bile acid cholic acid (INT-777) / Intercept - LARVOL DELTA

A novel Kupffer cell-targeting nanoparticle system to Mitigate alcohol-associated liver disease. (PubMed, Biomaterials) - "Treatment with CMC-coated PLGA NPs containing dexamethasone and INT-777 led to significantly decreased serum aspartate aminotransferase, alanine aminotransferase, and pro-inflammatory cytokines levels, and reduced liver inflammation as confirmed by Hematoxylin and Eosin, and Oil red O staining. These findings demonstrate that CMC-coated PLGA NPs hold significant potential as a treatment option for ALD-associated inflammation."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • GLI2

Mechanisms of GPCR19-Mediated Protection in Diabetic Kidney Disease: Regulation of Mitochondrial Homeostasis and Therapeutic Potential (ERA 2025) - "GPCR19 is downregulated in DKD, and its overexpression in renal tubular cells protects against tubulopathy by maintaining mitochondrial homeostasis. INT-777, a GPCR19 agonist, improves mitochondrial function and reduces apoptosis in high glucose conditions, suggesting its potential as a therapeutic agent in DKD. The PKA/CREB pathway, through regulation of BNIP3, is a key mechanism in GPCR19-mediated protection in diabetic nephropathy."

Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • BNIP3

Sodium butyrate regulates macrophage polarization by TGR5/β-arrestin2 in vitro. (PubMed, Mol Med) - "SB inhibited M1-like polarization and promoted M2-like polarization induced by LPS via TGR5/β-arrestin2 in RAW264.7 cells and TGR5 was the target of SB."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Targeted Protein Degradation • Ulcerative Colitis • ARRB1 • CD86 • IL10 • IL1B • MRC1

The discovery of a new nonbile acid modulator of Takeda G protein-coupled receptor 5: An integrated computational approach. (PubMed, Arch Pharm (Weinheim)) - "This was supported by MD simulation results, which indicated that a hydrogen bond interaction with Tyr240 is involved in TGR5 activation. Hit-3 (CSC089939231) represents a new nonsteroidal lead that can be further optimized to design potent TGR5 agonists."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Activation of TGR5 in the injured nerve site according to a prevention protocol mitigates partial sciatic nerve ligation-induced neuropathic pain by alleviating neuroinflammation. (PubMed, Pain) - "Perisciatic nerve administration of the TGR5 agonist, INT-777 according to a prevention protocol (50 μg/μL daily from postoperative day [POD] 0 to POD6) provided sustained relief from mechanical allodynia and spontaneous pain, whereas the TGR5 antagonist, SBI-115 worsened neuropathic pain...Furthermore, the activation of microglia in the spinal cord on POD7 and POD14 was altered when TGR5 in the sciatic nerve was manipulated. Collectively, TGR5 activation in the injured nerve site mitigates neuropathic pain by reducing neuroinflammation, while TGR5 knockdown in myeloid cells worsens pain by enhancing neuroinflammation."

Journal • Inflammation • Neuralgia • Oncology • Pain • CCL2 • CCL3 • CD86 • CXCL9 • IL1B • IL6 • MRC1 • TNFA

Emerging Roles of Bile Acids and TGR5 in the Central Nervous System: Molecular Functions and Therapeutic Implications. (PubMed, Int J Mol Sci) - "This review addresses the new challenges that face BA research for neuroscience, focusing on their molecular functions. We discuss their endogenous and exogenous sources in the CNS, their signaling through the TGR5 receptor, and their mechanisms of action as potential therapeutics for neuropathologies."

Journal • Review • Inflammation

Targeting TGR5 to mitigate liver fibrosis: Inhibition of hepatic stellate cell activation through modulation of mitochondrial fission. (PubMed, Int Immunopharmacol) - "Using the human hepatic stellate cell line LX-2 overexpressing hepatitis B virus X protein (HBX), this study revealed that TGR5 activation through INT-777 inhibits HBX-induced LX-2 cell activation, thereby ameliorating liver fibrosis, which is associated with the attenuation of mitochondrial fission and introduces a novel regulatory pathway in liver fibrosis...In vivo studies using TGR5 knockout mice substantiate these findings, demonstrating exacerbated fibrosis in the absence of TGR5 and its alleviation with the mitochondrial fission inhibitor Mdivi-1. Overall, this study provides insights into TGR5-mediated regulation of liver fibrosis through the modulation of mitochondrial fission in HSCs, suggesting potential therapeutic strategies for liver fibrosis intervention."

Journal • Fibrosis • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis

Bile acids differentially regulate longitudinal smooth muscle contractility in everted mouse ileum. (PubMed, FASEB Bioadv) - "The dose-dependent increase in contractility resulting from the application of ursodeoxycholic acid was recapitulated by INT-777, an agonist of the Takeda G protein-coupled receptor 5 (TGR5), and by cevimeline, a muscarinic acetylcholine receptor agonist. These results demonstrate that gentle eversion of intact mouse ileum facilitates the quantification of longitudinal smooth muscle contractile responses to individual bile acids. Prokinetic effects of ursodeoxycholic acid and low-dose deoxycholic acid are replicated by agonists to TGR5 and muscarinic acetylcholine receptors."

Journal • Preclinical • Gastrointestinal Disorder • EGFR

Biased GPBAR Signaling in Regulating Islet Homeostasis and Glucose Metabolism (ADA 2024) - "These findings collectively indicated that ligands of GPBAR with Gs-biased viability, may could better improve islet homeostasis and provide a rational design of GPBAR-targeting drugs for diabetes or other metabolic diseases."

Diabetes • Metabolic Disorders • ARRB1 • PDX1

Activation of TGR5 Increases Urine Concentration by Inducing AQP2 and AQP3 Expression in Renal Medullary Collecting Ducts. (PubMed, Kidney Dis (Basel)) - "Mice were treated with TGR5 agonists (LCA and INT-777) for 3 days...Collectively, our findings demonstrate that activation of TGR5 can promote urine concentration by upregulation of AQP2 and AQP3 expression in renal collecting ducts. TGR5 may represent an attractive target for the treatment of patients with urine concentration defect."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • AQP3

Lactobacillus reuteri JCM 1112 ameliorates chronic acrylamide-induced glucose metabolism disorder via the bile acid-TGR5-GLP-1 axis and modulates intestinal oxidative stress in mice. (PubMed, Food Funct) - "Here, C57BL/6N mice were orally administered with 5 mg per kg bw AA for 10 weeks, followed by another 3 weeks of glucagon-like peptide-1 (GLP-1) analogue (dulaglutide) treatment...Then, mice were administered with AA or AA + INT-777 (Takeda G-protein-coupled receptor 5 (TGR5) agonist) for 10 weeks...In addition, L. reuteri significantly enhanced ileal superoxide dismutase and catalase activities and total antioxidant capacity, thereby preventing chronic AA-induced oxidative stress. Our research provides new insights into the GMD toxicity of chronic low-dose AA and confirms the role of probiotics in alleviating AA-induced GMD."

Journal • Preclinical • Metabolic Disorders • CAT

Bile acid metabolism is altered in learning and memory impairment induced by chronic lead exposure. (PubMed, J Hazard Mater) - "In addition, supplementation with TUDCA or INT-777 significantly alleviated chronic lead exposure-induced learning and memory impairment, primarily through inhibition of the NLRP3 inflammasome in the hippocampus to relieve neuroinflammation. In conclusion, our findings suggested that dysregulation of host bile acid metabolism may be one of the mechanisms of lead-induced neurotoxicity, and supplementation of specific bile acids may be a possible therapeutic strategy for lead-induced neurotoxicity."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • Metabolic Disorders • Transplantation • NLRP3

Cognitive Impairment in Parkinson's Disease: An Updated Overview Focusing on Emerging Pharmaceutical Treatment Approaches. (PubMed, Medicina (Kaunas)) - "Accumulating preclinical and clinical evidence shows that several agents may provide beneficial effects on patients with PD and cognitive impairment, including ceftriaxone, ambroxol, intranasal insulin, nilotinib, atomoxetine, mevidalen, blarcamesine, prasinezumab, SYN120, ENT-01, NYX-458, GRF6021, fosgonimeton, INT-777, Neuropeptide S, silibinin, osmotin, cordycepin, huperzine A, fibroblast growth factor 21, Poloxamer 188, ginsenoside Rb1, thioredoxin-1, tangeretin, istradefylline and Eugenia uniflora. In this updated overview, we aim to cover the clinical aspects of the spectrum of PD-related cognitive impairment and discuss recent evidence on emerging treatment approaches that are under investigation at a preclinical and clinical level. Finally, we aim to provide additional insights and propose new ideas for investigation that may be feasible and effective for the spectrum of PD-related cognitive impairment."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation • Movement Disorders • Parkinson's Disease • FGF21

G protein-coupled bile acid receptor 1 reduced hepatic immune response and inhibited NFκB, PI3K/AKT and PKC/P38 MAPK signaling pathway in hybrid grouper. (PubMed, J Anim Sci) - "INT-777 agonist significantly decreased the expression of phosphorylated phosphoinositide 3-kinase (p-PI3K) protein and the ratio of phosphorylated and non-phosphorylated serine/threonine-protein kinase (p-AKT/AKT). In conclusion, activation of hepatic TGR5 inhibited the PKC/P38 MAPK, PI3K/AKT, NFκB signaling pathway, and improved hepatic immune responses of hybrid grouper in vivo and in vitro."

Journal • Inflammation • IL1B • TNFA

Differential Fibrotic Response of Muscle Fibroblasts, Myoblasts, and Myotubes to Cholic and Deoxycholic Acids. (PubMed, Adv Exp Med Biol) - "The same response was found in fibroblasts when activating TGR5 with the specific receptor agonist (INT-777)...On the other hand, DCA decreased the fibronectin in myoblasts and myotubes, whereas CA did not show any effect in these cell populations. Our results show that BA has different effects depending on the cell population to be analyzed."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis

The TGR5 Agonist INT-777 Promotes Peripheral Nerve Regeneration by Activating cAMP-dependent Protein Kinase A in Schwann Cells. (PubMed, Mol Neurobiol) - "Overall, these data indicate that INT-777 is capable of promoting peripheral nerve regeneration and functional recovery after injury, and these benefits are likely due to the activation of the TGR5/cAMP/PKA axis. As such, INT-777, together with other TGR5 agonists, may hold great therapeutic potential for treating peripheral nerve injury."

Journal

Secondary bile acid lithocholic acid attenuates neurally evoked ion transport in the rat distal colon. (PubMed, Biomed Res) - "The bile acid receptor TGR5 agonist INT-777 mimicked the LCA-induced inhibitory action...These results suggest that LCA inhibits neurally evoked Cl/HCO secretion through the activation of TGR5 on L cells and cholinergic- and VIP-secretomotor neurons in the submucosal plexus. Furthermore, the inhibitory mechanism may involve TGR5-stimulated PYY release from L cells and Y2R activation in VIP-secretomotor neurons."

Journal • Preclinical

Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis. (PubMed, Int J Mol Sci) - "Here, we investigated the potential role of TGR5 within Leydig cells using cell culture approaches combined with pharmacological exposure to the TGR5 agonist INT-777...In conclusion, the present work highlights the impact of the TGR5 signaling pathway on testosterone production and reinforces the links between bile acid signaling pathways and the testicular endocrine function. The testicular bile acid pathways need to be further explored to increase our knowledge of pathologies associated with impaired testicular endocrine function, such as fertility disorders."

Journal • Infertility • Sexual Disorders

Bile acids after bariatric surgery: a gateway to mitochondrial activation in human adipocytes (EASD 2022) - P=N/A | "Additionally, we examined mitochondrial activation in human primary preadipocytes treated during differentiation with an agonist (INT-777) targeting TGR5 BA-receptor and with DCA, a secondary BA, by cell respiration (Seahorse extracellular flux analyzer), mtDNA mass and mitochondrial transcripts (COX1, ND5, 12S-RNA; mean±SE)... Weight loss by surgery leads to increased levels of postprandial total, primary, conjugated, hydrophobic, non-hydroxylated and fasting BAs. AT shows signs of increased mitochondrial biogenesis after the surgery. Compounds mimicking the effects of BAs and TGR5 inducers in human adipocytes may have potential as mitochondrial activators."

Obesity

A new role of endoplasmic reticulum-mitochondria calcium coupling in nutrient-induced Glucagon-Like Peptide 1 (GLP-1) secretion by L cells (EASD 2022) - "Concerning DCA, its effect on MAMs is mediated through the TGR5-cAMP-PKA (Protein Kinase A) pathway as INT-777 (TGR5 agonist, 30µmol/l) and forskolin (cAMP formation inducer, 10 µmol/l) mimicked DCA effects on both contacts and secretion when H89 (PKA inhibitor, 10 µmol/l) prevented them... Altogether, these results demonstrate a new role of ER-mitochondria calcium coupling in nutrient-induced GLP-1 secretion in L cells. The signalling pathways involved in the regulation of MAMs vary between nutrients, with an electrogenic effect for glucose and an effect mediated through TGR5-cAMP-PKA pathway for DCA. Confirmation of these data in more physiological models is currently underway."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • STC1

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats. (PubMed, World J Gastroenterol) - "DJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB."

Journal • Preclinical • Diabetes • Metabolic Disorders • SIRT1

GPBAR1 preserves neurite and synapse of dopaminergic neurons via RAD21-OPCML signaling: role in preventing Parkinson's disease in mouse model and human patients. (PubMed, Pharmacol Res) - "Genetic downregulation of Gpbar1 in mouse mesencephalic DA neurons exacerbated MPTP-induced neurobehavioral and neuropathological deficits, whereas activation of central GPBAR1 with INT-777 (INT) relieved it...This neuroprotection, at least in part, is attributed to the RAD21-OPCML signaling in neurons. Hence, GPBAR1 may serve as a promising candidate target for PD treatment."

Journal • Preclinical • CNS Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • RAD21

The Bile Acid Membrane Receptor TGR5 in Cancer: Friend or Foe? (PubMed, Molecules) - "Several recent studies have demonstrated that TGR5 exerts inconsistent effects in different cancer cells upon activating via TGR5 agonists, such as INT-777, ursodeoxycholic acid (UDCA), and taurolithocholic acid (TLCA). In this review, we discuss both the 'friend' and 'foe' features of TGR5 by summarizing its tumor-suppressing and oncogenic functions and mechanisms."

Journal • Review • Biliary Cancer • Immunology • Inflammation • Oncology • RHOA • STAT3

Lithocholic acid inhibits dendritic cell activation by reducing intracellular glutathione via TGR5 signaling. (PubMed, Int J Biol Sci) - "In addition, LCA or INT-777 treatment increases the TGR5 expression in monocyte-derived dendritic cells (MD-DCs) of patients with active BD, whereas both LCA and TGR5 agonists inhibit the activation of MD-DCs. These results suggest that LCA and TGR5 agonists might be potential therapeutic drugs for the treatment of autoimmune uveitis."

Journal • Immunology • Ocular Inflammation • Ophthalmology • Uveitis • ITGAX

Structural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity. (PubMed, Proc Natl Acad Sci U S A) - "Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo...In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits."

Journal • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor