Cholecystectomy in mice (removal of gallbladder) negatively affected colonic microflora and increased levels of TUDCA, resulting in increased colon cancer. Is TUDCA part of the cause, or just an innocent bystander? I don’t have time to dig into the full paper at the moment.
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Would it be known after decades of use if UDCA increased cancer risk? If so, is UDCA safer than TUDCA?
On that topic these two papers might also help:
TUDCA is a taurine-conjugated bile acid with therapeutic properties.
TUDCA inhibits glucagon secretion from mouse pancreatic islets and αTC1-9 cells.
These effects involve the sphingosine-1-phosphate receptor 2 and the PI3K pathway.
TUDCA modulates KATP channel activity and Ca2+ signaling in pancreatic α-cells.
These findings extend the repertoire of TUDCA actions to pancreatic α-cell function.
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Indian paper, mentions indoles as well @John_Hemming:
The human gut microbiome produces a diverse range of metabolites that play critical roles in maintaining health and contributing to disease states. This review evaluates the therapeutic potential and characterization of gut-derived metabolites, emphasizing advanced extraction techniques, ligand-based drug design strategies, chemical-protein interaction (CPI) networks and molecular docking simulations for promising gut metabolites. The efficacy of various extraction methodologies such as Liquid Chromatography-Mass Spectrometry (LC-MS), Gas Chromatography-Mass Spectrometry (GC-MS), Liquid Chromatography-Magnetic Resonance (LC-MR), solvent extraction, solid-phase extraction, and microwave-assisted extraction is critically assessed for isolating bioactive compounds. Besides, Structure-Activity Relationship (SAR), pharmacophore modeling and machine learning-based tools are used to analyze the potential therapeutic role of gut metabolites. CPI network analysis found that ABCB11 had 11 human-gene interactions which is the highest. Cytochrome P450 family 7 subfamily A member 1 (CYP7A1) ranked second with 7 interactions. The results of binding studies proved that Ursodeoxycholic acid (UDCA) had the highest binding affinity, reaching energies from -6 to -8.3 kcal/mol and Tauroursodeoxycholic acid (TUDCA) displayed lower but still strong affinities of -6.9 to -7.7 kcal/mol. It becomes clear from these findings that bile acids and indole derivatives strongly affect protein activities, explaining one way gut metabolites shape health.
But… which proteins did they look at?!
Old paper, cell model, but interesting as these are patient-derived fibroblasts from sporadic (not genetic) AD:
Sporadic and PSEN1 fibroblasts share a changed mitochondrial phenotype.
This phenotype consists of reduced membrane potential and altered morphology.
Ursodeoxycholic acid corrects mitochondrial morphology and membrane potential.
Ursodeoxycholic acid effects act via action on Drp1 quantity and localization.
This paper highlights the potential use of UDCA to treat Alzheimer’s disease.
Good effect on MMP @John_Hemming:
Treatment with UDCA also increased MMP (controls 2.1 ± 1.6, sAD 11.2 ± 2, PSEN1 24.7 ± 1.5; p < 0.05; Fig. 3A). This increase varied across AD fibroblast lines with an increase in mitochondrial membrane potential of between 12% and 28% (Fig. 3A).
By the way, I switched from TUDCA to UDCA and I’m feeling way better on UDCA. I then increased my UDCA dose to 1 g/day. There’s also more data on UDCA regarding safety so I prefer using it.
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Unfortunately UDCA is prescription-only in the USA, while TUDCA is over the counter.
It’s also an Rx drug in Europe. That’s why I prefer it to TUDCA: more quality control and safer supply chains for regulated drugs than supplements. Fairly cheap here. Is it that hard to get it in the US?
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One of my colleagues prescribed it for me off-label after I had a retinal detachment, since there’s a study showing it can improve outcomes from that, but otherwise it might be a challenge to find a good reason for a health care provider to prescribe it since it only has specific indications that don’t include disease prevention.
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Ah OK that’s pretty bad. I think in Europe you can prescribe something without an indication. Or at least most pharmacies don’t check the indication. In some countries (e.g. Turkey or UAE) pharmacies don’t even ask for a prescription so you can get whatever you want (at least for “normal” drugs, o assume they check when someone asks for morphine…).
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Treatment of acyl-CoA oxidase 2 deficiency with ursodeoxycholic acid is discussed.
In ACOX2 deficiency there is evidence that liver disease may be improved by treatment with UDCA. UDCA does not inhibit the rate-limiting steps in bile acid synthesis but has unique choleretic properties that may improve bile flow when the production of conjugates of CDCA and CA is reduced.
Relevant @John_Hemming?
- AMX0035: sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]
- PSP: a Parkinsonian disorder that is different from Parkinson’s disease
It may link to ACBP, but I don’t know. I presume it is longer chain acyl groups.
More good news for UDCA?
Metabolomics reveals that influenza virus infection significantly reduced the concentrations of secondary bile acid (BA) in feces at 7 post-infection (dpi). Oral administration of B. dorei increased bile salt hydrolase (BSH) activity and restored the BA metabolism, thereby protecting wild-type but not TGR5-deficient mice from influenza virus infection. B.dorei-mediated TGR5 activation inhibited influenza virus-induced lung inflammation via cAMP-PKA pathway. Supplementing exogenous Ursodeoxycholic acid (UDCA) and Hyodeoxycholic acid (HDCA), two metabolites changed dramatically after B. dorei treatment, reproduced the protective effect of B. dorei.
UDCA and HDCA alleviate the severity of influenza infection
To explore whether UDCA or HDCA alone was sufficient to protect against influenza infection, the mice were also administered orally with UDCA or HDCA, as described previously. The results showed that UDCA slightly reduced weight loss, but significantly decreased lung index, protected the intestine, and inhibited viral replication at 7 dpi. HDCA dramatically reduced weight loss and lung index. No statistically significant differences were observed in colon shortening or M1 gene expression with HDCA treatment (Fig. 6A-D). Both UDCA and HDCA reduced inflammatory cell infiltration in lung tissue and the number of nucleated cells in BALF, which increased significantly after lung injury (Fig. 6E-F). As expected, UDCA and HDCA reduced the secretion of inflammatory factors in the lung caused by influenza virus, especially IL-1β (Fig. 6G). Western blot results also confirmed the activation of TGR5-cAMP-PKA pathway and inhibition of NLRP3 inflammasome activation (Fig. 6H). The above results suggest that UDCA and HDCA may provide protection against influenza infection and relieve lung inflammation, and UDCA has better effect than HDCA.
UDCA and HDCA inhibit NLRP3 inflammasome activation via cAMP-PKA pathway
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University of Helsinki
Hallmarks of sensorineural hearing loss are elevated hearing thresholds and defects in temporal auditory processing, the former being often caused by outer hair cell (OHC) damage, and the latter by the loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons. In the well-studied CBA/CaJ mouse strain, these impairments are disconnected, IHC synaptopathy preceding OHC loss. We have investigated the relationship between IHC synaptopathy and OHC loss in the C57BL/6J (B6) and ICR mouse strains that model accelerated age-related hearing loss. Regression analysis revealed a strong correlation between these variables across the high-to-low frequency axis of the cochlea. Using the fluorescent dye FM1–43 as a proxy for mechanotransduction (MET) in the hair-cell stereocilia bundle, we found that MET malfunction coexisted with synaptopathy in IHCs. Thus, our results suggest that a MET defect drives IHC synaptopathy in the B6 and ICR strains known to carry a missense mutation of Cadherin 23, encoding a stereocilia bundle protein. Previous data have suggested that OHC stereocilia abnormalities could trigger OHC death. Therefore, stereocilia defect could be a trigger of intracellular stress that drives both IHC synaptopathy and OHC loss. To determine whether tauroursodeoxycholic acid (TUDCA), known to target several stress signalling pathways, could influence cochlear pathology, we conducted long-term TUDCA delivery to ICR mice. TUDCA provided partial protection against IHC synaptopathy but did not prevent OHC loss. These results in two mouse models of accelerated cochlear pathology provide novel insights into the mechanisms behind age-related hearing loss.
Considering that TUDCA administration is well-tolerated in long-term use, shown in human studies as well (Parry et al., 2010, Zucchi et al., 2023), TUDCA might have potential as a pharmacotherapeutic agent against auditory synaptopathy. TUDCA might slow down ribbon synapse loss with age, like it has been shown to attenuate neurodegeneration in an animal model of spinocerebellar ataxia type 3 (Duarte-Silva et al., 2024). It could be speculated that TUDCA’s efficiency in the cochlea is better when IHC synapse loss has a slower path, like in ageing B6 mice and in humans (Wu et al., 2019). To progress to validate TUDCA’s therapeutic potential in the pathological cochlea, understanding of its mode of action is needed, including its impact on the poorly understood molecular pathways promoting ribbon synapse maintenance.
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Imperial College London + John Hopkings University: Protective effect of ursodeoxycholic acid upon the post-myocardial infarction heart 2025
Our hypothesis was that UDCA protects the post-MI failing heart against dangerous arrhythmia through its dual effect as an anti-fibrotic and anti-arrhythmic agent.
We investigated the effect of UDCA upon a 16-week post-MI rat model.
We found that chronic dietary supplementation of UDCA prevents adverse remodelling of the myocardium, maintaining function so that it was comparable to sham. UDCA attenuated the structural and functional remodelling of the LV in the MI rat heart, when monitored by echocardiogram. At 16 weeks post-surgery the LVEDd, LVESd, area at diastole and area at systole of the MI group were significantly higher than the sham group (Figure 1Ai, ii, iv and v), this corresponded with a reduction of LV ejection fraction and fractional area shortening (Figure 1Aiii and vi). UDCA-treated animals showed a significant improvement over the MI group in LVEDd, LVESd and area at systole, but not area at diastole. The UDCA-treated animals were comparable to the sham group in all parameters at 8 and 16 weeks post-MI.
Transferring our experimental data to an in silico 3D human LV model, we found that a combination of reduced arrhythmic substrate area and improved CV (two identified benefits of UDCA-treated post-MI rats) acted together to reduce arrhythmogenicity.
This study identifies that UDCA is anti-fibrotic and anti-arrhythmic in post-MI rat. We found that simulation of UDCA treatment on a human model reduced the occurrence of VT. This indicates that UDCA is a candidate treatment for the prevention of post-MI HF (& arrhythmia) through anti-fibrotic and anti-arrhythmic effects.
Oral Ursodeoxycholic Acid Is Associated With Decreased Rate of AMD 2025
A total of 5,863 patients taking UDCA and 17,164 matched controls were analyzed. In both cohorts after IPTW, roughly 56% of patients had cholelithiasis, 16% had cholecystitis, and 28% had cholecystectomy. Age and sex were balanced at baseline between cohorts (UDCA: 70.5 ± 9.54 years old and 58.6% female; controls: 70.3 ± 9.59 years old and 57.4% female). In the UDCA cohort, 384/5,705 (6.74%) were diagnosed with AMD. In the control cohort, 1,559/17,322 (9.00%) were diagnosed with AMD. This corresponded to a significantly decreased hazard of AMD (adjusted hazard ratio = 0.65, 95% CI: 0.58–0.74, P < 0.0001).
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Chinese preprint: PET-Microplastics Trigger Endothelial Glycocalyx Loss via ER Stress and ROS Unleashing IL-1β-Driven SMC Switching and Early Aortic Structural Impairment 2025
Polyethylene terephthalate microplastics (PET-MPs), a major microplastics component identified in human vasculature, pose emerging environmental health risks. This study systemically profiled MPs in human aortic tissues and investigated the mechanisms underlying PET-MPs-induced aortic injury in vivo and in vitro. Chronic oral exposure of Sprague-Dawley rats to PET-MPs (1.0-100 mg/L) resulted in endothelial glycocalyx loss and structural impairment of aortic elastic fibers, with MPs accumulating within aortic endothelial cells. Transcriptomic and biochemical analyses revealed that PET-MPs triggered endoplasmic reticulum stress (ERS) and reactive oxygen species (ROS) generation in human aortic endothelial cells (HAECs), driving glycocalyx degradation and NF-κB-mediated inflammation. Proteomic profiling identified endothelial-derived IL-1β as a key mediator, which subsequently induced phenotypic switching in human aortic smooth muscle cells (HASMCs) in vitro. Pharmacological inhibition of ERS (TUDCA), ROS (NAC), or IL-1β (Canakinumab) attenuated this pathogenic cascade. Crucially, restoration of the glycocalyx using Sulodexide mitigated endothelial dysfunction and downstream HASMC phenotypic switching. These findings establish endothelial glycocalyx degradation via ERS-ROS as a novel mechanism for PET-MPs-induced vascular injury and highlight glycocalyx protection as a potential strategy against environmental microplastic hazards.
ROS not only poses a direct threat to glycocalyx but also enhances its proteolysis by activating matrix metalloproteinases (MMPs) and inactivating endogenous protease inhibitors.(29, 30) Furthermore, existing literature reports that ER stress accompanies vascular calcification in mice and rats.(54, 55) NAC is a broad-spectrum antioxidant that directly scavenges ROS and enhances glutathione synthesis, while TUDCA inhibits the source of ER stress by blocking PERK/IRE1 pathway activation, thereby indirectly alleviating ER oxidative stress. Following treatment with TUDCA or NAC, PET-MPs-induced endothelial glycocalyx damage was significantly mitigated. This indicates that, distinct from factors like inflammation or mechanical stress dysregulation, PET-MPs elevate ROS by inducing ER oxidative stress, subsequently damaging the endothelial glycocalyx via oxidative stress. Notably, the inhibitory effect of TUDCA surpassed that of NAC, suggesting that ER oxidative stress may be the primary trigger for endothelial glycocalyx disruption.
@AlexKChen: TUDCA to protect from microplastics’ harm?
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Another weird paper on plasticizer and UDCA: Ursodeoxycholic Acid Attenuates B Cell Susceptibility to SARS-CoV-2 Spike Protein by Interfering Its Binding to ACE2
B cells are essential for the defense against various infectious agents including severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) causing coronavirus disease 2019 (COVID-19). COVID-19 is caused by interaction of the spike protein (SP) with the receptor-binding domain (RBD) and its receptor, angiotensin converting enzyme 2 (ACE2). Bisphenol A (BPA), a plasticizer and endocrine-disrupting chemical, can enter the human body through several exposure routes. Previously, we reported human B cell death by BPA treatment via autophagy induction. Here, we investigated whether the exposure to BPA affects B cell susceptibility to SP of COVID-19 and how to interfere the interaction of SP and ACE2. We observed an increase in ACE2 gene expression in human B cells by BPA treatment and more SP binding in BPA-treated B cells. Our data also showed more B cell death accompanying increased autophagic puncta count and lysosomal intracellular activity by co-treatment with BPA and SP compared to those in BPA treatment alone. Ursodeoxycholic acid (UDCA) reduced SP binding in B cells in BPA-exposed B cells. UDCA treatment also inhibited B cell death and lysosomal enzyme activity which were enhanced by co-treatment of BPA and SP. Taken together, results demonstrate that BPA-exposed B cells are more susceptible to COVID-19. It also suggests that UDCA could be protective to SP-responding B cells exposed to BPA.
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UDCA/TUDCA continue to amaze me with their potential health benefits. I’ve recently stopped my SGLT2i because it was elevating my hematocrit too much when combined with TRT, but the anti-fibrotic/anti-arrhythmic potential of TUDCA gives me hope that I’m still getting some similar benefits (albeit via different mechanisms) without the hematocrit elevation. 
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Another benefit of UDCA @Davin8r:
I read this paper back then but didn’t pay attention to UDCA: Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner 2025
Highlights
- Statin alters gut microbiota and dysregulates bile acid metabolism and glucose homeostasis
- Statin causes dysregulated gut microbiota and decrease of the genus Clostridium
- Decreased Clostridium-rich microbiota after statin inhibits HSDH and lowers UDCA
- Transplanting Clostridium sp. or supplying UDCA ameliorates statin-induced hyperglycemia
Summary
Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy.
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Interesting! I wish they’d also tested TUDCA…
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