The initiation and progression of colorectal cancer (CRC) are intimately associated with genetic, environmental and biological factors. Desulfovibrio vulgaris (DSV), a sulfate-reducing bacterium, has been found excessive growth in CRC patients, suggesting a potential role in carcinogenesis. However, the precise mechanisms underlying this association remain incompletely understood. We have found Desulfovibrio was abundant in high-fat diet-induced Apcmin/+ mice, and DSV, a member of Desulfovibrio, triggered colonocyte proliferation of germ-free mice. Furthermore, the level of DSV progressively rose from healthy individuals to CRC patients. Flagella are important accessory structures of bacteria, which can help them colonize and enhance their invasive ability. We found that D. vulgaris flagellin (DVF) drove the proliferation, migration, and invasion of CRC cells and fostered the growth of CRC xenografts. DVF enriched the epithelial-mesenchymal transition (EMT)-associated genes and characterized the facilitation of DVF on EMT. Mechanistically, DVF induced EMT through a functional transmembrane receptor called leucine-rich repeat containing 19 (LRRC19). DVF interacted with LRRC19 to modulate the ubiquitination of tumor necrosis factor receptor-associated factor (TRAF)6, rather than TRAF2. This interaction drove the ubiquitination of pivotal molecule TAK1, further enhancing its autophosphorylation and ultimately contributing to EMT. Collectively, DVF interacts with LRRC19 to activate the TRAF6/TAK1 signaling pathway, thereby promoting the EMT of CRC. These data shed new light on the role of gut microbiota in CRC and establish a potential clinical therapeutic target.

Gallstone disease, arising from the interplay between host metabolism and gut microbiota, represents a significant health concern. Dysbiosis of the gut microbiome and disruptions in circadian rhythm contribute to the pathogenesis of gallstones. This study conducted a comprehensive analysis of gut microbiota and metabolites derived from stool and serum samples of 28 patients with cholesterol gallstones (CGS) and 19 healthy controls, employing methodologies such as 16S rRNA sequencing, metaproteomics, metabolomics, and host genetic analysis. Additionally, a retrospective cohort study was utilized to assess the efficacy of probiotics or ursodeoxycholic acid (UDCA) in preventing CGS formation post-bariatric surgery.

In CGS patients, gut microbiota diversity shifted, with harmful bacteria rising and beneficial ones declining. The altered microbiota primarily affected amino acid, lipid, nucleotide, and carbohydrate metabolism. Metabolic abnormalities were noted in amino acids, glucose, lipids, and bile acids with decreased levels of ursodeoxycholic, glycosodeoxycholic, and glycolithocholic acids, and increased glycohyodeoxycholic and allocholic acids. Glutamine and alanine levels dropped, while phenylalanine and tyrosine rosed. Animal studies confirmed gene changes in gallbladder tissues related to bile acid, energy, glucose, and lipid metabolism. Importantly, UDCA and probiotics effectively reduced CGS risk post-bariatric surgery, especially when combined.

Multi-omics can clarify CGS pathology, by focusing on the gut-metabolism-gene axis, paving the way for future studies on CGS prevention and treatment through gut microbiota or metabolic interventions.

Cholelithiasis, the formation of stones in the gallbladder, is a common surgical condition with an increasing incidence. Laparoscopic cholecystectomy has become the gold standard for the treatment of symptomatic gallstones due to its favorable outcomes. However, with increasing recognition of the gallbladder's importance, this procedure no longer aligns with patients' desire to preserve the organ. Technological advancements and surgical innovations have led to emerging approaches such as natural orifice transluminal endoscopic surgery (NOTES), robot-assisted laparoscopic cholecystectomy, and cholangioscopy. This narrative review examines the current landscape of surgical interventions for gallstones, highlighting both gallbladder-preserving and removal approaches, and aims to provide insight into their respective outcomes and clinical implications.

This study aimed to assess the link between inflammatory biomarkers (like the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammatory index (SII), and systemic inflammation response index (SIRI)) and gallstones in American individuals aged under 50 years.

This study utilized data from the National Health and Nutrition Examination Survey (NHANES) covering 2017 to 2020, centering on individuals under 50 years with comprehensive data on NLR, SII, SIRI, and gallstones. It employed a weighted multiple logistic regression approach to investigate the link between inflammatory biomarkers and gallstones. Furthermore, dose-response relationships and threshold effects were evaluated utilizing restricted cubic spline (RCS) methods and segmented linear regression models. Subgroup examinations and interaction assessments were conducted, too.

The investigation encompassed a total of 3,295 individuals. Upon comprehensive adjustment for variables, multivariate logistic regression revealed a positive relationship between inflammatory biomarkers and gallstones: ln-NLR (OR = 1.68, 95% CI: 1.06-2.66, p = 0.033), ln-SII (OR = 1.79, 95% CI: 1.08-2.98, p = 0.032), and ln-SIRI (OR = 1.46, 95% CI: 1.07-1.99, p = 0.025). A non-linear association, shaped like an inverse "U", was noted between ln-SIRI and gallstones. To the left of the inflection point (ln-SIRI = 0.35, SIRI = 1.42), a positive link existed between ln-SIRI and gallstones (OR = 2.45, 95% CI: 1.20-5.03); whereas, to the right of the inflection point, the association was statistically insignificant (OR = 0.60, 95% CI: 0.21-1.73).

ln-NLR and ln-SII exhibited a linear and positive relationship with the likelihood of developing gallstones. ln-SIRI demonstrated a nonlinear dose-response relationship with gallstone risk, characterized by an inverted "U" shape.

Cholelithiasis is influenced by various factors, including genetic elements identified in genomewide association studies, but their biological functions are not fully understood.

Analyzing data from the Finngen database with 37,041 cholelithiasis cases and 330,903 controls, this study combined SNP data from GTEx v8 and linkage disequilibriums data from the 1000 Genomes Project. Using the Transcriptomewide Association Studies FUSION protocol and summary data-based Mendelian randomization analysis, it investigated the relationship between gene expression and cholelithiasis, using colocalization tests and conditional analyses to explore causality.

The study identified genes associated with cholelithiasis in the liver and whole blood, such as LINC01595, TTC39B, and UGT1A3, with several showing colocalization traits. Notably, RP11-378A13.1 and adenosine deaminase acting on RNA (ADAR) were significantly associated with the disease in both tissues.

This research provides insights into the genetic underpinnings of cholelithiasis, highlighting the significant role of gene expression in its development. It establishes new gene associations and identifies potential genetic markers for the disease.

Traditional Chinese Medicine (TCM), such as artemisinin, berberine and proanthocyanidin, has been considered an effective additive for broiler production. High density farming (HDF), which is the primary modern mode of chicken production, is associated with animal health problems. This work aimed to evaluate the effects of dietary TCMs (dihydroartemisinin, hydrochloride, and oligomeric proanthocyanidins) on improving the antioxidant capacity of chickens under HDF and their underlying mechanisms. A total of 360 Wuding chickens (134-day-old) were divided into five experimental groups: one normal stocking density (8 birds/m2, control group) and four high stocking density (16 birds/m2), with six replicates for each group. For four HDF groups, one group was fed the basal diet, and the other three groups were fed the basal diet supplemented with 80 mg/kg dihydroartemisinin, 600 mg/kg berberine hydrochloride, and 250 mg/kg grape oligomeric proanthocyanidins, respectively. HDF increased malondialadehyde level, but decreased superoxide dismutase, glutathione and glutathione peroxidase levels in the liver of broiler; however, dietary TCMs apparently alleviated this attenuation. Dietary TCMs significantly decreased the expression of genes involved in cholesterol synthesis in the liver and the levels of tripepides in the intestine of the HDF chickens. Meanwhile, dietary TCMs significantly altered the composition of the liver microbiome in the HDF chickens, expressing by reduced Pseudomonas but enriched Bradyrhizobium. The gut microbiota of the HDF chickens was also altered following dietary TCM administration, with a decreased abundance of Microbacter margulisiae and an increased abundance of acetate synthesis genes. Association analysis of the multi-omics results revealed negative correlations between liver cholesterol synthesis and antioxidant factors that could be regulated by gut microbiota-produced short-chain fatty acids. Furthermore, alleviating of oxidative stress by dietary TCMs also showed significant correlations with the liver microbiome, which could be mediated by tripeptides produced by the gut microbiota. These results indicated that dietary TCM is beneficial in improving antioxidant defenses in HDF chickens and interpreted the mechanisms of action of TCM from the perspective of modern science.

Cholesterol synthesis and gallstone formation are promoted by trimethylamine-N-oxide (TMAO), a derivative of trimethylamine, which is a metabolite of gut microbiota. However, the underlying mechanisms of TMAO-induced lithogenesis remain incompletely understood. This study aimed to explore the specific molecular mechanisms through which TMAO promotes gallstone formation.

Enzyme-linked immunosorbent assays were used to compare serum concentrations of TMAO, apolipoprotein A4 (APOA4), and proprotein convertase subtilisin/kexin type 9 (PCSK9) between patients with cholelithiasis and normal controls. A murine model of TMAO-induced cholelithiasis was employed, incorporating assays of gallstone weight and bile cholesterol content, along with RNA sequencing of murine hepatic tissue. A TMAO-induced AML12 hepatocyte line was constructed and transfected with targeted small interfering RNAs and overexpression plasmids. In vivo and in vitro experiments were performed to determine the expression and regulation of genes related to cholesterol metabolism.

Serum TMAO and PCSK9 levels were elevated, whereas APOA4 levels were reduced in patients with cholelithiasis. Furthermore, our murine model demonstrated that TMAO upregulated hepatic expression of PCSK9, 3-hydroxy-3-methylglutaryl-CoA reductase, and ATP-binding cassette sub-family G member 5/8, while reducing APOA4 expression, thereby modulating cholesterol metabolism and promoting lithogenesis. PCSK9 and APOA4 were identified as key regulatory genes in the cholesterol metabolic pathway. PCSK9 knockdown increased APOA4 expression, while APOA4 overexpression led to reduced PCSK9 expression.

TMAO upregulated hepatic PCSK9 expression and reduced APOA4 expression, initiating a feedback loop that dysregulated cholesterol metabolism and promoted lithogenesis.

Gallbladder cancer (GBC) is an aggressive malignancy, with gallstone disease (GSD) recognized as the primary risk factor. Although the precise mechanism linking GSD to GBC remains unclear, evidence suggests that gallstone characteristics play a significant role. This study investigates the physicochemical characteristics of gallstones critical for GBC development. We analyzed 40 gallstone samples from 30 GSD and 10 GBC with GSD (GBCGS) patients using advanced spectroscopic and imaging techniques such as fourier transform infrared (FTIR), powder X-ray diffraction (PXRD), nuclear magnetic resonance (NMR), and scanning electron microscopy energy-dispersive X-ray (SEM-EDX)). Subsequently, elemental analysis of 10 gallstones each from GBCGS and GSD was conducted via inductively coupled plasma-mass spectrometry (ICP-MS). Gallstones from the GSD group were identified as cholesterol (70%), mixed (13.3%), pigment (6.7%), and calcium carbonate (10%), while the GBCGS group included only cholesterol (70%) and mixed (30%) types. Cholesterol was the dominant organic component in most gallstones, with the cholesterol and mixed types exhibiting highly crystalline phases characterized by a stacked plate-like microstructure, particularly prominent in the GBCGS group. Additionally, the GBCGS group revealed significantly higher concentrations of carcinogenic elements such as arsenic, chromium, mercury, iron, and lead (p < 0.05), suggesting their accumulation in the gallbladder and gallstones. Consequently, our findings highlight that the physicochemical properties of cholesterol-rich gallstones and exposure to carcinogenic elements play a key role in the pathogenesis of GBC in Assam. These results emphasize the need for further research into cholesterol dysregulation and its link to elemental toxicity.

Gut microbiota plays a crucial role in resisting the invasion of pathogens, particularly multidrug-resistant (MDR) bacteria, which pose a significant threat to public health. While exercise offers numerous health benefits, its impact on host colonization resistance remains largely unclear. In this study, we demonstrate that moderate exercise significantly reduces gut colonization by methicillin-resistant Staphylococcus aureus (MRSA), a clinically important MDR pathogen. Moreover, we identify an understudied strain of the intestinal probiotic Dubosiella newyorkensis (L8) as a critical factor in mediating exercise-induced colonization resistance against MRSA. Mechanistically, L8 enhances the deprivation of fucose, a crucial carbon source essential for MRSA growth and pathogenicity. This process relies on the high binding affinity of pyruvate to the ILE257 site of the lactate dehydrogenase in L8. Overall, our work highlights the importance of moderate exercise in maintaining host colonization resistance and demonstrates L8 as a probiotic in protecting against MRSA colonization.

Pigmented gallstone disease (PGS) is prevalent in China. Biliary microbiota is certified to be related to the PGS formation.

We performed 16S sequencing on both bile and gallstone samples in 16 patients with gallstone disease. We analyzed the microbial composition of the biliary tract and identified crucial bacteria related to the formation of PGS.

Biliary tract bacterial composition analysis showed heterogeneity of dominated genus among individuals and correlation in bacterial composition between bile and gallstones. We screened 10 prevalent genera with significant abundance in the bile and gallstones. Actinomyces, Streptococcus, and Achromobacter had a significantly higher abundance in gallstones than in bile (P < 0.05). Furthermore, we identified 32 species that harbored uidA, pldA, and plc genes that encoded β-glucuronidase or phospholipase. Finally, we observed an enriched membrane transport for bile resistance through biliary microbiota.

β-glucuronidase-producing Streptococcus spp., including Streptococcus dysgalactiae and Streptococcus agalactiae, and Parabacteroides merdae, harbored both uidA and pldA genes and were found to be crucial bacterial species in PGS formation.

Cholelithiasis is one of the most common diseases of the biliary system. Neutrophil extracellular traps (NETs) in the liver play an important role in accelerating the formation of gallstones. The upstream mechanism of NETs formation remains unclear. In this study, 16S rRNA sequencing was used to screen the differential gut microbiota in mice with gallstones. Transcriptome sequencing was used to screen the differentially expressed core genes and signalling pathways of Clostridium scindens that acted on human colonic epithelial cells. Western blotting was used to verify the protein expression of TLR2 and the NF-κB pathway. RT-PCR was used to verify the mRNA expression of TLR2, CXCL1 and the NF-κB pathway. ELISA was used to verify CXCL1 expression in the supernatant or portal vein blood of mice. Immunofluorescence was used to detect NETs formation in cocultured neutrophils in vitro or in mouse livers. Clostridium scindens was the key differential strain in the formation of gallstones in mice. After treatment with Clostridium scindens, both in vitro and in vivo, the expression of TLR2 was upregulated, the secretion of CXCL1 was increased by regulating the NF-κB pathway. Finally, the formation of NETs and stones was significantly increased. This study reveals a new mechanism of the gut-liver immune axis in the formation of gallstones. Clostridium scindens acts on colonic epithelial cells through TLR2 to regulate the NF-κB pathway and increase the secretion of CXCL1. CXCL1 enters the liver via the portal vein and increases the formation of NETs in the liver, thereby accelerating gallstone formation.

To investigate the gut microbiome of lung cancer patients with brain metastases undergoing radiotherapy, identify key microorganisms associated with radiotherapy response, and evaluate their potential as biomarkers.

This study enrolled 55 newly diagnosed lung cancer patients with brain metastases. Fecal samples were collected before radiotherapy and analyzed by 16S rRNA sequencing to assess the gut microbiome's composition and function. Patients were categorized into response (n=28) and non-response (n=27) groups based on treatment efficacy, and α-diversity, β-diversity, and functional pathways were compared between them. Linear Discriminant Analysis Effect Size was used to identify microbial features associated with treatment efficacy. Logistic regression analyses were performed to evaluate the predictive capacity of clinical and microbial factors for treatment outcomes.

No significant difference in α-diversity was observed between the groups (P > 0.05), but β-diversity differed significantly (P = 0.036). Twelve characteristic microorganisms were identified in the response group, including g_ Oscillibacter and g_ Blautia, and nine in the non-response group, such as f_ Desulfovibrionaceae and g_ Megamonas. Metabolic pathways associated with treatment response included ketone body metabolism and pathways related to amyotrophic lateral sclerosis. Multivariate analysis identified g_Flavonifractor (odds ratio [OR] = 6.680, P = 0.004), g_Negativibacillus (OR = 3.862, P = 0.014), C-reactive protein (OR = 1.054, P = 0.017), and systemic inflammation response index (OR = 1.367, P = 0.043) as independent predictors of radiotherapy response. The nomogram and microbiome models achieved area under the curve (AUC) values of 0.935 and 0.866, respectively, demonstrating excellent predictive performance. Decision curve analysis further confirmed these models provided significant net benefits across risk thresholds.

The composition and functional characteristics of the gut microbiome in lung cancer patients with brain metastases prior to radiotherapy are associated with therapeutic response and possess potential as predictive biomarkers. Further studies are warranted to validate these findings.

Asymptomatic gallbladder and biliary tract calculus may make into symptomatic disease or bring anxiety for patients. The formation of gallstones was associated with genetic risk factors and metabolic abnormalities. Genome-wide association studies (GWAS) data of 1400 plasma metabolites (PMs) and 91 circulating inflammatory cytokines (CICs) were obtained from the GWAS catalog, while the GWAS data of calculus of gallbladder without cholecystitis and calculus of bile duct without cholangitis or cholecystitis were retrieved from the IEU OpenGWAS project. The causalities from PMs or CICs to asymptomatic bile duct or cholecyst calculus were explored by 2-sample Mendelian randomization (MR) analysis. Furthermore, the MR analyses were implemented from the identified PMs to CICs. Following the false discovery rate adjustment, the significant causalities, including 6 CICs and 5 PMs on asymptomatic biliary stone and 5 CICs and 48 PMs on asymptomatic gallstone, were identified. Fibroblast growth factor 19 (FGF-19) and aspartate/mannose ratio were the common protective factors of asymptomatic biliary tract calculus, while Monocyte chemoattractant protein 2 (CCL-2) may serve as a disease-promoting agent. Moreover, Bilirubin degradation product, C17H18N2O4 (1) levels, and Bilirubin (Z,Z)/etiocholanolone glucuronide ratio were associated with FGF-19 level, while aspartate/mannose ratio was related to TNF-related apoptosis-inducing ligand level. Based on MR analysis, we identified the multiple PMs and CICs, especially FGF-19, which may affect the formation of gallbladder and biliary tract calculus. Moreover, the partial CICs could be the downstream mediator of PMs related to asymptomatic gallbladder and biliary tract calculus. These results contributed to supporting previous studies and provided evidence for disease prevention or management.

Cholecystectomy (CCE) can affect the enterohepatic circulation of bile acids and result in gut microbiome changes. This systematic review aimed to clarify the effect of CCE on gut microbiome composition and its clinical impact.

A systematic search was conducted in PubMed, Web of Science, and Scopus, combining keywords such as "cholecystectomy" or "post-cholecystectomy" with "gut microbiome," "stool microbiome," or "gut dysbiosis." Data were extracted and synthesized using narrative review. Study quality was assessed using the Newcastle-Ottawa scale.

A total of 1373 articles were screened and 14 studies were selected. Significant but inconsistent microbiome changes were reported. Changes were observed in alpha and beta diversity. At phylum level, an increase in Bacteroides and Ascomycota, decrease in Firmicutes, Actinomycetes, and Basidiomycota, and both increase and decrease in Fusobacteria were reported. At genus level, an increase in Prevotella and a decrease in Faecalibacterium were reported. In post-CCE diarrhea, decreased beta diversity, a decreased F/B ratio, an increase in Prevotella, an increase in Phocaeicola vulgatus, and a decrease in Prevotella copri were noted. For post-CCE syndrome, a higher abundance of Proteobacteria and decreased Firmicutes/Bacteroides (F/B) ratio were reported. A decreased relative abundance of Bifidobacterium longum subsp. longum from controls to CCE without colonic neoplasia to CCE with colonic neoplasia, and an increased abundance of Candida glabrata from controls, to CCE without colonic neoplasia and CCE with colonic neoplasia, were reported.

Patients who underwent CCE had significant gut dysbiosis. However, current studies could not clarify the detailed gut microbial structural and functional changes associated with CCE.

Sterols and bile acids are vital signaling molecules that play key roles in systemic functions, influencing the composition of the human gut microbiota, which maintains a symbiotic relationship with the host. Additionally, gut microbiota-encoded enzymes catalyze the conversion of sterols and bile acids into various metabolites, significantly enhancing their diversity and biological activities. In this review, we focus on the microbial transformations of sterols and bile acids in the gut, summarize the relevant bacteria, genes, and enzymes, and review the relationship between the sterols and bile acids metabolism of gut microbiota and human health. This review contributes to a deeper understanding of the crucial roles of sterols and bile acids metabolism by gut microbiota in human health, offering insights for further investigation into the interactions between gut microbiota and the host.

Depression may be a contributing factor to cholelithiasis. However, the exact correlation between cholelithiasis and depression severity remains unclear.

First, a two-sample Mendelian randomization (MR) analysis was performed to validate previous research findings, utilizing separate datasets for major depressive disorder (MDD) and cholelithiasis. The MDD dataset (135,458 cases, 344,901 controls) came from a published GWAS, and cholelithiasis data (19,023 cases, 195,144 controls) were sourced from FinnGen. The primary analytical approach for the MR study was the inverse variance weighting (IVW) method. Second, an observational study based on the National Health and Nutrition Examination Survey (NHANES) was conducted to explore the relationship between the severity of depression and cholelithiasis. 7071 participants were included in the observational study in total. Depression severity (no, mild, moderate, severe) was measured by Patient Health Questionnaire-9 (PHQ-9). Weighted multivariable-adjusted logistic regression was employed to assess the association between depression severity and cholelithiasis.

In the MR study, the IVW analysis revealed that MDD may increase the risk of cholelithiasis (OR 1.25, 95% CI 1.07-1.45, P = 0.004). The observational study showed that moderate (OR 1.06, 95% CI 1.00-1.11, p = 0.037) and severe (OR 1.07, 95% CI 1.00-1.15, p = 0.044) depression rises the incidence of cholelithiasis. However, no significant association was found between mild depression and cholelithiasis (p = 0.275).

Moderate and severe depression might rise the incidence of cholelithiasis, while mild depression may not. Further validation through prospective studies is necessary.

Gallstone disease is a common and complex condition, strongly associated with abnormal cholesterol metabolism, changes in bile composition, and impaired gallbladder motility. Recent studies have suggested that the gut microbiota, particularly probiotics like lactic acid bacteria, may play a significant role in the prevention and treatment of cholesterol gallstones. This study aims to optimize the cholesterol gallstone model in C57BL/6 mice and evaluate the effects of Lactobacillus intervention on gallstone formation induced by a high-fat diet. In this study, 8-week-old male C57BL/6 mice were randomly divided into four groups: a high-fat diet + saline group (HF-S), a high-fat diet + probiotic group (HF-P), a normal diet + saline group (ND-S), and a normal diet + probiotic group (ND-P), to assess the effect of probiotics on gallstone formation. The results showed significant differences among the four groups in body weight gain, liver weight, gallstone formation, and histopathology. Based on these preliminary findings, we added two more experimental groups: a 2-week probiotic pretreatment + high-fat diet group (Pre2w-HF) and a 4-week probiotic pretreatment + high-fat diet group (Pre4w-HF), to further investigate the dose-dependence and efficacy of probiotic pretreatment. The results indicated that probiotic intervention significantly reduced the incidence and severity of gallstones induced by a high-fat diet, with the pretreatment groups showing more pronounced effects. Histological analysis also revealed that probiotic intervention reduced inflammation and pathological changes in the liver and gallbladder. This study suggests that probiotics have potential therapeutic value in the prevention and treatment of cholesterol gallstones. Future research should explore the effects of different strains and doses, as well as the underlying mechanisms involved.

The lipid-lowering activity of fucoidan has been widely reported, but the exploration of its mechanisms is relatively limited, and studies on its direct targets are even scarcer. Additionally, it is unclear whether different administration methods affect the lipid-lowering activity of fucoidan. In current study, we used fucoidan derived from Saccharina japonica (SJF) to investigate its targets. The results showed that not only did SJF directly inhibit the Niemann-Pick C1-like 1 (NPC1L1)-mediated cholesterol transport, but it also reduced the solubility of cholesterol in mixed micelles, thereby interfering with the cholesterol uptake. Furthermore, SJF not only directly inhibited the activity of pancreatic triglyceride lipase (PTL), but also interfered with the overall catalytic process facilitated by colipase, thereby reducing the absorption of triglycerides. Moreover, comparative studies on the lipid-lowering activity of SJF administered via different methods demonstrated that dietary supplementation with SJF provided better lipid-lowering effects compared with gavage administration. Our research not only elucidates the targets and mechanisms of SJF but also provides theoretical basis for the selection of administration methods for fucoidan in lipid-lowering therapy.

Cholesterol gallstones (CGS) still lack effective noninvasive treatment. The etiology of experimentally proven cholesterol stones remains underexplored. This cross-sectional study aims to comprehensively evaluate potential biomarkers in patients with gallstones and assess the effects of microbiome-targeted interventions in mice. Microbiome taxonomic profiling was conducted on 191 samples via V3-V4 16S rRNA sequencing. Next, 60 samples (30 age- and sex-matched CGS patients and 30 controls) were selected for metagenomic sequencing and fecal metabolite profiling via liquid chromatography-mass spectrometry. Microbiome and metabolite characterizations were performed to identify potential biomarkers for CGS. Eight-week-old male C57BL/6J mice were given a lithogenic diet for 8 weeks to promote gallstone development. The causal relationship was examined through monocolonization in antibiotics-treated mice. The effects of short-chain fatty acids such as sodium butyrate, sodium acetate (NaA), sodium propionate, and fructooligosaccharides (FOS) on lithogenic diet-induced gallstones were investigated in mice. Gut microbiota and metabolites exhibited distinct characteristics, and selected biomarkers demonstrated good diagnostic performance in distinguishing CGS patients from healthy controls. Multi-omics data indicated associations between CGS and pathways involving butanoate and propanoate metabolism, fatty acid biosynthesis and degradation pathways, taurine and hypotaurine metabolism, and glyoxylate and dicarboxylate metabolism. The incidence of gallstones was significantly higher in the Clostridium glycyrrhizinilyticum group compared to the control group in mice. The grade of experimental gallstones in control mice was significantly higher than in mice treated with NaA and FOS. FOS could completely inhibit the formation of gallstones in mice. This study characterized gut microbiome and metabolome alterations in CGS. C. glycyrrhizinilyticum contributed to gallstone formation in mice. Supplementing with FOS could serve as a potential approach for managing CGS by altering the composition and functionality of gut microbiota.

Gallstones, a common surgical condition globally, affect around 20% of patients. The development of gallstones is linked to abnormal cholesterol and bilirubin metabolism, reduced gallbladder function, insulin resistance, biliary infections, and genetic factors. In addition to these factors, research has shown that mucins play a role in gallstone formation. This study aims to explore the connection between different types of gallstones and mucin gene polymorphisms.

For this purpose, a total of 121 patients with gallbladder stones PNS and 107 patients with healthy controls PNS were enrolled in this case-control study. One SNPs (rs4072037) of MUC1 gene、 three SNPs (rs2856111、rs41532344、rs41349846) of MUC2 gene、four SNPs (rs712005、rs2246980、rs2258447、rs2259292) of MUC4 gene、seven SNPs (rs28415193、rs56047977、rs2037089、rs2075854、rs3829224、rs2672785、rs2735709) of MUC5 gene、eight SNPs (rs10902268、rs61869016、rs573849895、rs59257210、rs7396383、rs74644072、rs7481521、rs9704308) of MUC6 gene、five SNPs (rs10229731、rs73168398、rs4729655、rs55903219、rs74974199) of MUC17 gene. We amplified SNP sites by polymerase chain reaction (PCR) using specific primer sets followed by DNA sequencing.

The frequencies of MUC2 rs2856111 C/T genotype (OR = 3.81, 95%CI: 1.06-13.68) was higher than the control group. MUC17 rs10229731 A/C genotype (OR = 0.33, 95%CI: 0.12-0.95), rs73168398 G/A genotype (OR = 0.26, 95%CI: 0.07-0.98), MUC6 rs10902268 G/A genotype (OR = 0.40, 95%CI: 0.17-0.95) at lower frequencies than controls. The frequencies of MUC2 rs41532344 T allele (OR = 2.55, 95%CI: 1.06-6.13), MUC4 rs712005 G allele (OR = 2.51, 95%CI: 1.20-5.22), MUC5B rs2037089 C allele (OR = 3.54, 95%CI: 1.14-11.01) and MUC5AC rs28415193 G allele (OR = 1.77, 95%CI: 1.02-3.07) were higher than the control group. MUC6 rs10902268 A allele (OR = 0.004, 95%CI: 0.00-0.27), rs61869016 C allele (OR = 0.07, 95%CI: 0.01-0.63) at lower frequencies than controls.

Polymorphisms in the mucin gene were linked to the formation of gallbladder stones. The MUC4 rs712005 G allele, MUC5B rs2037089 C allele, MUC2 rs41532344 T allele and MUC5AC rs28415193 G allele were found to predispose individuals to the development of the disease. MUC6 rs10902268 A allele and rs61869016 C allele were identified as protective factors. Meanwhile, MUC2 rs2856111 CT genotype was found to predispose individuals to the development of the disease. MUC17 rs10229731 AC genotype, rs73168398 GA genotype and MUC6 rs10902268 GA genotype were identified as protective factors.

Cholelithiasis is a common biliary system disease with a high incidence worldwide. Abnormal lipid metabolism has been shown to play a key role in the mechanism of gallstones. Therefore, recent research literature on the genes, proteins, and molecular substances involved in lipid metabolism during the pathogenesis of gallstones has been conducted. This study aimed to determine the role of lipid metabolism in the pathogenesis of gallstones and provide insights for future studies using previous research in genomics, metabolomics, transcriptomics, and other fields.

Autophagic activation in immune cells, gut microbiota dysbiosis, and metabolic abnormalities have been reported separately as characteristics of systemic lupus erythematosus (SLE). Elucidating the crosstalk among the immune system, commensal microbiota, and metabolites is crucial to understanding the pathogenesis of autoimmune diseases. Emerging evidence shows that basophil activation plays a critical role in the pathogenesis of SLE; however, the underlying mechanisms remain largely unknown. Here, we investigated the effects of autophagic inhibition on the pathogenesis of basophils in SLE using Autophagy-related gene 5 (Atg5) knockout (Atg5-/-) as an autophagic inhibitor. Specifically, we knocked out basophilic Atg5 in vivo to investigate its impact on lupus metabolism. Furthermore, Atg5-/- basophils were transferred to basophil-depleted MRL/MpJ-Faslpr (MRL/lpr) mice to study their effect on disease metabolism. Metagenomic and targeted metabolomic sequencing results indicated considerable reduction in the levels of plasma autoantibodies and inflammatory cytokines in the Atg5-/- basophil transfer group compared with that in the control group. Transplanting Atg5-/- basophils improved the gut microbiota balance in MRL/lpr mice, increasing the abundance of beneficial bacteria, such as Ligilactobacillus murinus and Faecalitalea rodentium, and reducing that of potentially pathogenic bacteria such as Phocaeicola salanitronis. The transplantation of Atg5-deficient basophils improved lupus symptoms by modulating lipid and amino acid metabolism. This improvement was linked to changes in the gut microbiota, particularly an increase in Ligilactobacillus murinus and Faecalitalea rodentium populations. These microbial shifts are believed to promote the production of beneficial metabolites, such as γ-linolenic acid and oleoyl-1-palmitoyl-sn-glycero-3-phosphocholine, while reducing the levels of harmful metabolites such as arginine. These alterations in the metabolic profile contribute to the alleviation of lupus symptoms. Collectively, these findings reveal a novel role of basophil autophagy in SLE, highlighting its potential as a therapeutic target.

The present study was conducted to analyze the correlation between the milk fat content of Binglangjiang buffaloes and their microbial and host metabolites. The 10 buffaloes with the highest milk fat content (HF, 5.60 ± 0.61%) and the 10 with the lowest milk fat content (LF, 1.49 ± 0.13%) were selected. Their rumen fluid and plasma were collected for rumen microbiota and metabolome analysis. The results showed that the rumen bacteria abundance of Synergistota, Quinella, Selenomonas, and Fretibacterium was significantly higher in the HF buffaloes. The abundance of 14 rumen fungi, including Candida, Talaromyces, Cyrenella, and Stilbella, was significantly higher in the HF buffaloes. The analysis of the metabolites in the rumen and plasma showed that several metabolites differed between the HF and LF buffaloes. A total of 68 and 42 differential metabolites were identified in the rumen and plasma, respectively. By clustering these differential metabolites, most of those clustered in the HF group were lipid and lipid-like molecules such as secoeremopetasitolide B, lucidenic acid J LysoPE (0:0/18:2 (9Z, 12Z)), and 5-tetradecenoic acid. Spearman's rank correlations showed that Quinella, Fretibacterium, Selenomonas, Cyrenella, and Stilbella were significantly positively correlated with the metabolites of the lipids and lipid-like molecules in the rumen and plasma. The results suggest that rumen microbiota such as Quinella, Fretibacterium, Selenomonas, and Cyrenella may regulate milk fat synthesis by influencing the lipid metabolites in the rumen and plasma. In addition, the combined analysis of the rumen microbiota and host metabolites may provide a fundamental understanding of the role of the microbiota and host in regulating milk fat synthesis.

This study prepared enzymatic theabrownins (TBs-e), alkaline theabrownins (TBs-a), and Pu-erh tea theabrownins (TBs-f), and investigated whether different preparation processes affected the structures, nonvolatile metabolites, and biofunctional activities of TBs. Structural characterization revealed that TBs were polymeric phenolic compounds rich in hydroxyl and carboxyl groups. Nontargeted metabolomics revealed that amino acids were the primary nonvolatile metabolites in TBs-e and TBs-a, accounting for over 70 % of the total nonvolatile content. TBs-f contained more polyphenols, caffeine, and flavonoids, accounting for 14.2 %, 3.9 %, and 0.8 % of total nonvolatile content, respectively. In vivo, at 560 mg/kg body weight, TBs-f were associated with regulation of blood glucose and lipid concentrations in mice. Moreover, 16S rRNA indicated that at 1120 mg/kg body weight, TBs-a were associated with increased numbers of microbiota linked with hypolipidemic activity. This study explores the impacts of different preparation processes on TBs and provides a theoretical foundation for the understanding of TBs.

The conversion of primary bile acids to secondary bile acids by the gut microbiota has been implicated in colonic inflammation. This study investigated the role of gut microbiota related bile acid metabolism in colonic inflammation in both patients with inflammatory bowel disease (IBD) and a murine model of dextran sulfate sodium (DSS)-induced colitis.

Bile acids in fecal samples from patients with IBD and DSS-induced colitis mice, with and without antibiotic treatment, were analyzed using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). The composition of the microbiota in fecal samples from IBD patients and DSS-colitis mice was characterized via Illumina MiSeq sequencing of the bacterial 16S rRNA gene V3-V4 region. Metagenomic profiling further identified metabolism-related gene signatures in stool samples from DSS-colitis mice. Histological analysis, quantitative PCR (qPCR) and Western Blotting were conducted on colonic samples from DSS-induced colitis mice to assess colonic inflammation, mucosal barrier integrity, and associated signaling pathways. The multivariate analysis of bile acids was conducted using Soft Independent Modelling of Class Analogy (SIMCA, Umetrics, Sweden). The relation between the relative abundance of specific phyla/genera and bile acid concentration was assess through Spearman's correlation analyses. Finally, lithocholic acid (LCA), the key bile acid, was administered via gavage to evaluate its effect on colonic inflammation and mucosal barrier integrity.

In patients with IBD, the composition of colonic bile acids and gut microbiota was altered. Moreover, changes in the gut microbiota further modulate the composition of bile acids in the intestine. As the gut microbiota continues to shift, the bile acid profile undergoes additional alterations. The aforementioned alterations were also observed in mice with DSS-induced colitis. The study revealed a correlation between dysbiosis of the gut microbiota and modifications in the profile of colonic bile acids, notably LCA observed in both patients with IBD and mice with DSS-induced colitis. Through multivariate analysis, LCA was identified as the key bile acid that significantly affects colonic inflammation and the integrity of mucosal barrier. Subsequent experiments confirmed that LCA supplementation effectively mitigated the inhibitory effects of gut microbiota on colitis progression in mice, primarily through the activation of the sphingosine-1-phosphate receptor 2 (S1PR2)/NF-κB p65 signaling pathway. Analysis of the microbiome and metagenomic data revealed changes in the gut microbiota, notably an increased abundance of an unclassified genus within the family Prevotellaceae in DSS-induced colitis mice. Furthermore, a positive correlation was observed between the relative abundance of Prevotellaceae and bile acid biosynthesis pathways, as well as colonic LCA level.

These findings suggest that LCA and its positively correlated gut bacteria, Prevotellaceae, are closely associated with intestinal inflammation. Targeting colonic inflammation may involve inhibiting LCA and members of the Prevotellaceae family as potential therapeutic strategies.

Hibernation is a necessary means for animals to maintain survival while coping with low temperatures and food shortages. While most studies have largely focused on mammalian hibernation, its reptilian equivalent has been less studied. In order to provide insights into the energy metabolism and potential microbial regulatory mechanisms in hibernating snakes, the serum, liver, gut content samples were measured by multi-omic methods. Here we show the active snakes have more vigorous lipid metabolism, whereas snakes in hibernation groups have higher sphingolipid metabolism. Furthermore, the results indicate that the potential energy supply pathway was gluconeogenesis. Microbial analysis reveals that Proteobacteria and Firmicutes showed dynamic changes with the transformation among active, pre-hibernation and hibernation periods. The correlation analysis reveals the potential role of Romboutsia, Providencia and Vagococcus in regulating above metabolism by producing certain metabolites. The results advance the understanding of the complex energy-saving strategy in hibernating poikilotherms.

Surgical intervention is currently the primary treatment for hepatolithiasis; however, some patients still experience residual stones and high recurrence rates after surgery. Cholesterol metabolism seems to play an important role in hepatolithiasis pathogenesis. A high cholesterol diet is one of the significant reasons for the increasing incidence of hepatolithiasis. Therefore, regular diet and appropriate medical intervention are crucial measures to prevent hepatolithiasis and reduce recurrence rate after surgery. Reducing dietary cholesterol and drugs that increase cholesterol stone solubility are key therapeutic approaches in treating hepatolithiasis. This article discusses the cholesterol metabolic pathways related to the pathogenesis of hepatolithiasis, as well as food intake and targeted therapeutic drugs.

Gallstone diseases affect intestinal inflammation, bile flow, and gut microbiota, which in turn may increase the risk of inflammatory bowel disease (IBD). However, epidemiological studies exploring the associations between gallstone diseases and subsequent IBD risk have been limited.

This is a combined analysis of 3 prospective cohort studies (Nurses' Health Study, Nurses' Health Study II, and UK Biobank) and replicated in a case-control study (Chinese IBD Etiology Study). We evaluated the hazard ratios (HRs)/odds ratios (ORs) between gallstone diseases with IBD risk by Cox logistic regression or conditional logistic regression, adjusting for demographic characteristics, lifestyles, comorbidities, and medication usage.

We identified 3,480 cases of IBD over 2,127,471 person-years of follow-up in the 3 cohort studies. The participants with gallstone disease had a 38% increase in the risk of IBD (HR 1.38, 95% confidence intervals [CI] 1.21-1.59), 68% increase in Crohn's disease (HR 1.68, 95% CI 1.38-2.06), and 24% increase in ulcerative colitis (HR 1.24, 95% CI 1.03-1.49). In Chinese IBD Etiology Study, we found even larger magnitude of effects between gallstone diseases and IBD risk (IBD: OR 3.03, 95% CI 2.32-3.97; Crohn's disease: OR 5.31; 95% CI 3.71-7.60; ulcerative colitis: OR 1.49; 95% CI 1.07-2.06). There were no major differences in the estimated associations between the presence of unremoved gallstones and prior cholecystectomy with IBD risk.

Gallstone disease was linked to an increased risk of IBD and its subtypes, independent of traditional risk factors. Further research is needed to confirm these associations and clarify the underlying biological mechanisms.

Bile acids (BAs), a category of amphiphilic metabolites synthesized by liver cells and released into the intestine via the bile duct, serve a vital role in the emulsification of ingested fats during the digestive process. Beyond their conventional emulsifying function, BAs, with their diverse structures, also act as significant hormones within the body. They are pivotal in facilitating nutrient absorption by interacting with the farnesoid X receptor (FXR), and they serve as key regulators of lipid and glucose metabolism, as well as immune system balance. Consequently, BAs contribute to the metabolism of glucose and lipids, enhance the digestion and absorption of lipids, and maintain the equilibrium of the bile pool. Their actions are instrumental in addressing obesity, managing cholestasis, and treating diabetes, and are involved in the onset and progression of cancer. This paper presents an updated systematic review of the pharmacological mechanisms by which BAs target the FXR, incorporating recent findings and discussing their signaling pathways in the context of novel research, including their distinct roles in various disease states and populations. The aim is to provide a theoretical foundation for the continued research and clinical application of BAs.

The exact triggers of gallstone formation remain incompletely understood, but research indicates that microbial infection is a significant factor and can interfere with treatment. There is no consensus on the bile microbial culture profiles in previous studies, and determining the microbial profile could aid in targeted prevention and treatment. The primary aim of this study is to investigate the differences in microbial communities cultured from bile specimens of patients with gallstones.

We collected the clinical characteristics and bile microbial status of 9,939 gallstone patients. Statistical analysis was employed to assess the relationship between microbes and clinical features, and a random forest model was utilized to predict recurrence.

Results showed a higher proportion of females among patients, with the age group of 60-74 years being the most prevalent. The most common type of gallstone was solitary gallbladder stones. A total of 76 microbes were cultured from 5,153 patients, with Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis being the most frequently identified. Significant differences in microbial diversity and positive detection rates were observed across different age groups, types of gallstones, and recurrence status. Positive frequencies of E. coli, Enterococcus faecium, and K. pneumoniae varied significantly by age group and gallstone type. The microbial diversity in the recurrence group was significantly lower compared to the non-recurrence group. The recurrence rate was significantly higher in the group with single microbial species compared to those with no microbes or multiple microbes. For the recurrence group, there were significant differences in the frequencies of seven microbes (Aeromonas hydrophila, Enterococcus casseliflavus, Enterococcus faecium, E. coli, K. pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa) before and after recurrence, with these microbes appearing in a higher number of patients after recurrence. Regression analysis identified patient age, stone size, diabetes, venous thrombosis, liver cirrhosis, malignancy, coronary heart disease, and the number of microbial species as important predictors of recurrence. A random forest model constructed using these variables demonstrated good performance and high predictive ability (ROC-AUC = 0.862).

These findings highlight the significant role of microbial communities in gallstone formation and recurrence. Furthermore, the identified predictors of recurrence, including clinical factors and microbial diversity, may help develop personalized prevention and recurrence strategies for gallstone patients.

The liver makes bile, an aqueous solution critical for fat absorption, which is secreted into the duodenum. Despite extensive studies on bile salts, other components of bile are less well characterized. Here we used global metabolomic analysis on bile from specific-pathogen-free, germ-free, Citrobacter rodentium-infected or Listeria monocytogenes-infected mice and identified a metabolome of 812 metabolites that were altered by both microbiota and enteric infection. Hepatic transcriptomics identified enteric-infection-triggered pathways that probably underlie bile remodelling. Enteric infection increased levels of four dicarboxylates in bile, including itaconate. Analysis of Acod1-/- mice indicated that increased itaconate also increased tuft cell abundance, altered microbiota composition and function as detected by metagenomic analysis, and modulated host defence, leading to reduced Vibrio cholerae colonization. Our data suggest that enteric-infection-associated signals are relayed between the intestine and liver and induce transcriptional programmes that shape the bile metabolome, modifying the immunomodulatory and host defence functions of bile.

This study investigated the causal relationship between gut microbiota (GM), serum metabolome, and host transcriptome in the development of gout and hyperuricemia (HUA) using genome-wide association studies (GWAS) data and HUA mouse model experiments.

Mendelian randomization (MR) analysis of GWAS summary statistics was performed using an inverse variance weighted (IVW) approach to determine or predict the causal role of the GM on gout. The HUA mouse model was used to characterize changes in the gut microbiome, host metabolome, and host kidney transcriptome by integrating cecal 16S rRNA sequencing, untargeted serum metabolomics, and host mRNA sequencing.

Our analysis demonstrated causal effects of seven GM taxa on gout, including genera of Ruminococcus, Odoribacter, and Bacteroides. Thirty eight immune cell traits were associated with gout. Dysbiosis of Dubosiella, Lactobacillus, Bacteroides, Alloprevotella, and Lachnospiraceae_NK4A136_group genera were associated with changes in the serum metabolites and kidney transcriptome of the HUA model mice. The changes in the gut microbiome of the HUA model mice correlated significantly with alterations in the levels of serum metabolites such as taurodeoxycholic acid, phenylacetylglycine, vanylglycol, methyl hexadecanoic acid, carnosol, 6-aminopenicillanic acid, sphinganine, p-hydroxyphenylacetic acid, pyridoxamine, and de-o-methylsterigmatocystin, and expression of kidney genes such as CNDP2, SELENOP, TTR, CAR3, SLC12A3, SCD1, PIGR, CD74, MFSD4B5, and NAPSA.

Our study demonstrated a causal relationship between GM, immune cells, and gout. HUA development involved alterations in the vitamin B6 metabolism because of GM dysbiosis that resulted in altered pyridoxamine and pyridoxal levels, dysregulated sphingolipid metabolism, and excessive inflammation.

Gallstone formation is a common digestive ailment, with unclear mechanisms underlying its development. Dysfunction of the gallbladder smooth muscle (GSM) may play a crucial role, particularly with a high-fat diet (HFD). This study aimed to investigate the effects of an HFD on GSM and assess how it alters contractility through changes in the extracellular matrix (ECM).

Guinea pigs and C57BL/6 mice were fed either an HFD or normal diet (ND). Primary cultures of their (guinea pigs) gallbladder smooth muscle cells (GSMCs) were used for in vitro experiments. Histological stains, RNA-sequencing, bioinformatics analysis, three-dimensional tissue culture, real-time polymerase chain reaction (PCR), Western blot, atomic force microscopy, and muscle tension measurements were performed.

Histological evidence indicated structural changes in the gallbladder muscle layer and ECM collagen deposition in the HFD group. The HFD group also showed increased expression of collagen, integrin family, and matrix metalloproteinase (MMP) and the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway. Compared with GSMCs cultured on Matrigel containing 1 mg/mL of collagen I, those cultured with 2 mg/mL showed a phenotype change from contractile to synthetic cells. Consistent with these findings, the HFD group also demonstrated increased ECM stiffness and decreased smooth muscle contractility.

Our findings reveal a mechanism by which an HFD alters the ECM composition of the gallbladder muscle, activating the integrin/PI3K-Akt/MMP signaling pathway, thereby impacting GSMC phenotype and contractility. These insights enhance the understanding of gallstone formation mechanism and provide potential therapeutic targets to treat gallbladder dysfunction.

Diabetic peripheral neuropathic pain (DPNP) is a major complication of diabetes that markedly affects the quality of life and health status of patients. Recent studies have investigated the potential regulatory influence of gut flora and bile acids on DPNP via the TGR5/TRPV1 signaling pathway. Dysbiosis of the gut flora not only directly affects bile acid metabolism but also significantly correlates with diabetes-associated neuropathy through interactions with the bile acid receptor TGR5 and the ion channel TRPV1. This review describes how alterations in the gut flora and bile acid metabolism contribute to the pathogenesis of DPNP through the TGR5/TRPV1 signaling pathway, revealing potential applications for this pathway in DPNP management. Furthermore, experimental and clinical studies have demonstrated the modulation of gut flora and bile acid metabolism as well as targeting the TGR5/TRPV1 signaling pathway as an innovative therapeutic approach. Further studies are warranted to elucidate the underlying mechanism and develop treatment modalities based on gut flora regulation and signaling pathway interventions, thus providing novel insights and approaches for DPNP therapy.