CRLM (Colorectal liver metastasis), a prevalent form of distant metastasis in colorectal cancer, is a leading cause of mortality in affected patients. Despite advancements in immunotherapy for colorectal cancer, clinical benefits in CRLM patients remain limited. The immunosuppressive liver microenvironment plays a pivotal role in facilitating metastatic colonization and disease progression.

We performed fecal metabolomics in ABX (antibiotic-treated) mice and single-cell RNA sequencing on hepatic tissues from four cohorts: CRC (colorectal cancer) , CRLM, LCA-fed CRC, and LCA-fed CRLM mice, to delineate intergroup immune heterogeneity. Cellular and molecular profiling across groups was conducted via Luminex multiplex assays, flow cytometry, and immunofluorescence. Integrated multi-omics analyses elucidated LCA-driven pathways modulating metastatic progression RESULTS: We demonstrated that LCA (lithocholic acid), a gut microbiota-derived metabolite, activates TGR5 in hepatic CAFs (cancer-associated fibroblasts) to upregulate CCL3 secretion. Elevated CCL3 levels subsequently recruit MDSCs (myeloid-derived suppressor cells) into metastatic niches. While MDSCs primarily suppress T-cell activation, we identified a paradoxical role of MDSC-derived CCL2 in attenuating immunosuppression via CCR2 signaling, suggesting a compensatory pro-inflammatory axis within the tumor microenvironment CONCLUSIONS: These findings suggest new immunotherapeutic strategies for the treatment of CRLM.

Dietary polyphenols represent a diverse group of plant-derived compounds known for their extensive biological activities, offering significant promise in the prevention and treatment of various chronic illnesses. Despite their potential, advancements in their research have been curtailed by challenges in structural analysis and limitations in existing research models. This review marks a pioneering exploration into how bile acids, gut microbiota, and the gut-brain axis serve as conduits through which dietary polyphenols can exert therapeutic effects on Inflammatory Bowel Disease (IBD). This review enriches understanding of their biological functions and addresses common obstacles in the study of natural polyphenols. It provides a comprehensive examination of the role of dietary polyphenols in modulating bile acid metabolism and mitigating IBD, covering aspects such as polyphenols, bile acid metabolism, oxidative stress, inflammation, and the nervous system. This work opens new vistas in appreciating the full spectrum of polyphenol benefits, laying the groundwork for future explorations in this domain.

Bile acids and their corresponding intestinal epithelial receptors, the farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5), play crucial roles in the physiological and pathological processes of intestinal epithelial cells. These acids and receptors are involved in the regulation of intestinal absorption, signal transduction, cellular proliferation and repair, cellular senescence, energy metabolism, and the modulation of gut microbiota. A comprehensive literature search was conducted using PubMed, employing keywords such as bile acid, bile acid receptor, FXR (nr1h4), TGR5 (gpbar1), intestinal epithelial cells, proliferation, differentiation, senescence, energy metabolism, gut microbiota, inflammatory bowel disease (IBD), colorectal cancer (CRC), and irritable bowel syndrome (IBS), with a focus on publications available in English. This review examines the diverse effects of bile acid signaling and bile receptor pathways on the proliferation, differentiation, senescence, and energy metabolism of intestinal epithelial cells. Additionally, it explores the interactions between bile acids, their receptors, and the microbiota, as well as the implications of these interactions for host health, particularly in relation to prevalent intestinal diseases. Finally, the review highlights the importance of developing highly specific ligands for FXR and TGR5 receptors in the context of metabolic and intestinal disorders.

Huangqin Decoction (HQD), a traditional Chinese medicine (TCM) formula documented in Shang Han Lun, has demonstrated safety and efficacy in the treatment of ulcerative colitis (UC). Recent studies also suggest that HQD exerts therapeutic effects on colorectal cancer (CRC). However, the underlying mechanisms remain unclear.

This study aimed to investigate the therapeutic effects of HQD on CRC and explore its potential mechanisms of action.

The active ingredients and potential targets of HQD were identified through network pharmacology-based analyses. The CRC-related targets were compared with those of HQD. Shared targets were subjected to Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and a protein-protein interaction (PPI) network was constructed. Additionally, APCmin/+ mice were treated with 0.2 % deoxycholic acid (DCA) and gavaged with low or high doses of HQD. Tumor morphology was assessed using hematoxylin and eosin (HE) staining. Immunohistochemical staining was performed to evaluate the expression of Ki-67, Caspase-3, and MUC2 in the intestine. Periodic acid-Schiff (PAS) and PAS-alcian blue (PAS-AB) staining were utilized to detect mucin distribution and the number of goblet cells in the intestines of the mice. The mRNA expression levels of interleukin 6 (IL-6), mitogen-activated protein kinase 8 (MAPK8), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), albumin (ALB), and Caspase 3 (CASP3) were quantified using quantitative reverse-transcription PCR (qRT-PCR). Immunofluorescence was employed to assess the degree of apoptosis. Additionally, 16S ribosomal RNA gene sequencing, sequence curation and annotation, and metagenomic sequencing were performed to analyze changes in the composition of the mouse intestinal microbiota and related functions and signaling pathways.

The active ingredients of HQD were identified. GO and KEGG pathway enrichment analyses indicated that the shared targets were primarily involved in tumor suppression. HQD effectively treated DCA-induced CRC in mice. Furthermore, positive PAS and PAS-AB staining was significantly increased in the intestines of mice treated with HQD. HQD enhanced the abundance of Lachnospiraceae, Firmicutes, Fusobacteria, and Clostridium, while reducing the abundance of Eggerthellales. Additionally, HQD modulated secondary bile acid metabolism, carbohydrate synthesis, and other energy metabolism pathways, which may underlie its therapeutic effects.

HQD effectively treated CRC in mice, and its mechanisms of action may be related to the regulation of the gut microbiota.

Colorectal cancer (CRC) is one of the most common cancers; however, accurately predicting prognosis based on existing molecular subtypes remains challenging. The XELOX regimen, which combines oxaliplatin and capecitabine, is the cornerstone of chemotherapy for CRC treatment. However, there is a notable lack of reliable predictive models for determining the sensitivity of this treatment. This study aimed to establish a novel classification system for CRC and develop a predictive model for XELOX chemotherapeutic sensitivity using serum metabolomics. We recruited 89 patients with CRC and 89 age- and sex-matched healthy controls for untargeted metabolomic studies to identify tumor-specific serum metabolites. The patients were grouped into distinct metabolic subtypes using unsupervised clustering. A serum metabolite combination predictive of the efficacy of XELOX was established using Cox regression analysis in 34 patients with stage III CRC. Using unsupervised clustering based on the serum metabolites, three distinct clusters were identified. Notably, Cluster 3, which was characterized by uniform lipid and amino acid levels, demonstrated the best prognosis. Our analysis revealed that D-glucose 6-phosphate, presqualene diphosphate, and leukotriene B4 levels were negatively correlated with XELOX sensitivity, whereas 15-HETE and N-acetyl-l-methionine levels were positively correlated. Based on these findings, we constructed a predictive model validated in an independent cohort of 34 patients with stage III CRC. In summary, this study identified a novel classification of CRC based on serum metabolites and developed a potential prognostic model for XELOX chemotherapeutic efficacy, which may have direct effects on the treatment and prognosis of CRC.

Clostridium scindens is a commensal gut bacterium capable of forming the secondary bile acids as well as converting glucocorticoids to androgens. Historically, only two strains, C. scindens ATCC 35704 and C. scindens VPI 12708, have been characterized to any significant extent. The formation of secondary bile acids is important in the etiology of cancers of the GI tract and in the prevention of Clostridioides difficile infection. We determined the presence and absence of bile acid inducible (bai) and steroid-17,20-desmolase (des) genes among C. scindens strains and the features of the pangenome of 34 cultured strains of C. scindens and a set of 200 metagenome-assembled genomes (MAGs) to understand the variability among strains. The results indicate that the C. scindens cultivars have an open pangenome with 12,720 orthologous gene groups and a core genome with 1630 gene families, in addition to 7051 and 4039 gene families in the accessory and unique (i.e., strain-exclusive) genomes, respectively. The pangenome profile including the MAGs also proved to be open. Our analyses reveal that C. scindens strains are distributed into two clades, indicating the possible onset of C. scindens separation into two species, as suggested by gene content, phylogenomic, and average nucleotide identity (ANI) analyses. This study provides insight into the structure and function of the C. scindens pangenome, offering a genetic foundation of significance for many aspects of research on the intestinal microbiota and bile acid metabolism.

The development and progression of cancer can be impacted by the nutrients and components contained in the diet. This research seeks to explore the relationship between the antioxidant and pro-inflammatory properties of diet and the risk of all-cause mortality among cancer survivors.

Adults aged 20 and above who had been diagnosed with cancer and participated in the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2018 were selected for this study. Their survival status was verified using death certificate information from the National Death Index. The study employed two established measures, the Composite Dietary Antioxidant Index (CDAI) and the Dietary Inflammatory Index (DII), to evaluate the antioxidant and inflammatory properties of participants' diets. A non-linear association between these two dietary indices and mortality was examined respectively using restricted cubic spline (RCS) regression. To quantify the relationship between the indices and mortality risk, multivariable Cox proportional hazards models were employed, generating hazard ratios and corresponding 95% confidence intervals. Furthermore, the study also explored the connection between the CDAI and DII.

In this study, a total of 3,507 cancer survivors, representing an estimated 20,016,255 cancer survivors in the US, were included in the baseline analysis. The results showed that patients with lower DII or higher CDAI values had better survival rates. RCS regression revealed that both indicators showed linear relationships with all-cause mortality in the crude and adjusted models. It was consistently noted higher CDAI or lower DII was related to a reduced risk of all-cause mortality in cancer survivors in the Cox regression. Moreover, the subgroup analysis demonstrated that these associations hold true across various subgroups, lending credibility to the overall findings of the study. At last, an inverse correlation was observed between CDAI and DII in the diets of cancer survivors.

The research suggests that adopting a diet that low in pro-inflammatory foods and high in antioxidants may lower the all-cause mortality in cancer survivors. However, further prospective cohort studies are necessary to confirm these findings.

Bile acids, a representative diagnostic indicator of liver function, are used to visualize the extent of liver injury. Numerous studies have shown that triclosan (TCS) exposure leads to abnormal bile acid metabolism. As a result, there is a requirement to develop a fast and smart means to quantitatively monitor abnormal bile acids from exposure to triclosan in bio-sample. In this work, solid-phase microextraction (SPME) probes of sea urchin-like covalent organic frameworks (COF) were in situ synthesized on steel needles by using 1,3,5-tris(4-aminophenyl)benzene (TAPB) and 2,5-dimethoxybenzene-1,4-dicarboxaldehyde (DMTP) as two organic units and employed for extraction of bile acids. This TAPB-DMTP-COF-SPME possessed an excellent specified surface area (3351 m2 g-1) and a high regular porosity (∼3.6 nm), which was an ideal adsorbent to concentrate bile acids efficiently. The created probe, together with electrospray ionization mass spectrometry (ESI/MS), proved to be a fast and specific assay for the detection of bile acids in bio-samples. The proposed method had a low limitation of detection (0.03 μg L-1), good linearity (R2 ≥ 0.9931), wide linear range (0.10-1000.00 μg L-1) and excellent enrichment factor (63.60-252.00). Based on these excellent properties, it was successful application for the analyzing of bile acids in mice liver and feces, demonstrating the great potential of TAPB-DMTP-COF-SPME-ESI/MS in bile acids detection and liver injury diagnosis.

While dietary fat intake has long been implicated as a risk factor for colorectal cancer, evidence from prospective cohort studies remains inconsistent. Moreover, previous meta-analyses examining the link between dietary fat intake and risk of colorectal cancer have not explored the dose-response relationships. Therefore, the current systematic review and meta-analysis was conducted to assess the dose-response associations of intakes of specific types (MUFA, PUFA and SFA) and sources (animal, plant) of dietary fat with the risk of colorectal, colon or rectal cancer.

A comprehensive literature search of relevant online databases was performed to detect eligible studies until May 2023, identifying 21 prospective cohort studies with a total sample size of 2311,737 participants. The follow-up periods ranged from 7 to 19.4 years, during which 21,125 cases of colorectal, colon or rectal cancer were recorded.

Comparing extreme intake levels of total fat revealed the summary relative risk (RR) of 1.05 (95 % CI: 0.96-1.15) for colorectal cancer, 0.99 (95 % CI: 0.87-1.11) for colon cancer, and 1.09 (0.95 % CI: 0.93-1.13) for rectal cancer, indicating no significant association. Neither animal nor plant fat intake was associated with the risk of cancers. While no significant findings were also observed for MUFA or PUFA, the highest versus lowest comparison showed that a high intake of SFA was associated with a reduced risk of both colorectal 0.91 (95 % CI: 0.85-0.99) and colon cancer 0.86 (95 % CI: 0.75-0.98). However, in the non-linear dose-response analysis, the inverse association was seen within a certain range (<40 g/day).

These findings suggest that dietary SFA intake, less than 40 g/day, may have a protective effect against colorectal cancer. Further studies are needed to confirm our findings.

Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colorectum, posing a significant global health burden. Recent studies highlight the critical role of gut microbiota and its metabolites, particularly bile acids (BAs), in UC's pathogenesis. The relationship between BAs and gut microbiota is bidirectional: microbiota influence BA composition, while BAs regulate microbiota diversity and activity through receptors like Farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Targeting bile-acid metabolism to reshape gut microbiota presents a promising therapeutic strategy for UC. This review examines the classification and synthesis of BAs, their interactions with gut microbiota, and the potential of nutritional and microbial interventions. By focusing on these therapies, we aim to offer innovative approaches for effective UC management.

Colon cancer (CC) is one of the most common cancers globally, which is associated with the gut microbiota intimately. In current research, exploring the complex interaction between microbiomes and CC is a hotspot. However, the information on microbiomes in most previous studies is based on fecal, which does not fully display the microbial environment of CC. Herein, we collected mucosal and tissue samples from both the tumor and normal regions of 19 CC patients and clarified the composition of mucosal microbiota by 16S rRNA and metagenomic sequencing. Additionally, RNA-Seq was also conducted to identify the different expression genes between tumor and normal tissue samples. We revealed significantly different microbial community structures and expression profiles to CC. Depending on correlation analysis, we demonstrated that 1,472 genes were significantly correlated with CC tumor microbiota. Our study reveals a significant enrichment of Campylobacter jejuni in the mucosa of CC, which correlates with bile secretion. Additionally, we observe a negative correlation between C. jejuni and immune cells CD4+ Tem and mast cells. Finally, we discovered that metabolic bacterial endosymbiont of Bathymodiolus sp., Bacillus wiedmannii, and Mycobacterium tuberculosis had a significant survival value for CC, which was ignored by previous research. Overall, our study expands the understanding of the complex interplay between microbiota and CC and provides new targets for the treatment of CC.

This study contributes to our understanding of the interaction between microbiota and colon cancer (CC). By examining mucosal and tissue samples rather than solely relying on fecal samples, we have uncovered previously unknown aspects of CC-associated microbiota. Our findings reveal distinct microbial community structures and gene expression profiles correlated with CC progression. Notably, the enrichment of Campylobacter jejuni in CC mucosa, linked to bile secretion, underscores potential mechanisms in CC pathogenesis. Additionally, observed correlations between microbial taxa and immune cell populations offer new avenues for immunotherapy research in CC. Importantly, this study introduces CC-associated microbiota with survival implications for CC, expanding therapeutic targets beyond conventional strategies. By elucidating these correlations, our study not only contributes to uncovering the potential role of gut microbiota in colon cancer but also establishes a foundation for mechanistic studies of gut microbiota in colon cancer, emphasizing the broader impact of microbiota research on cancer biology.

Colorectal liver metastasis (CRLM) represents a major therapeutic challenge in colorectal cancer (CRC), with complex interactions between the gut microbiota and the liver tumor microenvironment (TME) playing a crucial role in disease progression via the gut-liver axis. The gut barrier serves as a gatekeeper, regulating microbial translocation, which influences liver colonization and metastasis. Through the gut-liver axis, the microbiota actively shapes the TME, where specific microbial species and their metabolites exert dual roles in immune modulation. The immunologically "cold" nature of the liver, combined with the influence of the gut microbiota on liver immunity, complicates effective immunotherapy. However, microbiota-targeted interventions present promising strategies to enhance immunotherapy outcomes by modulating the gut-liver axis. Overall, this review highlights the emerging evidence on the role of the gut microbiota in CRLM and provides insights into the molecular mechanisms driving the dynamic interactions within the gut-liver axis.

Colorectal cancer (CRC) is a malignant tumor that originates from the epithelial cells of the colon and rectum. Global epidemiological data shows that in 2020, the incidence and mortality rate of CRC ranked third and second, respectively, posing a serious threat to people's health and lives. The factors influencing CRC are numerous and can be broadly categorized as modifiable and non-modifiable based on whether they can be managed or intervened upon. Non-modifiable factors include age, gender, family history, among others. Among the modifiable factors, dietary habits and behavioral practices are the main intervention measures that people can take to prevent CRC. Numerous studies indicate that a high intake of red and processed meats, fats, as well as habits such as smoking, alcohol consumption, and prolonged sitting, increase the risk of developing CRC. Conversely, consuming ample vegetables, fruits, high dietary fiber, and engaging in moderate regular exercise may reduce the risk of CRC. This article primarily discusses the impact of dietary habits and behavioral practices on the occurrence and development of CRC, along with possible mechanisms, laying the foundation and providing direction for the prevention and control of CRC occurrence and development.

Hepatocellular carcinoma (HCC) is viewed as a metabolism associated disease, and bile acid metabolism is reported to occupy a significant role in the progression of HCC. However, little is known about the association between gut microbes and bile acid metabolism in HCC. Our study was designed to clarify the role of bile acid metabolism and microbiome in the progression of HCC. We investigated the relationship between bile acid metabolism and prognosis and immune cells by mining GSE14520. We studied the microbial profiles and metabolic alterations between the low bile acid group and high bile acid group using 16S rRNA sequencing and metabolomics. HCC patients in the high bile acid metabolism group showed better survival outcome compared with those in the low bile acid metabolism. Immune analysis displayed the close correlation between low bile acid metabolism and infiltration of CD4 + T cells, and the close relationship between high bile acid metabolism and infiltration of CD8 + T cells, macrophage cells in HCC. 16S rRNA sequencing results demonstrated that Blautia, Ruminococcus_gnavus_group, Erysipelotrichaceae_UCG-003 were mostly enriched in the low bile acid group. Metabolomics of the 109 fecal samples showed that the most enriched metabolites in the low total bile acid group were dihydrocytochalasin B, cucurbic acid and 27-Norcholestanehexol. Finally, KEGG enrichment analysis identified secondary bile acid biosynthesis and endocrine resistance as the most significant metabolic pathways. High bile acid metabolism was associated with more infiltration of CD8 + T cells, macrophage cells, and better prognosis in HCC. Levels of bile acid were significantly associated with altered gut microbes and metabolites in HCC. Further research related to gut microbes and bile acid metabolism may provide a novel insight into the pathogenesis and therapeutic strategy of HCC.

Liver metastasis is the leading cause of colorectal cancer (CRC)‑related mortality. Microbiota dysbiosis serves a role in the pathogenesis of colorectal liver metastases. Bile acids (BAs), cholesterol metabolites synthesized by intestinal bacteria, contribute to the metastatic cascade of CRC, encompassing colorectal invasion, migration, angiogenesis, anoikis resistance and the establishment of a hepatic pre‑metastatic niche. BAs impact inflammation and modulate the immune landscape within the tumor microenvironment by activating signaling pathways, which are used by tumor cells to facilitate metastasis. Given the widespread distribution of BA‑activated receptors in both tumor and immune cells, strategies aimed at restoring BA homeostasis and blocking metastasis‑associated signaling are of importance in cancer therapy. The present study summarizes the specific role of BAs in each step of colorectal liver metastasis, elucidating the association between BA and CRC progression to highlight the potential of BAs as predictive biomarkers for colorectal liver metastasis and their therapeutic potential in developing novel treatment strategies.

Circulating metabolic profiles have shown promising potential in identifying high-risk populations for various diseases, while metabolic perturbation plays an important role in gastric cancer. In this study, we conducted a cross-sectional study with 1800 participants to identify plasma metabolite signatures associated with environmental risk factors of gastric cancer. Subsequently, we evaluated the association between these signatures and gastric cancer risk in a nested case-control study involving 326 gastric cancer cases and 326 matched cancer-free controls. We conducted mediation analyses to elucidate the potential impact of metabolites on the association between environmental factors and gastric cancer. In the cross-sectional study, we identified 46 metabolites associated with Helicobacter pylori (H. pylori) infection, 365 with alcohol drinking, and 154 with smoking status. In the nested case-control study, 60 plasma metabolites, comprising 30 lipids, 15 amino acids, 6 xenobiotics, 3 nucleotides, 2 cofactors and vitamins, 2 carbohydrate, 1 energy, and 1 peptide, were associated with gastric cancer risk. A one-standard deviation increment in the H. pylori infection-related metabolomic signature was associated with an increased risk of gastric cancer (OR = 1.66, 95% CI: 1.32-2.09, p = 1.62 × 10-5). Furthermore, the effect of H. pylori infection on gastric cancer was partially mediated by the metabolomic signature (23.28%, 95% CI: 0.09-0.56) or adenine (13.69%, 95% CI: 0.05-0.31). In conclusion, we have identified metabolites associated with environmental factors and demonstrated the association between the H. pylori infection signature and gastric cancer risk. The findings provide novel insights into characterizing high-risk population for gastric cancer.

Colorectal cancer (CRC), an emerging public health concern, is one of the leading causes of cancer morbidity and mortality worldwide. An increasing body of evidence shows that dysfunction in metabolic reprogramming is a crucial characteristic of CRC progression. Specifically, metabolic reprogramming abnormalities in glucose, glutamine and lipid metabolism provide the tumour with energy and nutrients to support its rapid cell proliferation and survival. More recently, microRNAs (miRNAs) appear to be involved in the pathogenesis of CRC, including regulatory roles in energy metabolism. In addition, it has been revealed that dysbiosis in CRC might play a key role in impairing the host metabolic reprogramming processes, and while the exact interactions remain unclear, the link may lie with miRNAs. Hence, the aims of the current review include first, to delineate the metabolic reprogramming abnormalities in CRC; second, to explain how miRNAs mediate the aberrant regulations of CRC metabolic pathways; third, linking miRNAs with metabolic abnormalities and dysbiosis in CRC and finally, to discuss the roles of miRNAs as potential biomarkers.

Colorectal cancer (CRC) is the third most common malignancy globally and the second leading cause of cancer-related mortality. Its development is a multifactorial and multistage process influenced by a dynamic interplay between gut microbiota, environmental factors, and fatty acid metabolism. Dysbiosis of intestinal microbiota and abnormalities in microbiota-associated metabolites have been implicated in colorectal carcinogenesis, highlighting the pivotal role of microbial and metabolic interactions. Fatty acid metabolism serves as a critical nexus linking dietary patterns with gut microbial activity, significantly impacting intestinal health. In CRC patients, reduced levels of short-chain fatty acids (SCFAs) and SCFA-producing bacteria have been consistently observed. Supplementation with SCFA-producing probiotics has demonstrated tumor-suppressive effects, while therapeutic strategies aimed at modulating SCFA levels have shown potential in enhancing the efficacy of radiation therapy and immunotherapy in both preclinical and clinical settings. This review explores the intricate relationship between gut microbiota, fatty acid metabolism, and CRC, offering insights into the underlying mechanisms and their potential translational applications. Understanding this interplay could pave the way for novel diagnostic, therapeutic, and preventive strategies in the management of CRC.

Disorder in bile acid (BA) metabolism is known to be an important factor contributing to diarrhea. However, the pathogenesis of BA disorder-induced diarrhea remains unclear.

The colonic BA pool and microbiota between health piglets and BA disorder-induced diarrheal piglets were compared. Fecal microbiota transplantation and various cell experiments further indicated that chenodeoxycholic acid (CDCA) metabolic disorder produced CDCA-3β-glucuronide, which is the main cause of BA disorder diarrhea. Non-targeted metabolomics uncovered the inhibition of the BA glucuronidation by Lactobacillus reuteri (L. reuteri) is through deriving indole-3-carbinol (I3C). In vitro, important gene involved in the reduction of BA disorder induced-diarrhea were screened by RNA transcriptomics sequencing, and activation pathway of FXR-SIRT1-LKB1 to alleviate BA disorder diarrhea and P53-mediated apoptosis were proposed in vitro by multifarious siRNA interference, CO-IP, immunofluorescence, and so on, which mechanism was also verified in a variety of mouse models.

Here, we reveal for the first time that core microbiota derived I3C represses gut epithelium glucuronidation, particularly 3β-glucuronic CDCA production, which reaction is mediated by host UDP glucuronosyltransferase family 1 member A4 (UGT1A4) and necessary of BA disorder induced diarrhea. Mechanistically, L. reuteri derived I3C activates aryl hydrocarbon receptor to decrease UGT1A4 transcription and CDCA-3β-glucuronide content, thereby upregulating FXR-SIRT1-LKB1 signal. LKB1 binds with P53 based on protein interaction, ultimately resists to apoptosis and diarrhea. Moreover, I3C assists CDCA to attain the ameliorative effects of FXR activation in BA disorder diarrhea, through reversion of abnormal metabolism pathway, improving the outcomes of CDCA supplement.

These findings uncover the crucial interplay between gut epithelial cells and microbes, highlighting UGT1A4-mediated conversion of CDCA-3β-glucuronide as a key target for ameliorating BA disorder-induced diarrhea. Video Abstract.

With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis. Therefore, harnessing nuclear receptors to modulate HSC activation may be an effective approach to resolving the complex liver fibrosis caused by various factors. In this comprehensive review, we systematically explore the structure and physiological functions of nuclear receptors, shedding light on their multifaceted roles in HSC activation. Recent advancements in drug development targeting nuclear receptors are discussed, providing insights into their potential as rational and effective therapeutic targets for modulating HSC activation in the context of liver fibrosis. By elucidating the intricate interplay between nuclear receptors and HSC activation, this review contributes to the discovery of new nuclear receptor targets in HSCs for resolving hepatic fibrosis.

Background: Chronic stress and chronic pain are closely linked by the capacity to exacerbate each other, sharing common roots in the brain and in the gut. The strict intersection between these two neurological diseases makes important to have a therapeutic strategy aimed at preventing both to maintain mental health in patients. Diet is an modifiable lifestyle factor associated with gut-brain axis diseases and there is growing interest in its use as adjuvant to main therapies. Several evidence attest the impact of specific diets or nutrients on chronic stress-related disorders and pain with a good degree of certainty. A daily adequate intake of foods containing micronutrients such as amino acids, minerals and vitamins, as well as the reduction in the consumption of processed food products can have a positive impact on microbiota and gut health. Many nutrients are endowed of prebiotic, anti-inflammatory, immunomodulatory and neuroprotective potential which make them useful tools helping the management of chronic stress and pain in patients. Dietary regimes, as intermittent fasting or caloric restriction, are promising, although further studies are needed to optimize protocols according to patient's medical history, age and sex. Moreover, by supporting gut microbiota health with diet is possible to attenuate comorbidities such as obesity, gastrointestinal dysfunction and mood disorders, thus reducing healthcare costs related to chronic stress or pain.Objective: This review summarize the most recent evidence on the microbiota-mediated beneficial effects of macro- and micronutrients, dietary-related factors, specific nutritional regimens and dietary intervention on these pathological conditions.

Nutrition, the gut microbiota and immunity are all important factors in the maintenance of health. However, there is a growing realization of the complex interplay between these elements coalescing in a nutrition-gut microbiota-immunity axis. This regulatory axis is critical for health with disruption being implicated in a broad range of diseases, including autoimmune disorders, allergies and mental health disorders. This new perspective continues to underpin a growing number of innovative therapeutic strategies targeting different elements of this axis to treat relevant diseases. This review describes the inter-relationships between nutrition, the gut microbiota and immunity. It then details several human diseases where disruption of the nutrition-gut microbiota-immunity axis has been identified and presents examples of how the various elements may be targeted therapeutically as alternate treatment strategies for these diseases.

Colorectal cancer has the second highest mortality among cancer sites worldwide, with increasing morbidity, high recurrence rates, and even poorer postoperative quality of life. Therefore, preventive strategies for colorectal cancer should be established. This study aimed to cross-sectionally explore dietary patterns affecting the intestinal metabolism of bile acids (BAs), a risk factor for colorectal cancer, in young Japanese women. We collected fecal samples for intestinal microbiota and BA analysis. We used the Bristol scale to determine 1-week defecation status. Moreover, the brief-type self-administered diet history questionnaire was used for habitual dietary intake status. Reduced-rank regression analysis revealed dietary patterns related to fecal BA levels. The relationship between dietary patterns and fecal BA levels was adjusted for defecation status and intestinal microbiota variables using analysis of covariance. Reduced-rank regression analysis generated two dietary pattern scores related to fecal BA levels. First, the score was associated with a greater intake of leafy and root vegetables, and higher values were associated with greater fecal cholic and chenodeoxycholic acid levels and lower deoxycholic and lithocholic acid levels. Second, the score was associated with greater rice intake and lower Western sweets, pork, beef, and egg intake, and higher values were associated with lower deoxycholic and lithocholic acid levels. These relationships remained after adjusting for intestinal microbiota and defecation status variables.

Many infants consume both human milk and infant formula (mixed-fed); however, few studies have investigated how mixed feeding affects the gut microbiome composition and metabolic profiles compared to exclusive breastfeeding or formula feeding. Herein, how delivery mode and early nutrition affect the microbiome and metabolome of 6-week-old infants in the STRONG Kids2 cohort was investigated. Fecal samples were collected from exclusively breastfed (BF; n = 25), formula-fed (FF; n = 25) or mixed-fed (MF; n = 25) participants. Within each feeding group, infants were either delivered vaginally (VD; n = 13) or by Cesarean section (CS; n = 12). Feeding mode affects the fecal microbiome diversity, composition, and functional potential, as well as metabolomic profiles regardless of delivery mode. Alpha and beta diversity of MF differed from that of BF (p < 0.05) but were comparable to FF infants. Functional analyses have shown 117 potential metabolic pathways differed between BF and FF, 112 between BF and MF, and 8 between MF and FF infants (p < 0.05, q < 0.10). Fecal metabolomic profiles of MF and FF clustered together and separated from BF infants. In total, 543 metabolites differed between BF and FF, 517 between BF and MF, and 3 between MF and FF (p < 0.05, q < 0.10). Delivery mode affected overall microbial composition (p = 0.022) at the genus level and 24 potential functional pathways, with 16 pathways being higher in VD than CS infants (p < 0.05, q < 0.10). Metabolomic analysis identified 47 differential metabolites between CS and VD, with 39 being lower in CS than VD (p < 0.05, q < 0.10). In summary, fecal microbiota composition and function and metabolite profiles of 6-week-old MF infants are closer to FF than BF infants.

Clostridium scindens is a keystone bacterial species in the mammalian gut that, while low in abundance, has a significant impact on bile acid and steroid metabolism. Numerous studies indicate that the two most studied strains of C. scindens (i.e. ATCC 35704 and VPI 12708) are important for a myriad of physiological processes in the host. We focus on both historical and current microbiological and molecular biology work on the Hylemon-Björkhem pathway and the steroid-17,20-desmolase pathway that were first discovered in C. scindens. Our most recent analysis now calls into question whether strains currently defined as C. scindens represent two separate taxonomic groups. Future directions include developing genetic tools to further explore the physiological role of bile acid and steroid metabolism by strains of C. scindens and the causal role of these pathways in host physiology and disease.

The human microbiota plays a crucial role in maintaining overall health and well-being. The gut microbiota has been implicated in developing and progressing various diseases, including cancer. This review highlights the related mechanisms and the compositions that influence cancer pathogenesis with a highlight on gastric cancer. We provide a comprehensive overview of the mechanisms by which the microbiome influences cancer development, progression, and response to treatment, with a focus on identifying potential biomarkers for early detection, prevention strategies, and novel therapeutic interventions that leverage microbiome modulation. This comprehensive review can guide future research and clinical practices in understanding and harnessing the microbiome to optimize gastric cancer therapies.

The gut microbiota, a dynamic ecosystem of trillions of microorganisms, produces secondary metabolites that profoundly influence host health. Recent research has highlighted the significant role of these metabolites, particularly short-chain fatty acids, indoles, and bile acids, in modulating immune responses, impacting epigenetic mechanisms, and contributing to disease processes. In gastrointestinal (GI) cancers such as colorectal, liver, and gastric cancer, microbial metabolites can drive tumorigenesis by promoting inflammation, DNA damage, and immune evasion. Conversely, these same metabolites hold therapeutic promise, potentially enhancing responses to chemotherapy and immunotherapy and even directly suppressing tumor growth. In addition, gut microbial metabolites play crucial roles in infectious disease susceptibility and resilience, mediating immune pathways that impact pathogen resistance. By consolidating recent insights into the gut microbiota's role in shaping disease and health, this review underscores the therapeutic potential of targeting microbiome-derived metabolites for treating GI cancers and infectious diseases and calls for further research into microbiome-based interventions.

Feeding sheep with high-concentrate diet (HCD) to shorten production cycle is a well-developed feeding strategy to increase lamb production. Here, metabolomics were performed to explore the mechanism that HCD changes lamb nutrition composition. Differential metabolites were enriched in primary bile acid biosynthesis. Significantly higher content of bile acids including taurodeoxycholic acid sodium salt (TDCA), taurochenodeoxycholic acid sodium salt (TCDCA) and taurocholic acid (TCA) was observed in lamb of HCD, while the content of lithocholic acid (LCA), cholic acid (CA), chenodeoxycholic acid (CDCA) and Chenodeoxycholic acid-3-beta-D-glucuronide (CDCA-3Gln) were higher in the controls. Furthermore, a significantly decreased content of fatty acids was observed in lamb of HCD group. Finally, primary skeletal cells treated with CA or TCA showed a significant decrease in contents of fatty acids, while TCA showed a stronger effect in decreasing fatty acid contents. Collectively, we suggest that HCD decreases lamb fatty acid contents by regulating bile acid composition.

The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator. This abstract aims to elucidate the connection between the gut microbiota and angiogenesis in various diseases. The gut microbiota influences angiogenesis through various mechanisms, including the production of metabolites that directly or indirectly affect vascularization. For example, short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are known to regulate immune responses and inflammation, thereby affecting angiogenesis. In the context of cardiovascular diseases, the gut microbiota promotes atherosclerosis and vascular dysfunction by producing trimethylamine N-oxide (TMAO) and other metabolites that promote inflammation and endothelial dysfunction. Similarly, in neurodegenerative diseases, the gut microbiota may influence neuroinflammation and the integrity of the blood-brain barrier, thereby affecting angiogenesis. In cases of fractures and wound healing, the gut microbiota promotes angiogenesis by activating inflammatory responses and immune effects, facilitating the healing of tissue damage. In cancer, the gut microbiota can either inhibit or promote tumor growth and angiogenesis, depending on the specific bacterial composition and their metabolites. For instance, some bacteria can activate inflammasomes, leading to the production of inflammatory factors that alter the tumor immune microenvironment and activate angiogenesis-related signaling pathways, affecting tumor angiogenesis and metastasis. Some bacteria can directly interact with tumor cells, activating angiogenesis-related signaling pathways. Diet, as a modifiable factor, significantly influences angiogenesis through diet-derived microbial metabolites. Diet can rapidly alter the composition of the microbiota and its metabolic activity, thereby changing the concentration of microbial-derived metabolites and profoundly affecting the host's immune response and angiogenesis. For example, a high animal protein diet promotes the production of pro-atherogenic metabolites like TMAO, activating inflammatory pathways and interfering with platelet function, which is associated with the severity of coronary artery plaques, peripheral artery disease, and cardiovascular diseases. A diet rich in dietary fiber promotes the production of SCFAs, which act as ligands for cell surface or intracellular receptors, regulating various biological processes, including inflammation, tissue homeostasis, and immune responses, thereby influencing angiogenesis. In summary, the role of the gut microbiota in angiogenesis is multifaceted, playing an important role in disease progression by affecting various biological processes such as inflammation, immune responses, and multiple signaling pathways. Diet-derived microbial metabolites play a crucial role in linking the gut microbiota and angiogenesis. Understanding the complex interactions between diet, the gut microbiota, and angiogenesis has the potential to uncover novel therapeutic targets for managing these conditions. Therefore, interventions targeting the gut microbiota and its metabolites, such as through fecal microbiota transplantation (FMT) and the application of probiotics to alter the composition of the gut microbiota and enhance the production of beneficial metabolites, present a promising therapeutic strategy.

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

Fat malabsorption in children with cystic fibrosis (CF) leads to poor nutritional status and altered colonic microbiota. This study aimed at establishing the faecal lipid profile in children with CF, and exploring associations between the faecal lipidome and microbiota.

Cross-sectional observational study with children with CF and an age-matched control group. Faecal lipidome was analysed by UHLC-HRMS and microbiota profiling by 16S rRNA amplicon sequencing.

Among 234 identified lipid species, five lipidome clusters (LC) were obtained with significant differences in triacylglycerols (TG), diacylglycerols (DG), monoacylglycerols (MG) and fatty-acids (FA): LC1 subjects with good digestion and absorption: low TG and low MG and FA; LC2 good digestion and poor absorption: low TG and high MG and FA; LC3 Mild digestion and poor absorption: intermediate TG and high MG and FA; LC4 poor digestion and absorption: high TG and high MG and FA; LC5 outliers. Bacteroidota and Verrucomicrobiota decreased over LC1-LC4, while Proteobacteria increased. Nutritional status indicators were significantly higher in LC1 and decreased over LC2-LC4.

Assessing faecal lipidome may be relevant to determine how dietary lipids are digested and absorbed. This new evidence might be a method to support targeted nutritional interventions towards reverting fat maldigestion or malabsorption.

Lipidomic analysis enabled the identification of the lipid species related to maldigestion (triglycerides) or malabsorption (monoglycerides and fatty acids). Children with cystic fibrosis can be grouped depending on the faecal lipidome profile related to dietary fat maldigestion or malabsorption. The lipidome profile in faeces is related to the composition of microbiota and nutritional status indicators.

Multiple diet patterns play a crucial role in the development of colorectal cancer and its precursor, colorectal adenoma, but mediating effect of plasma metabolite profiles is unclear.

A total of 95,275 participants from UK Biobank with plasma metabolomics and dietary information were analyzed. Metabolite profile scores for 14 dietary patterns were estimated through elastic net regression. Cox regression analysis assessed the associations of dietary patterns and their metabolite profile scores with colorectal tumor risk. Mediating effects of identified metabolite profile scores were estimated in the associations.

Fourteen metabolite profile scores, including a range of 28 to 205 signatures, were weak to moderate correlation with dietary patterns (all p < 0.001). Multivariable Cox regression analyses revealed that five dietary patterns were significantly correlated with a decreased risk of colorectal tumor after FDR correction and adjustment for covariates. HRs (95% CIs) per 1 SD for these diet patterns were as follows: WCRF (0.93, 0.90-0.96), CRC score (0.94, 0.92-0.97), AHEI-2010 (0.95, 0.92-0.97), DASH (0.94, 0.91-0.97), and hPDI (0.95, 0.93-0.98). Similarly, metabolite profile scores for these five dietary patterns were inversely associated with colorectal tumor risk, with HRs (95% CIs) per 1 SD as follows: WCRF (0.59, 0.49-0.70), CRC score (0.67, 0.58-0.77), AHEI-2010 (0.73, 0.65-0.80), DASH (0.75, 0.66-0.84), and hPDI (0.56, 0.47-0.67). The mediation proportions of five metabolite profile scores between dietary patterns and colorectal tumor risk ranged from 6.37 to 27.23% (all p < 0.001).

Five dietary patterns and their metabolite profile scores, were inversely correlated with colorectal tumor risk. These findings highlight the potential of metabolite profiles as mediators in the association between dietary patterns and the risk of colorectal tumor, further contributing to the prevention of colorectal cancer or adenoma and providing new insights for future research.

Salmonella Typhimurium (S. Typhimurium) is a common pathogenic microorganism and poses a threat to the efficiency of poultry farms. As signaling molecules regulating the interaction between the host and gut microbiota, bile acids (BAs) play a protective role in maintaining gut homeostasis. However, the antibacterial effect of BAs on Salmonella infection in broilers has remained unexplored. Therefore, the aim of this study was to investigate the potential role of feeding BAs in protecting against S. Typhimurium infection in broilers.

A total of 144 1-day-old Arbor Acres male broilers were randomly assigned to 4 groups, including non-challenged birds fed a basal diet (CON), S. Typhimurium-challenged birds (ST), S. Typhimurium-challenged birds treated with 0.15 g/kg antibiotic after infection (ST-ANT), and S. Typhimurium-challenged birds fed a basal diet supplemented with 350 mg/kg of BAs (ST-BA).

BAs supplementation ameliorated weight loss induced by S. Typhimurium infection and reduced the colonization of Salmonella in the liver and small intestine in broilers (P < 0.05). Compared to the ST group, broilers in ST-BA group had a higher ileal mucosal thickness and villus height, and BAs also ameliorated the increase of diamine oxidase (DAO) level in serum (P < 0.05). It was observed that the mucus layer thickness and the number of villous and cryptic goblet cells (GCs) were increased in the ST-BA group, consistent with the upregulation of MUC2 gene expression in the ileal mucosa (P < 0.05). Moreover, the mRNA expressions of Toll-like receptor 5 (TLR5), Toll-like receptor 4 (TLR4), and interleukin 1 beta (IL1b) were downregulated in the ileum by BAs treatment (P < 0.05). 16S rDNA sequencing analysis revealed that, compared to ST group, BAs ameliorated the decreases in Bacteroidota, Bacteroidaceae and Bacteroides abundances, which were negatively correlated with serum DAO activity, and the increases in Campylobacterota, Campylobacteraceae and Campylobacter abundances, which were negatively correlated with body weight but positively correlated with serum D-lactic acid (D-LA) levels (P < 0.05).

Dietary BAs supplementation strengthens the intestinal mucosal barrier and reverses dysbiosis of gut microbiota, which eventually relieves the damage to the intestinal barrier and weight loss induced by S. Typhimurium infection in broilers.

Flaxseed meal is a by-product of flaxseed oil extraction. In this research, lactic acid bacteria suitable for modification of flaxseed gum were screened based on cellulase activity and the extraction rate of flaxseed gum. The enzyme-weight method was employed to extract flaxseed gum (SDF). The influences of fermentation modification on the extraction yield, structure, function, and antioxidant activity of flaxseed gum was investigated. Based on the enzyme-producing activity and extraction rate, Lactobacillus plantarum (LP-3), Bacillus paracaetocasei (KLDS-82), and Lactobacillus acidophilus (LAC-11) were identified as the most suitable strains for modifying flaxseed gum. The results indicated that the extraction yield of flaxseed gum was 18.45 % ± 0.2 % after fermentation with KLDS-82, which was significantly higher than that of the unmodified group. After fermentation, the microstructure of flaxseed gum became looser and more porous. The characteristic absorption peak of polysaccharide was observed through scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), and X-ray diffraction (XRD), and the crystallization area was reduced. Simultaneously, its swelling capacity, water-holding capacity, oil-holding capacity, and other physicochemical properties have also been enhanced. The glucose adsorption capacity, cholesterol adsorption capacity, sodium cholic acid adsorption capacity, cation exchange capacity, α-glucosidase inhibitory activity, and antioxidant properties of SDF modified by Bacillus paracaetocasei (F-SDF) were significantly higher than those of Lactobacillus acidophilus modified SDF (S-SDF), Lactobacillus plantarum modified SDF (Z-SDF), and unmodified SDF (U-SDF). In conclusion, the modification effect of KLDS-82 is the most remarkable. Therefore, it can be utilized as a functional raw material in food.

Iron overload is a common complication in various chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD). Lipid and bile acid metabolism disorders are regarded as crucial hallmarks of NAFLD. However, effects of iron accumulation on lipid and bile acid metabolism are not well understood. Ferulic acid (FA) can chelate iron and regulate lipid and bile acid metabolism, but its potential to alleviate lipid and bile acid metabolism disorders caused by iron overload remains unclear. Here, in vitro experiments, iron overload induced oxidative stress, apoptosis, genomic instability, and lipid deposition in AML12 cells. FA reduced lipid and bile acid synthesis while increasing fatty acid β-oxidation and bile acid export, as indicated by increased mRNA expression of PPARα, Acox1, Adipoq, Bsep, and Shp, and decreased mRNA expression of Fasn, Acc, and Cyp7a1. In vivo experiments, FA mitigated liver injury in mice caused by iron overload, as indicated by reduced AST and ALT activities, and decreased iron levels in both serum and liver. RNA-seq results showed that differentially expressed genes were enriched in biological processes related to lipid metabolism, lipid biosynthesis, lipid storage, and transport. Furthermore, FA decreased cholesterol and bile acid contents, downregulated lipogenesis protein FASN, and bile acid synthesis protein CYP7A1. In conclusion, FA can protect the liver from lipid and bile acid metabolism disorders caused by iron overload by targeting FASN and CYP7A1. Consequently, FA, as a dietary supplement, can potentially prevent and treat chronic liver diseases related to iron overload by regulating lipid and bile acid metabolism.

The microbiota inhabits the epithelial surfaces of hosts, which influences physiological functions from helping digest food and acquiring nutrition to regulate metabolism and shaping host immunity. With the deep insight into the microbiota, an increasing amount of research reveals that it is also involved in the initiation and progression of cancer. Intriguingly, gut microbiota can mediate the biotransformation of drugs, thereby altering their bioavailability, bioactivity, or toxicity.

The review aims to elaborate on the role of gut microbiota and microbial metabolites in the efficacy and adverse effects of chemotherapeutics. Furthermore, we discuss the clinical potential of various ways to harness gut microbiota for cancer chemotherapy.

Recent evidence shows that gut microbiota modulates the efficacy and toxicity of chemotherapy agents, leading to diverse host responses to chemotherapy. Thereinto, targeting the microbiota to improve efficacy and diminish the toxicity of chemotherapeutic drugs may be a promising strategy in tumor treatment.

We aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs.

Newborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA), or increasing doses of obeticholic acid (OCA) for 19 days.

Enteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic cyp7a1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC$ and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP.

Enteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter FXR target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of FXR agonism in the prevention of PNALD in piglets.

Clostridium scindens is a commensal gut bacterium capable of forming the secondary bile acids deoxycholic acid and lithocholic acid from the primary bile acids cholic acid and chenodeoxycholic acid, respectively, as well as converting glucocorticoids to androgens. Historically, only two strains, C. scindens ATCC 35704 and C. scindens VPI 12708, have been characterized in vitro and in vivo to any significant extent. The formation of secondary bile acids is important in maintaining normal gastrointestinal function, in regulating the structure of the gut microbiome, in the etiology of such diseases such as cancers of the GI tract, and in the prevention of Clostridium difficile infection. We therefore wanted to determine the pangenome of 34 cultured strains of C. scindens and a set of 200 metagenome-assembled genomes (MAGs) to understand the variability among strains. The results indicate that the 34 strains of C. scindens have an open pangenome with 12,720 orthologous gene groups, and a core genome with 1,630 gene families, in addition to 7,051 and 4,039 gene families in the accessory and unique (i.e., strain-exclusive) genomes, respectively. The core genome contains 39% of the proteins with predicted metabolic function, and, in the unique genome, the function of storage and processing of information prevails, with 34% of the proteins being in that category. The pangenome profile including the MAGs also proved to be open. The presence of bile acid inducible ( bai ) and steroid-17,20-desmolase ( des ) genes was identified among groups of strains. The analysis reveals that C. scindens strains are distributed into two clades, indicating the possible onset of C. scindens separation into two species, confirmed by gene content, phylogenomic, and average nucleotide identity (ANI) analyses. This study provides insight into the structure and function of the C. scindens pangenome, offering a genetic foundation of significance for many aspects of research on the intestinal microbiota and bile acid metabolism.

The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an "opportunistic pathogenic factor" in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.