Bile Acid Receptor Research Articles

Obeticholic acid alleviates intrauterine growth restriction induced by di-ethyl-hexyl phthalate in pregnant female mice by improving bile acid disorder.

Di-(2-ethylhexyl)-phthalate (DEHP) is a ubiquitous environmental pollutant and is widely used in industrial plastics. Intrahepatic cholestasis of pregnancy (ICP), distinguished by maternal pruritus and elevated serum bile acid levels, is linked to unfavorable pregnancy consequences. Few studies have investigated the potential effect of gestational DEHP exposure on the cholestasis in pregnant female mice, and the underlying mechanisms remain unclear. In the present study, a mouse model of cholestasis during pregnancy was established by DEHP exposure. We found that DEHP induces elevated bile acid levels by affecting bile acid synthesis and transporter receptor expression in the maternal liver and placenta of pregnant female mice, ultimately leading to intrauterine growth restriction (IUGR). In addition, DEHP changed the bile acid composition of maternal serum and liver as well as placenta and amniotic fluid in pregnant female mice; Importantly, we found that DEHP down-regulates the expression of farnesoid X receptor (FXR), which is considered to be a bile acid receptor. FXR agonist obeticholic acid (OCA) effectively alleviated the adverse effects of DEHP on pregnant female mice. While, OCA itself had no adverse effects on normal pregnant female mice. In summary, DEHP could induces bile acid disorder and IUGR in pregnant female mice by affect FXR, which was reversed by OCA.

OR09-05 GPBAR1- Understanding Its Function In The Secretory Endometrium

Abstract Disclosure: M. Saad-Naguib: None. P. Timmins: None. L. George: None. C. Samuels: None. N. Douglas: None. A.V. Babwah: None. Every successful pregnancy relies on implantation of an embryo into a receptive uterine endometrium. While implantation failure accounts for 50% of pregnancy failures, it remains the least understood aspect of pregnancy. In the mid-secretory (MS) phase of the menstrual cycle, under the influence of progesterone and cAMP, fibroblasts decidualize, a critical requirement for implantation. Decidualization involves the differentiation of stromal fibroblasts into secretory epithelioid cells that contribute to the formation of the decidua, the support of the pregnancy prior to placentation. A defective decidua can lead to implantation failure, but if implantation occurs, it could compromise placenta formation and function. Several studies have demonstrated the importance of G protein-coupled receptors (GPCRs) in mouse endometrial receptivity and decidualization. GPCRs are transmembrane signaling molecules that are ubiquitously expressed in the body and regulate almost every cellular and physiological process. They are major pharmaceutical targets, with 35% of all the drugs approved by the US FDA targeting GPCRs. To identify novel GPCR regulators of embryo implantation, we conducted bulk RNA sequencing of the human endometrium at the periovulatory (PO) and mid-secretory (MS) phase in natural menstrual cycles in healthy women of reproductive age and observed that genes encoding 11 GPCRs, not previously reported to regulate implantation, were differentially expressed between these two time points. Among these was the gene encoding the G protein-coupled bile acid receptor 1 (GPBAR1), and this was upregulated 4.6-fold in the MS vs PO phase. Single cell RNA sequence analysis showed that within the human endometrium, GPBAR1 mRNA expression is mostly and strongly localized to stromal fibroblasts. Upon activation by secondary bile acids, GPBAR1 couples to Gαs leading to an increase in intracellular cAMP levels. We hypothesize that in the MS endometrium, upon ligand binding, GPBAR1 produces cAMP and induces human endometrial stromal cell (HESC) decidualization. This hypothesis is being tested in vitro using primary HESCs. Interestingly, in the pregnant mouse, GPBAR1 mRNA is barely expressed at the implantation site on E7.5, and therefore unlikely plays a role in stromal cell decidualization in the mouse. Whether Gpbar1 is expressed in the pregnant mouse endometrium prior to implantation and plays a role in regulating endometrial receptivity is being investigated. Overall, our studies have uncovered a GPCR, that to our knowledge, has not been previously described in the human endometrium. Our data show that the expression of this GPCR is upregulated at the time of endometrial stromal cell decidualization, and therefore it might regulate decidualization and/or be required for decidual function in women. These possibilities are being examined. Presentation: Friday, June 16, 2023

Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation

BackgroundHigh-fat diet (HFD) is closely associated with the increased prevalence of inflammatory bowel disease (IBD). Excessive gut microbial metabolite deoxycholic acid (DCA) caused by HFD plays significant roles in eliciting intestinal inflammation, however, the mechanism underlining the induction of inflammatory response by DCA has not been fully elucidated. The purpose of this study was to investigate the role of DCA in the triggering of inflammation via affecting CD4+ T cell differentiation.ResultsMurine CD4+T cells were cultured under Th1, Th2 or Th17-polarizing conditions treated with or without different dosage of DCA, and flowcytometry was conducted to detect the effect of DCA on CD4+ T cell differentiation. Alteration of gene expression in CD4+ T cells upon DCA treatment was determined by RNA-sequencing and qRT-PCR. Bioinformatic analysis, cholesterol metabolic profiling, ChIP assay and immuno-fluorescent staining were further applied to explore the DCA-regulated pathway that involved in CD4+T cell differentiation. The results showed that DCA could dose-dependently promote the differentiation of CD4+ T cell into Th17 linage with pathogenic signature. Mechanistically, DCA stimulated the expression of cholesterol biosynthetic enzymes CYP51 and led to the increased generation of endogenous RORγt agonists, including zymosterol and desmosterol, therefore facilitating Th17 differentiation. Up-regulation of CYP51 by DCA was largely mediated via targeting transcription factor SREBP2 and at least partially through bile acid receptor TGR5. In addition, DCA-supplemented diet significantly increased intestinal Th17 cell infiltration and exacerbated TNBS-induced colitis. Administration of cholestyramine to eliminate fecal bile acid obviously alleviated colonic inflammation accompanied by decreased Th17 cells in HFD-fed mice.ConclusionsOur data establish a link between DCA-induced cholesterol biosynthesis in immune cells and gut inflammation. Modulation of bile acid level or targeting cholesterol metabolic pathway may be potential therapeutic measurements for HFD-related colitis.

Clinical Significance of Sphingosine 1-phosphate Receptor 2 and Takeda G Protein-coupled Receptor 5 in Extrahepatic Cholangiocarcinoma Patients.

In biliary epithelial cells, two bile acid receptors, sphingosine 1-phosphate receptor 2 (S1PR2) and Takeda G protein-coupled receptor 5 (TGR5) have been reported to trigger cell proliferation, as well as neoplastic cell invasiveness. In this study, we aimed to investigate the clinical significance of S1PR2/ TGR5 expression in extrahepatic cholangiocarcinoma (CCA) patients. Patients who underwent surgical resection of extrahepatic CCA at Korea University Guro Hospital between 2002 and 2018 were included. Data on immunohistochemical staining and H-score of S1PR2 and TGR5 were evaluated using digital image analysis. A total of 115 cases of invasive CCA were analyzed. The H-score of S1PR2 showed a decrease in invasive CCA (p=0.052) but that of TGR5 showed a significant increase (p=0.02). Overall survival and disease-free survival were significantly lower in the low S1PR2 expression group (p<0.05) than in the control group; however, TGR5 expression was not significant (p=0.096). In multivariate analysis, low S1PR2 was only significant for poor prognosis. Low S1PR2 level was the only independent poor prognostic factor in patients with resected extrahepatic CCA.

An Update on Role of Bile Acids in Neurological Functions and Neurodegenerative Diseases: A Narrative Review

Having previously reviewed the role of Bile Acids (BAs) in obesity, NAFLD/NASH/HCC and crosstalk of Gut Microbiome in numerous body disorders here we further attempted to assess part of BAs in normal brain physiology and in different Neurodegenerative Diseases (NDD). BAs constitute significant physiological molecules which apart from modulating nutrient absorption as well as metabolism in peripheral tissues influence neuromodulatory actions in the Central Nervous System (CNS). The formation of bile acids takes place basically from cholesterol in the liver by the canonical as well as alternate pathwaysor in the brain started by the neuron particular sterol Cholesterol-24 hydroxylase (CYP46A1) modulated pathway. Circulating BAs possess the capacity of crossing the Blood Brain Barrier (BBB) and thus gaining entry into the CNS via passive diffusion or through BAs transporters. Brain BAs act in the CNS via activation of membrane or nuclear receptors or influence the working of the neurotransmitter receptors. Indirect signal might be further given to the CNS through the Farsenoid X Receptor (FXR) based Fibroblast growth factor 15/19 (FGF15/19) pathway or the takeda G Protein Coupled (GPC) bile acid receptor 5 (TGR5) based Glucagon Like Peptide 1(GLP) pathway. In case of pathological situations, changes in BAs have been observed to probably aid in the pathogenesis of different neurological diseases. Of greater significance is the supplementationof hydrophilic amidated Ursodeoxycholic Acid (UDCA) or Tauroursodeoxycholic Acid (TUDCA) have been corroborated to illustrate therapeutic advantagesby hampering the neuroinflammatory reactions, apoptosis, Oxidative Stress (OS), Endoplasmic Reticulum (ER) stress, mitochondrial protection or work in the form of probable chaperone for correction of misfolding of proteins in the treatment of different neurological diseases. This yields opportunity of utilization of UDCA along with TUDCA in the treatment of different neurodegenerative diseases inclusive of Alzheimer’s disease; Parkinson’s disease, Huntingtons disease, Amyotrophic Lateral sclerosis, and prion disease.

Exosomal EIF5A derived from Lewis lung carcinoma induced adipocyte wasting in cancer cachexia

Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.

Estrogen deficiency induces bone loss through the gut microbiota

Postmenopausal osteoporosis is a common bone metabolic disease, and gut microbiota (GM) imbalance plays an important role in the development of metabolic bone disease. Here, we show that ovariectomized mice had high levels of lipopolysaccharide in serum and gut microbiota dysbiosis through increases in luminal Firmicutes:Bacteroidetes ratio. We depleted the GM through antibiotic treatment and observed improvements in bone mass, bone microstructure, and bone strength in ovariectomized mice. Conversely, transplantation of GM adapted to ovariectomy induced bone loss. However, GM depletion reversed ovariectomy-induced gene expression in the tibia and increased periosteal bone formation. Furthermore, bioinformatics analysis revealed that the G-protein-coupled bile acid receptor (TGR5) and systemic inflammatory factors play key roles in bone metabolism. Silencing TGR5 expression through small interfering RNA (siRNA) in the local tibia and knockout of TGR5 attenuated the effects of GM depletion in ovariectomized mice, confirming these findings. Thus, this study highlights the critical role of the GM in inducing bone loss in ovariectomized mice and suggests that targeting TGR5 within the GM may have therapeutic potential for postmenopausal osteoporosis.

Farnesoid X receptor enhances epithelial ACE2 expression and inhibits virally induced IL-6 secretion: implications for intestinal symptoms of SARS-CoV-2.

Intestinal inflammation and diarrhea are often associated with SARS-CoV-2 infection. The angiotensin converting enzyme 2 (ACE2) receptor plays a key role in SARS-CoV-2 pathogenesis, facilitating entry of the virus into epithelial cells, while also regulating mucosal inflammatory responses. Here, we investigated roles for the nuclear bile acid receptor farnesoid X receptor (FXR) in regulating ACE2 expression and virally mediated inflammatory responses in intestinal epithelia. Human colonic or ileal enteroids and cultured T84 and Caco-2 monolayers were treated with the FXR agonists, obeticholic acid (OCA) or GW4064, or infected with live SARS-CoV-2 (2019-nCoV/USA_WA1/2020). Changes in mRNA, protein, or secreted cytokines were measured by qPCR, Western blotting, and ELISA. Treatment of undifferentiated colonic or ileal enteroids with OCA increased ACE2 mRNA by 2.1 ± 0.4-fold (n = 3; P = 0.08) and 2.3 ± 0.2-fold (n = 3; P < 0.05), respectively. In contrast, ACE2 expression in differentiated enteroids was not significantly altered. FXR activation in cultured epithelial monolayers also upregulated ACE2 mRNA, accompanied by increases in ACE2 expression and secretion. Further experiments revealed FXR activation to inhibit IL-6 release from both Caco-2 cells infected with SARS-CoV-2 and T84 cells treated with the viral mimic, polyinosinic:polycytidylic acid, by 46 ± 12% (n = 3, P < 0.05) and 35 ± 6% (n = 8; P < 0.01), respectively. By virtue of its ability to modulate epithelial ACE2 expression and inhibit virus-mediated proinflammatory cytokine release, FXR represents a promising target for the development of new approaches to prevent intestinal manifestations of SARS-CoV-2.NEW & NOTEWORTHY Activation of the nuclear bile acid receptor, farnesoid X receptor (FXR), specifically upregulates ACE2 expression in undifferentiated colonic epithelial cells and inhibits virus-induced proinflammatory cytokine release. By virtue of these actions FXR represents a promising target for the development of new approaches to prevent intestinal manifestations of SARS-CoV-2 infection.

Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations.

It has been known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in Western countries, but the reason responsible for this difference still remains a major knowledge gap. Using GeneChip® miRNA array to analyze the global microRNA expression in B lymphocytes from Asian and Western CLL patients and healthy individuals, we have identified microRNA with CLL-promoting or suppressive functions that are differentially expressed in Asian and Western individuals. In particular, miR-4485 is upregulated in CLL patients of both ethnic groups, and its expression is significantly lower in Asian healthy individuals. Genetic silencing of miR-4485 in CLL cells suppresses leukemia cell growth, whereas ectopic expression of miR-4485 promotes cell proliferation. Mechanistically, miR-4485 exerts its CLL-promoting activity by inhibiting the expression of TGR5 and activating the ERK1/2 pathway. In contrast, miR-138, miR-181a, miR- 181c, miR-181d, and miR-363 with tumor-suppressive function are highly expressed in Asian healthy individuals. Our study suggests that differential expression of several important microRNA with pro- or anti-CLL functions in Asian and Western B lymphocytes likely contributes to the difference in CLL incidence between the two ethnic groups, and that miR-4485 and its downstream molecule TGR5 could be potential therapeutic targets.

Prophylactic feeding of neomycin to Holstein calves alters gut microbiota, bile acid metabolism, and expression of genes involved in immunometabolic regulation.

The objective of this study was to evaluate the effects of prophylactic neomycin administration on Holstein bull calves' intestinal microbiota, bile acid (BA) metabolism, and transcript abundance of genes related to BA metabolism. A total of 36 calves were blocked by body weight and assigned to either non-medicated milk replacer (CTL), or neomycin for 14 days (ST) or 28 days (LT) in their milk replacer. At the end of the study, calves were euthanized to collect tissue and digesta samples from the gastrointestinal tract, liver, and adipose tissue for analysis of intestinal microbial diversity, bile acid concentration and profile in various body tissues, and gene expression related to bile acid, lipid, carbohydrate metabolism, and inflammation. Calves that received prophylactic administration of neomycin for 28 d (LT) had reduced species richness (chao1 index), and tended to have reduced phylogenetic diversity in the ileum tissue. The relative abundance of Lactobacillus, and Bifidobacterium in ileum and colon digesta were decreased in LT compared with CTL. Concentrations of primary, secondary, and total BA were increased by ST in ileal tissue. In plasma, ST and LT treatments had lower concentrations of secondary BA. Gene expression of the BA receptor FXR was increased in ileum and liver by LT compared to CTL. The expression of FXR and TGR5 in the liver was increased in the ST group compared with CTL, and in adipose tissue, 5 genes related to triglyceride, gluconeogenesis, and immune activation were differentially expressed between CTL and ST. In conclusion, we provide evidence that prophylactic administration of neomycin leads to aberrant changes in BA concentration and profile in different compartments of the enterohepatic system through a process that possibly entails antimicrobial disruption of key bacterial groups, which persists even after cessation of neomycin administration. Additionally, we uncovered an apparent link between dysregulated BA metabolism and changes in lipid metabolism and immune activation in adipose tissue and liver.

FXR Maintains the Intestinal Barrier and Stemness by Regulating CYP11A1-Mediated Corticosterone Synthesis in Biliary Obstruction Diseases.

Biliary obstruction diseases are often complicated by an impaired intestinal barrier, which aggravates liver injury. Treatment of the intestinal barrier is often neglected. To investigate the mechanism by which intestinal bile acid deficiency mediates intestinal barrier dysfunction after biliary obstruction and identify a potential therapeutic modality, we mainly used a bile duct ligation (BDL) mouse model to simulate biliary obstruction and determine the important role of the bile acid receptor FXR in maintaining intestinal barrier function and stemness. Through RNA-seq analysis of BDL and sham mouse crypts and qRT-PCR performed on intestinal epithelial-specific Fxr knockout (FxrΔIEC) and wild-type mouse crypts, we found that FXR might maintain intestinal stemness by regulating CYP11A1 expression. Given the key role of CYP11A1 during glucocorticoid production, we also found that FXR activation could promote intestinal corticosterone (CORT) synthesis by ELISA. Intestinal organoid culture showed that an FXR agonist or corticosterone increased crypt formation and organoid growth. Further animal experiments showed that corticosterone gavage treatment could maintain intestinal barrier function and stemness, decrease LPS translocation, and attenuate liver injury in BDL mice. Our study hopefully provides a new theoretical basis for the prevention of intestinal complications and alleviation of liver injury after biliary obstruction.

Discovery, Structure-Activity Relationships, and In Vivo Activity of Dihydropyridone Agonists of the Bile Acid Receptor TGR5.

A novel series of potent agonists of the bile acid receptor TGR5 bearing a dihydropyridone scaffold was developed from a high-throughput screen. Starting from a micromolar hit compound, we implemented an extensive structure-activity-relationship (SAR) study with the synthesis and biological evaluation of 83 analogues. The project culminated with the identification of the potent nanomolar TGR5 agonist 77A. We report the GLP-1 secretagogue effect of our lead compound ex vivo in mouse colonoids and in vivo. In addition, to identify specific features favorable for TGR5 activation, we generated and optimized a three-dimensional quantitative SAR model that contributed to our understanding of our activity profile and could guide further development of this dihydropyridone series.

The Crosstalk between Gut Microbiota and Bile Acids Promotes the Development of Non-Alcoholic Fatty Liver Disease.

Recently the roles of gut microbiota are highly regarded in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The intestinal bacteria regulate the metabolism of bile acids depending on bile salt hydrolase (BSH), 7-dehydroxylation, hydroxysteroid dehydrogenase (HSDH), or amide conjugation reaction, thus exerting effects on NAFLD development through bile acid receptors such as farnesoid X receptor (FXR), Takeda G-protein-coupled bile acid protein 5 (TGR5), and vitamin D receptor (VDR), which modulate nutrient metabolism and insulin sensitivity via interacting with downstream molecules. Reversely, the composition of gut microbiota is also affected by the level of bile acids in turn. We summarize the mutual regulation between the specific bacteria and bile acids in NAFLD and the latest clinical research based on microbiota and bile acids, which facilitate the development of novel treatment modalities in NAFLD.

Research Progress of Takeda G Protein-Coupled Receptor 5 in Metabolic Syndrome.

Bile acids are acknowledged as signaling molecules involved in metabolic syndrome. The Takeda G protein-coupled receptor 5 (TGR5) functions as a significant bile acid receptor. The accumulated evidence suggests that TGR5 involves lipid homeostasis, glucose metabolism, and inflammation regulation. In line with this, recent preclinical studies also demonstrate that TGR5 plays a significant role in the generation and progression of metabolic syndrome, encompassing type 2 diabetes mellitus, obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). In this review, we discuss the role of TGR5 in metabolic syndrome, illustrating the underlying mechanisms and therapeutic targets.

Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis.

Bile acids (BAs) play a crucial role in nutrient absorption and act as key regulators of lipid and glucose metabolism and immune homeostasis. Through the enterohepatic circulation, BAs are synthesized, metabolized, and reabsorbed, with a portion entering the vascular circulation and distributing systemically. This allows BAs to interact with receptors in all major organs, leading to organ-organ interactions that regulate both local and global metabolic processes, as well as the immune system. This review focuses on the whole-body effects of BA-mediated metabolic and immunological regulation, including in the brain, heart, liver, intestine, eyes, skin, adipose tissue, and muscle. Targeting BA synthesis and receptor signaling is a promising strategy for the development of novel therapies for various diseases throughout the body.

Insulin alleviates murine colitis through microbiome alterations and bile acid metabolism

BackgroundInsulin has been reported to exhibit anti-inflammatory activities in the context of bowel inflammation. However, the role of the interaction between insulin and the microbiota in gut health is unclear. Our goal was to investigate the mechanism of action of insulin in bowel inflammation and the relationship between insulin and the gut microbiota.MethodsWe used acute and chronic murine models of inflammatory bowel disease (IBD) to evaluate whether insulin influences the progression of colitis. Colonic tissues, the host metabolome and the gut microbiome were analyzed to investigate the relationship among insulin treatment, the microbiome, and disease. Experiments involving antibiotic (Abx) treatment and fecal microbiota transplantation (FMT) confirmed the association among the gut microbiota, insulin and IBD. In a series of experiments, we further defined the mechanisms underlying the anti-inflammatory effects of insulin.ResultsWe found that low-dose insulin treatment alleviated intestinal inflammation but did not cause death. These effects were dependent on the gut microbiota, as confirmed by experiments involving Abx treatment and FMT. Using untargeted metabolomic profiling and 16S rRNA sequencing, we discovered that the level of the secondary bile acid lithocholic acid (LCA) was notably increased and the LCA levels were significantly associated with the abundance of Blautia, Enterorhadus and Rumi-NK4A214_group. Furthermore, LCA exerted anti-inflammatory effects by activating a G-protein-coupled bile acid receptor (TGR5), which inhibited the polarization of classically activated (M1) macrophages.ConclusionTogether, these data suggest that insulin alters the gut microbiota and affects LCA production, ultimately delaying the progression of IBD.Graphical

Hyocholic acid retards renal fibrosis by regulating lipid metabolism and inflammatory response in a sheep model

The kidneys are vital organs that regulate metabolic homeostasis in the body, filter waste products from the blood, and remove extrahepatic bile acids. We previously found that the dietary supplementation of hyocholic acid alleviated the sheep body lipid deposition and decreased kidney weight. This study evaluated hyocholic acid’s (HCA) roles and mechanisms on lipid metabolism and anti-inflammatory function in the kidney under a high-energy diet. Histomicrograph showing the apparent improvement by HCA by attenuating structural damage. The HCA treatment reduced the renal accumulation of cholesterol. Bile acid receptors such as LXR and FXR were activated at the protein level. HCA significantly altered several genes related to immune response (NF-κB, IL-6, and MCP1) and fibrosis (TGF-β, Col1α1, and α-SMA). These significant changes correlated with renal lipid accumulation. The KEGG pathways including non-alcoholic fatty liver disease, insulin resistance, TNF signaling pathway, and Th17 cell differentiation were enriched and NF-κB, IL-6, and TGF-β were identified as the core interconnected genes. This study revealed that HCA plays an efficient role in alleviating kidney lipids accumulation and inflammatory response through crucial genes such as FXR, LXR, HMGCR, NF-κB, IL-6, MCP1, and TGF-β, and expand our understanding of HCA's role in kidney function. In conclusion, HCA mitigated kidney fibrosis, lipid metabolism disorders and immune responses induced by a high-energy diet by regulating a potential LXR/SREBP2/TGF-β-NF-κB signaling pathway.

Bile Acids, Intestinal Barrier Dysfunction, and Related Diseases.

The intestinal barrier is a precisely regulated semi-permeable physiological structure that absorbs nutrients and protects the internal environment from infiltration of pathological molecules and microorganisms. Bile acids are small molecules synthesized from cholesterol in the liver, secreted into the duodenum, and transformed to secondary or tertiary bile acids by the gut microbiota. Bile acids interact with bile acid receptors (BARs) or gut microbiota, which plays a key role in maintaining the homeostasis of the intestinal barrier. In this review, we summarize and discuss the recent studies on bile acid disorder associated with intestinal barrier dysfunction and related diseases. We focus on the roles of bile acids, BARs, and gut microbiota in triggering intestinal barrier dysfunction. Insights for the future prevention and treatment of intestinal barrier dysfunction and related diseases are provided.

Bile Acids and Microbiota Interplay in Pancreatic Cancer.

Evidence suggests the involvement of the microbiota, including oral, intra-tumoral and gut, in pancreatic cancer progression and response to therapy. The gut microbiota modulates the bile acid pool and is associated with maintaining host physiology. Studies have shown that the bile acid/gut microbiota axis is dysregulated in pancreatic cancer. Bile acid receptor expression and bile acid levels are dysregulated in pancreatic cancer as well. Studies have also shown that bile acids can cause pancreatic cell injury and facilitate cancer cell proliferation. The microbiota and its metabolites, including bile acids, are also altered in other conditions considered risk factors for pancreatic cancer development and can alter responses to chemotherapeutic treatments, thus affecting patient outcomes. Altogether, these findings suggest that the gut microbial and/or bile acid profiles could also serve as biomarkers for pancreatic cancer detection. This review will discuss the current knowledge on the interaction between gut microbiota interaction and bile acid metabolism in pancreatic cancer.

P19-029-23 Gut Microbiota-Derived Secondary Bile Acids, Bile Acids Receptor Polymorphisms, and Risk of Cardiovascular Disease in Individuals With Newly Diagnosed Type 2 Diabetes

P19-029-23 Gut Microbiota-Derived Secondary Bile Acids, Bile Acids Receptor Polymorphisms, and Risk of Cardiovascular Disease in Individuals With Newly Diagnosed Type 2 Diabetes