Deoxycholic Acid

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.

High-fat diet (HFD) leads to systemic low-grade inflammation, which has been involved in the pathogenesis of diverse metabolic and inflammatory diseases. Colon is thought to be the first organ suffering from inflammation under HFD conditions due to the pro-inflammatory macrophages infiltration, however, the mechanisms concerning the induction of pro-inflammatory phenotype of colonic macrophages remains unclear. In this study, we show that HFD increased the percentage of gram-positive bacteria, especially genus Clostridium, and resulted in the significant increment of fecal deoxycholic acid (DCA), a gut microbial metabolite produced by bacteria mainly restricted to genus Clostridium. Notably, reducing gram-positive bacteria with vancomycin diminished fecal DCA and profoundly alleviated pro-inflammatory macrophage infiltration in colon, whereas DCA-supplemented feedings to vancomycin-treated mice provoked obvious pro-inflammatory macrophage infiltration and colonic inflammation. Meanwhile, intra-peritoneal administration of DCA also elicited considerable recruitment of macrophages with pro-inflammatory phenotype. Mechanistically, DCA dose-dependently promoted M1 macrophage polarization and pro-inflammatory cytokines production at least partially through toll-like receptor 2 (TLR2) transactivated by M2 muscarinic acetylcholine receptor (M2-mAchR)/Src pathway. In addition, M2-mAchR mediated increase of TLR2 transcription was mainly achieved via targeting AP-1 transcription factor. Moreover, NF-κB/ERK/JNK signalings downstream of TLR2 are involved in the DCA-induced macrophage polarization. In conclusion, our findings revealed that high level DCA induced by HFD may serve as an initiator to activate macrophages and drive colonic inflammation, thus offer a mechanistic basis that modulation of gut microbiota or intervening specific bile acid receptor signaling could be potential therapeutic approaches for HFD-related inflammatory diseases.

Background and aimsObesity is a global health challenge significantly increasing cardiovascular disease (CVD) burden. Effective prevention and treatment necessitate targeting early pathological changes, particularly obesity-induced endothelial dysfunction (ED). This study aimed to characterize ED heterogeneity in non-hypertensive obese (NHO) individuals, investigate the association of serum metabolites with obesity-induced ED, and identify potentially predictive and therapeutic metabolites.MethodsUtilizing wire myograph, this study assessed ED of ex vivo arterioles from omental adipose tissue of 213 NHO patients, categorized into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO). Targeted metabolomic profiling identified associations between serum metabolites and ED.ResultsObesity-induced ED in NHO patients lacked correlations with many traditional cardiovascular risk factors. The MHO and MUO individuals exhibited similar ED and metabolomic profile characteristics. Serum metabolomics identified bile acids (BAs), particularly chenodeoxycholic acid (CDCA), as negatively correlated with ED in NHO patients. Taurochenodeoxycholic acid (TCDCA), a taurine-conjugated derivative of CDCA, protected against obesity-induced ED and hypertension. Mechanistically, endothelial Farnesoid X receptor (FXR) deletion aggravated obesity-induced ED and hypertension, negating the beneficial effects of bariatric surgery or TCDCA treatment. The TCDCA-FXR activation in endothelial cells upregulated ATF4 transcription, which was suppressed by PHB1, thereby enhancing serine and one-carbon metabolism.ConclusionsThis study suggests CDCA as a promising biomarker for identification of obesity-induced ED. Taurochenodeoxycholic acid demonstrates significant therapeutic potential for alleviating various forms of obesity-induced ED. This effect is mediated by the endothelial TCDCA-FXR-PHB1-ATF4 axis, which upregulates serine and one-carbon metabolism, thereby offering a novel strategy to delay the onset of hypertension and other CVDs.