Tauroursodeoxycholic acid (TUDCA) is neuroprotective in a chronic mouse model of Parkinson’s disease

Cuevas, Elvis; Burks, Susan M.; Raymick, James; Robinson, Bonnie; Gómez-Crisóstomo, Nancy Patricia; Escudero‐Lourdes, Claudia; Lopez, A.; Chigurupati, Srinivasulu; Hanig, Joseph P.; Ferguson, Sherry; Sarkar, Sumit

doi:10.1080/1028415x.2020.1859729

Cited by 30 publications

(22 citation statements)

References 55 publications

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“…Specifically, altered bile acid profiles were associated with cognitive impairment in Alzheimer’s and Parkinson’s disease ( MahmoudianDehkordi et al, 2019 ; Baloni et al, 2020 ; Li et al, 2021 ). Bile acid administration, particularly that of TUDCA and UDCA, contributed to neurologic symptom improvements in animal models of Alzheimer’s, Parkinson’s, and Huntington disease ( Keene et al, 2002 ; Lo et al, 2013 ; Cuevas et al, 2020 ). However, bile acid metabolism in depression has rarely been described.…”

Section: Discussionmentioning

confidence: 99%

Gut Microbiota-Mediated Elevated Production of Secondary Bile Acids in Chronic Unpredictable Mild Stress

Zhao

et al. 2022

Front. Pharmacol.

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A growing body of evidence suggests that gut microbiota could participate in the progression of depression via the microbiota–gut–brain axis. However, the detailed microbial metabolic profile changes in the progression of depression is still not fully elucidated. In this study, a liquid chromatography coupled to mass spectrometry-based untargeted serum high-throughput metabolomics method was first performed to screen for potential biomarkers in a depressive-like state in a chronic unpredictable mild stress (CUMS)-induced mouse model. Our results identified that the bile acid and energy metabolism pathways were significantly affected in CUMS progression. The detailed bile acid profiles were subsequently quantified in the serum, liver, and feces. The results showed that CUMS significantly promoted the deconjugation of conjugated bile acid and secondary bile acid biosynthesis. Furthermore, 16S rRNA gene sequencing revealed that the increased secondary bile acid levels in the feces positively correlated with Ruminococcaceae_UCG-010, Ruminococcus, and Clostridia_UCG-014 abundance. Taken together, our study suggested that changes in family Ruminococcaceae abundance following chronic stress increased biosynthesis of deoxycholic acid (DCA), a unconjugated secondary bile acid in the intestine. Aberrant activation of secondary bile acid biosynthesis pathway thereby increased the hydrophobicity of the bile acid pool, which might, in turn, promoted metabolic disturbances and disease progression in CUMS mice.

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Section: Discussionmentioning

confidence: 99%

Gut Microbiota-Mediated Elevated Production of Secondary Bile Acids in Chronic Unpredictable Mild Stress

Zhao

et al. 2022

Front. Pharmacol.

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“…In a chronic PD mouse model, pretreatment with tauroursodeoxycholic acid can protect against dopaminergic neuronal damage, prevent microglial and astroglial activation, as well as the dopamine and 3-4dihydroxyphenulacetic acid reductions caused by MPTP. Pretreatment with tauroursodeoxycholic acid can prevent protein oxidation and autophagy, in addition to inhibiting asynuclein aggregation (77). This finding suggests that fecal biliary abnormalities may also play a crucial role in PD pathogenesis, and targeting microbial-derived secondary bile acids may be a new avenue for the earlier PD diagnosis and alleviation of PD symptoms.…”

Section: Altered Gut Microbiota Functions In Pdmentioning

confidence: 94%

Gut Microbiota: A Novel Therapeutic Target for Parkinson’s Disease

Zhu

Liu

et al. 2022

Front. Immunol.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by motor dysfunction. Growing evidence has demonstrated that gut dysbiosis is involved in the occurrence, development and progression of PD. Numerous clinical trials have identified the characteristics of the changed gut microbiota profiles, and preclinical studies in PD animal models have indicated that gut dysbiosis can influence the progression and onset of PD via increasing intestinal permeability, aggravating neuroinflammation, aggregating abnormal levels of α-synuclein fibrils, increasing oxidative stress, and decreasing neurotransmitter production. The gut microbiota can be considered promising diagnostic and therapeutic targets for PD, which can be regulated by probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, diet modifications, and Chinese medicine. This review summarizes the recent studies in PD-associated gut microbiota profiles and functions, the potential roles, and mechanisms of gut microbiota in PD, and gut microbiota-targeted interventions for PD. Deciphering the underlying roles and mechanisms of the PD-associated gut microbiota will help interpret the pathogenesis of PD from new perspectives and elucidate novel therapeutic strategies for PD.

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“…Fusion between lysosomes and autophagosomes is a key step in the progression of autophagy. Two studies reported that TUDCA decreased autophagy and protein levels of LAMP1 in both TGF-β1 treated fibroblasts and in a mouse model of Parkinson’s Disease (50, 51). TUDCA may attenuate autophagy caused by C. difficile toxins, although further proteomic and phenotypic analyses are needed to pinpoint the direct mechanism between TUDCA and these pathways.…”

Section: Discussionmentioning

confidence: 99%

Tauroursodeoxycholic acid inhibits Clostridioides difficile toxin induced apoptosis

Pike

Tam

Melnyk

et al. 2022

Preprint

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C. difficile infection (CDI) is a highly inflammatory disease mediated by the production of two large toxins that weaken the intestinal epithelium and cause extensive colonic tissue damage. Antibiotic alternative therapies for CDI are urgently needed as current antibiotic regimens prolong the perturbation of the microbiota and lead to high disease recurrence rates. Inflammation is more closely correlated with CDI severity than bacterial burden, thus therapies that target the host response represent a promising yet unexplored strategy for treating CDI. Intestinal bile acids are key regulators of gut physiology that exert cytoprotective roles in cellular stress, inflammation and barrier integrity, yet the dynamics between bile acids and host cellular processes during CDI have not been investigated. Here we show that several bile acids are protective against apoptosis caused by C. difficile toxins in Caco-2 cells and that protection is dependent on conjugation. Out of 20 tested bile acids, taurine conjugated ursodeoxycholic acid (TUDCA) was the most potent inhibitor yet unconjugated UDCA did not alter toxin-induced apoptosis. TUDCA treatment decreased expression of genes in lysosome associated and cytokine signaling pathways. TUDCA did not affect C. difficile growth or toxin activity in vitro whereas UDCA significantly reduced toxin activity in a Vero cell assay and decreased tcdA gene expression. These results demonstrate that bile acid conjugation can have profound effects on C. difficile as well as the host and that conjugated and unconjugated bile acids may exert different therapeutic mechanisms against CDI.

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Tauroursodeoxycholic acid (TUDCA) is neuroprotective in a chronic mouse model of Parkinson’s disease

Cited by 30 publications

References 55 publications

Gut Microbiota-Mediated Elevated Production of Secondary Bile Acids in Chronic Unpredictable Mild Stress

Gut Microbiota-Mediated Elevated Production of Secondary Bile Acids in Chronic Unpredictable Mild Stress

Gut Microbiota: A Novel Therapeutic Target for Parkinson’s Disease

Tauroursodeoxycholic acid inhibits Clostridioides difficile toxin induced apoptosis

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