Eubacterium nodatum group (OR = 1.080, 95%CI: 1.018-1.145, p = 0.025), Butyricimonas (OR = 1.118, 95%CI: 1.014-1.233, p = 0.002), and Bacteroidetes (OR = 1.274, 95%CI: 1.014-1.233, p < 0.001) increase constipation risk. In the reverse MR analysis, constipation was found to influence the abundance of certain taxa, including Family XIII, Porphyromonadaceae, Proteobacteria, Lentisphaeria, Veillonellaceae, Victivallaceae, Catenibacterium, Sellimonas, and Victivallales, indicating a bidirectional relationship. Sensitivity analyses confirmed the robustness of these findings, with no evidence of heterogeneity or horizontal pleiotropy.

The relationship between our study gut microbiota and constipation interacts at the genetic level, which gut microbiota can influence the onset of constipation, and constipation can alter the gut microbiota. Coprococcus1, Coprococcus3, Desulfovibrio, Flavonifractor and Lachnospiraceae UCG004 play a protective role against constipation, while Ruminococcaceae UCG005, Eubacterium nodatum group, Butyricimonas, and Bacteroidetes are associated with an increased risk. In addition, constipation correlates positively with the abundance of Family XIII, Porphyromonadaceae and Proteobacteria, while negatively with Lentisphaeria, Veillonellaceae, Victivallaceae, Catenibacterium, Sellimonas, and Victivallales.

Previous studies have shown the harmful effects of nanoscale particles on the intestinal tracts of organisms. However, the specific mechanisms remain unclear. Our present study focused on examining the uptake and distribution of polystyrene nanoplastics (PS-NPs) in zebrafish larvae, as well as its toxic effects on the intestine. It was found that PS-NPs, marked with red fluorescence, primarily accumulated in the intestine section. Subsequently, zebrafish larvae were exposed to normal PS-NPs (0.2-25 mg/L) over a critical 10-day period for intestinal development. Histopathological analysis demonstrated that PS-NPs caused structural changes in the intestine, resulting in inflammation and oxidative stress. Additionally, PS-NPs disrupted the composition of the intestinal microbiota, leading to alterations in the abundance of bacterial genera such as Pseudomonas and Aeromonas, which are associated with intestinal inflammation. Metabolomics analysis showed alterations in metabolites that are primarily involved in glycolipid metabolism. Furthermore, MetOrigin analysis showed a significant correlation between bacterial flora (Pedobacter and Bacillus) and metabolites (D-Glycerate 2-phosphate and D-Glyceraldehyde 3-phosphate), which are related to the glycolysis/gluconeogenesis pathways. These findings were further validated through alterations in multiple biomarkers at various levels. Collectively, our data suggest that PS-NPs may impair the intestinal health, disrupt the intestinal microbiota, and subsequently cause metabolic disorders.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.

Myriad associations between the microbiome and various facets of liver physiology and pathology have been described in the literature. Building on descriptive and correlative sequencing studies, metagenomic studies are expanding our collective understanding of the functional and mechanistic role of the microbiome as mediators of the gut-liver axis. Based on these mechanisms, the functional activity of the microbiome represents an attractive, tractable, and precision medicine therapeutic target in several liver diseases. Indeed, several therapeutics have been used in liver disease even before their description as a microbiome-dependent approach. To bring successful microbiome-targeted and microbiome-inspired therapies to the clinic, a comprehensive appreciation of the different approaches to influence, collaborate with, or engineer the gut microbiome to coopt a disease-relevant function of interest in the right patient is key. Herein, we describe the various levels at which the microbiome can be targeted-from prebiotics, probiotics, synbiotics, and antibiotics to microbiome reconstitution and precision microbiome engineering. Assimilating data from preclinical animal models, human studies as well as clinical trials, we describe the potential for and rationale behind studying such therapies across several liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cirrhosis, HE as well as liver cancer. Lastly, we discuss lessons learned from previous attempts at developing such therapies, the regulatory framework that needs to be navigated, and the challenges that remain.

Drug efflux transporters are a major determinant of drug efficacy and toxicity. A canonical example is P-glycoprotein (P-gp), an efflux transporter that controls the intestinal absorption of diverse compounds. Despite a rich literature on the dietary and pharmaceutical compounds that impact P-gp activity, its sensitivity to gut microbial metabolites remains an open question. Surprisingly, we found that the cardiac drug-metabolizing gut Actinobacterium Eggerthella lenta increases drug absorption in mice. Experiments in cell culture revealed that E. lenta produces a soluble factor that post-translationally inhibits P-gp ATPase efflux activity. P-gp inhibition is conserved in the Eggerthellaceae family but absent in other Actinobacteria. Comparative genomics identified genes associated with P-gp inhibition. Finally, activity-guided biochemical fractionation coupled to metabolomics implicated a group of small polar metabolites with P-gp inhibitory activity. These results highlight the importance of considering the broader relevance of the gut microbiome for drug disposition beyond first-pass metabolism.

To assess the effectiveness and safety of combining Saccharomyces boulardii powder with triple therapy as a primary approach for eradicating H. pylori infection, a total of 144 patients who tested positive for H. pylori and diagnosed with non-ulcer dyspepsia underwent endoscopy at two national centers between June 2017 and March 2019 were included. The patients were categorized into three groups using a subsection randomization method and received initial H. pylori eradication treatments. Microbial composition, eradication rates, symptom alleviation, and adverse reactions were monitored on the 14th and 44th days post-treatment. According to PP analysis showed the eradication rates for the SRAC group was 75%, BRAC was 93.18% and RAC was 65.2%. Group BRAC exhibited a marginally higher eradication rate compared to other groups. However, patients receiving Saccharomyces boulardii treatment exhibited an overall reduction in initial dyspepsia symptoms by the end of the treatment period. When employed as a primary strategy, the combination of Saccharomyces boulardii powder with triple therapy displayed notable efficacy and smaller gastrointestinal side effects in eradicating initial H. pylori infections among non-ulcer dyspepsia patients. Moreover, this approach demonstrated advantages in alleviating symptoms, exhibited favorable tolerance, and maintained a high level of clinical safety.