Trending
By Devin Miles, ND and Elizabeth Sutherland, ND
Emerging research highlights TUDCA’s potential to reduce neuroinflammation, prevent cell death, and mitigate the effects of metabolic dysfunction in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis.
Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, is gaining attention for its neuroprotective properties. This article explores TUDCA’s mechanisms of action, including its ability to reduce endoplasmic reticulum stress, inhibit apoptosis, and cross the blood-brain barrier, offering potential therapeutic benefits for neurodegenerative conditions.
Tauroursodeoxycholic acid (TUDCA) is one of the most hydrophilic bile acids.1 It is synthesized in hepatocytes by the conjugation of ursodeoxycholic acid (UDCA) with the amino acid taurine. UDCA, which is made by gut bacteria, is FDA-approved in the United States for the treatment of certain cholestatic liver diseases.Â
Humans make TUDCA to some extent, but it is found in copious amounts in the bile of bears. It’s fascinating, therefore, to note that bear bile has been used therapeutically in Chinese Medicine for centuries.
TUDCA is classified as a chemical chaperone.2 Chemical chaperones are naturally occurring substances that are able to correct inappropriately localized or aggregated proteins in the endoplasmic reticulum (ER) by stabilizing a protein’s structure and facilitating its folding process.3 If this process becomes deranged, as can happen during oxidative stress, it signals an ER stress response, which is associated with reduced protein synthesis, malfunction of the unfolded protein response, and, finally, cell death.4 TUDCA attenuates the ER stress response, inhibits cell death, and preserves cellular function.5
Brachial artery flow-mediated dilation (FMD) was measured at baseline, and at 60 and 120 min after an oral glucose challenge in 12 young healthy subjects (seven men, five women). Subjects were tested twice after oral ingestion of TUDCA or placebo capsules. FMD was reduced from baseline during hyperglycemia under placebo (-32% at 60 min and -28% at 120 min post oral glucose load; P<0.05 from baseline) but not with TUDCA ingestion (-4% at 60 min and +0.3% at 120 min post oral glucose load; P>0.05 from baseline). Thus, postprandial hyperglycemia may cause endothelial dysfunction through ER stress, and hyperglycemia-induced endothelial dysfunction may be mitigated by TUDCA ingestion.6
Bile acids are an important aid to lipid absorption in the intestines,2 and in regulating cholesterol homeostasis.7 Cholesterol and related lipid molecules are critical components of myelin, and neuronal and glial cell membranes.8,9
Given that bile acids play a key role in regulating lipid and glucose metabolism,10Â and that epidemiological studies have identified metabolic syndrome as an independent risk factor for neurodegenerative disorders, the signaling pathways of bile acids, such as TUDCA, are being studied for their therapeutic potential.1
Studies are pointing to the possibility that neurodegenerative diseases may also originate from early life movements and trauma, as well as worsening with age. Neurological dysfunction occurring during middle-aged and elderly years can significantly decrease quality of life. With Alzheimer’s disease (AD) expected to continue with a rise in life expectancy, there is a pressing need to find effective treatments.11 Furthermore, evidence continues to support a strong correlation between metabolic disorders and AD. Disturbances in insulin resistance and lipid metabolism are considered potential risk factors for AD.
Aging has been associated with insulin resistance and hyperinsulinemia, contributing to the prevalence of Type 2 Diabetes. In 18 mo old mice models (considered old mice), TUDCA was shown to reduce body weight, adiposity, and liver lipid accumulations, as well as improve glucose tolerance, insulin sensitivity, and insulin clearance. TUDCA also reversed age-related memory loss in these mouse models.12
The greatest risk factor by far for neurodegenerative disorders is aging. The aging process has wide-spread effects, including potentially disrupting the gut microbiome-brain axis. Diminished bioavailability of microbial metabolites, like secondary bile acids and short-chain fatty acids –which have immunoregulatory properties – can lead to persistent inflammation; gut mucosal thinning; and reduced microbiome diversity and stability.13,14,15 Bile acid-mediated signaling is likely bidirectional within the gut microbiome-brain axis to modulate metabolic status and cholesterol balance centrally. Dysregulation of homeostasis in this pathway has been associated with neurodegenerative conditions. For example, high levels of secondary bile acids are found in the neurodegenerating brain, possibly due to increased bile acid production by a disordered microbiome. Increased levels of bile acids in systemic circulation can also adversely affect blood-brain barrier permeability.16
Serum levels of 15 primary and secondary bile acids were measured in 1464 subjects: 24% of subjects were healthy adults with normal cognitive function; approximately 19% had early mild cognitive impairment; 34% had late mild cognitive impairment; and 21% were diagnosed with AD. Significantly lower serum concentrations of cholic acid (CA), a primary bile acid, and higher levels of the bacterially produced, secondary bile acid, deoxycholic acid, were found in AD subjects compared to cognitively normal adults. An increased deoxycholic acid:CA ratio, mediated by gut bacteria, is associated with cognitive decline. This study encourages more research into the role of gut dysbiosis in the pathogenesis of AD.17
Hydrophilic bile acids, in particular TUDCA, are able to cross the blood–brain barrier. They can act as bile acid receptor agonists and appear to confer neuroprotective effects.18,19
TUDCA has been shown to have neuroprotective effects by inhibiting cell death in several neurodegenerative conditions that are characterized by dysregulations in apoptosis, for example, Alzheimer’s disease,20,21,22,23Â Parkinson’s disease,24Â Huntington’s disease,25,26Â and amyotrophic lateral sclerosis.27Â The mechanisms of action that underlie the anti-apoptotic properties of TUDCA include its ability to:
A 2020 study found that adult and pediatric patients with multiple sclerosis (MS) had lower levels of circulating bile acid metabolites when compared with controls. Alterations in bile acid metabolite levels were most pronounced in adults with progressive forms of MS. Receptors for bile acids were also noted on immune and glial cells in the white matter brain lesions of post-mortem human tissue samples. In an in vitro experiment, TUDCA was found to prevent expression of the neurotoxic phenotype of astrocytes and the proinflammatory phenotype of microglia in a dose-dependent manner. Activated astrocytes and microglia are known to play important roles in MS pathophysiology, especially in the progressive phase. It is possible that reduced signaling through bile acid receptors is associated with increased neuroinflammation. Supplementation with TUDCA in an animal model of MS improved signs of neuropathology and reduced disease severity.30
Markers for dopaminergic function, neuroinflammation, oxidative stress and autophagy were assessed in a progressive mouse model of Parkinson’s disease. Pretreatment with TUDCA alleviated dopaminergic neuronal damage, attenuated microglial and astroglial activation, and prevented dopamine and DOPAC (3-4-dihydroxyphenulacetic acid – a metabolite of dopamine31) reductions, and reduced protein oxidation and autophagy.32
Bile acids can be absorbed into circulation and have systemic effects.2 TUDCA has extensive therapeutic benefits beyond the hepatobiliary system in, for example, inflammatory metabolic disorders such as atherosclerosis, diabetes, and renal disease.33
Although considered a vascular disease, reports of diabetic retinopathy have shown that retinal neurons are also affected. TUDCA was shown to notably reduce cell death in cultured retinal neural cells affected by increased glucose concentration, prevented mitochondrial and nuclear release of apoptosis-inducing factor (AIF), and reduced oxidative stress biomarkers.34
Tail vein injection of TUDCA-treated CKD-hMSCs in a CKD murine hindlimb ischemia model led to improvements in blood perfusion ratio, blood vessel formation, kidney recovery, and limb salvage, suggesting a promising new intervention that addresses cardiovascular problems and CKD in patients.35
Orally ingested TUDCA is able to cross the blood-brain barrier to reach neuronal tissue and to prevent cell death.36Â Though further human studies need to be conducted, evidence continues to mount in support of its potential clinical application as part of a therapeutic approach to the treatment of neuroinflammatory and neurodegenerative conditions.
Dr. Elizabeth (Liz) Sutherland began her undergraduate degree at the University of Cambridge in Classics and finished it at Tufts University with a BS in Biopsychology. She earned her doctorate in naturopathic medicine (ND) from National University of Natural Medicine (NUNM), in Portland, OR, after which she completed post-doctoral research fellowships at the Kaiser Permanente Northwest (KPNW) Center for Health Research (where she subsequently became the first KPNW Research Associate to hold an ND degree) and the University of Arizona College of Medicine. She also earned a Certificate in Human Investigations for clinical trials at Oregon Health and Science University. Dr. Sutherland has served as co-investigator on a number of NIH-funded studies and is primary author or co-author on multiple peer-reviewed publications. She was Chair of the Institutional Review Board at NUNM, and also taught and redesigned the Mind-Body medicine curriculum. Currently, Dr. Sutherland serves as Vice President of Continuing Education Compliance for AARM, and editor in chief of the Journal of Restorative Medicine. In addition, she helps physicians and scientists from several wellness and medical disciplines write grant proposals, books, and manuscripts for submission to academic journals.
Dr. Miles is a clinician who provides integrative and natural approaches to kidney function, cardiovascular health, digestion, autoimmunity, and prevention. She graduated from Sonoran University of Health Sciences (previously Southwest College of Naturopathic Medicine) in Arizona. She enjoys educating patients via social media, webinars, and in-person presentations and has been interviewed in various podcasts and radio shows. Dr. Miles has also launched an online course sharing natural support for kidney and blood pressure health. She is a medical writer and has written for traditional, integrative, naturopathic, and functional medicine sources. Dr. Miles is a Medical Advisor for Restorative Formulations.
References
By Devin Miles, ND and Elizabeth Sutherland, ND
Emerging research highlights TUDCA’s potential to reduce neuroinflammation, prevent cell death, and mitigate the effects of metabolic dysfunction in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis.
Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, is gaining attention for its neuroprotective properties. This article explores TUDCA’s mechanisms of action, including its ability to reduce endoplasmic reticulum stress, inhibit apoptosis, and cross the blood-brain barrier, offering potential therapeutic benefits for neurodegenerative conditions.
Tauroursodeoxycholic acid (TUDCA) is one of the most hydrophilic bile acids.1 It is synthesized in hepatocytes by the conjugation of ursodeoxycholic acid (UDCA) with the amino acid taurine. UDCA, which is made by gut bacteria, is FDA-approved in the United States for the treatment of certain cholestatic liver diseases.Â
Humans make TUDCA to some extent, but it is found in copious amounts in the bile of bears. It’s fascinating, therefore, to note that bear bile has been used therapeutically in Chinese Medicine for centuries.
TUDCA is classified as a chemical chaperone.2 Chemical chaperones are naturally occurring substances that are able to correct inappropriately localized or aggregated proteins in the endoplasmic reticulum (ER) by stabilizing a protein’s structure and facilitating its folding process.3 If this process becomes deranged, as can happen during oxidative stress, it signals an ER stress response, which is associated with reduced protein synthesis, malfunction of the unfolded protein response, and, finally, cell death.4 TUDCA attenuates the ER stress response, inhibits cell death, and preserves cellular function.5
Brachial artery flow-mediated dilation (FMD) was measured at baseline, and at 60 and 120 min after an oral glucose challenge in 12 young healthy subjects (seven men, five women). Subjects were tested twice after oral ingestion of TUDCA or placebo capsules. FMD was reduced from baseline during hyperglycemia under placebo (-32% at 60 min and -28% at 120 min post oral glucose load; P<0.05 from baseline) but not with TUDCA ingestion (-4% at 60 min and +0.3% at 120 min post oral glucose load; P>0.05 from baseline). Thus, postprandial hyperglycemia may cause endothelial dysfunction through ER stress, and hyperglycemia-induced endothelial dysfunction may be mitigated by TUDCA ingestion.6
Bile acids are an important aid to lipid absorption in the intestines,2 and in regulating cholesterol homeostasis.7 Cholesterol and related lipid molecules are critical components of myelin, and neuronal and glial cell membranes.8,9
Given that bile acids play a key role in regulating lipid and glucose metabolism,10Â and that epidemiological studies have identified metabolic syndrome as an independent risk factor for neurodegenerative disorders, the signaling pathways of bile acids, such as TUDCA, are being studied for their therapeutic potential.1
Studies are pointing to the possibility that neurodegenerative diseases may also originate from early life movements and trauma, as well as worsening with age. Neurological dysfunction occurring during middle-aged and elderly years can significantly decrease quality of life. With Alzheimer’s disease (AD) expected to continue with a rise in life expectancy, there is a pressing need to find effective treatments.11 Furthermore, evidence continues to support a strong correlation between metabolic disorders and AD. Disturbances in insulin resistance and lipid metabolism are considered potential risk factors for AD.
Aging has been associated with insulin resistance and hyperinsulinemia, contributing to the prevalence of Type 2 Diabetes. In 18 mo old mice models (considered old mice), TUDCA was shown to reduce body weight, adiposity, and liver lipid accumulations, as well as improve glucose tolerance, insulin sensitivity, and insulin clearance. TUDCA also reversed age-related memory loss in these mouse models.12
The greatest risk factor by far for neurodegenerative disorders is aging. The aging process has wide-spread effects, including potentially disrupting the gut microbiome-brain axis. Diminished bioavailability of microbial metabolites, like secondary bile acids and short-chain fatty acids –which have immunoregulatory properties – can lead to persistent inflammation; gut mucosal thinning; and reduced microbiome diversity and stability.13,14,15 Bile acid-mediated signaling is likely bidirectional within the gut microbiome-brain axis to modulate metabolic status and cholesterol balance centrally. Dysregulation of homeostasis in this pathway has been associated with neurodegenerative conditions. For example, high levels of secondary bile acids are found in the neurodegenerating brain, possibly due to increased bile acid production by a disordered microbiome. Increased levels of bile acids in systemic circulation can also adversely affect blood-brain barrier permeability.16
Serum levels of 15 primary and secondary bile acids were measured in 1464 subjects: 24% of subjects were healthy adults with normal cognitive function; approximately 19% had early mild cognitive impairment; 34% had late mild cognitive impairment; and 21% were diagnosed with AD. Significantly lower serum concentrations of cholic acid (CA), a primary bile acid, and higher levels of the bacterially produced, secondary bile acid, deoxycholic acid, were found in AD subjects compared to cognitively normal adults. An increased deoxycholic acid:CA ratio, mediated by gut bacteria, is associated with cognitive decline. This study encourages more research into the role of gut dysbiosis in the pathogenesis of AD.17
Hydrophilic bile acids, in particular TUDCA, are able to cross the blood–brain barrier. They can act as bile acid receptor agonists and appear to confer neuroprotective effects.18,19
TUDCA has been shown to have neuroprotective effects by inhibiting cell death in several neurodegenerative conditions that are characterized by dysregulations in apoptosis, for example, Alzheimer’s disease,20,21,22,23Â Parkinson’s disease,24Â Huntington’s disease,25,26Â and amyotrophic lateral sclerosis.27Â The mechanisms of action that underlie the anti-apoptotic properties of TUDCA include its ability to:
A 2020 study found that adult and pediatric patients with multiple sclerosis (MS) had lower levels of circulating bile acid metabolites when compared with controls. Alterations in bile acid metabolite levels were most pronounced in adults with progressive forms of MS. Receptors for bile acids were also noted on immune and glial cells in the white matter brain lesions of post-mortem human tissue samples. In an in vitro experiment, TUDCA was found to prevent expression of the neurotoxic phenotype of astrocytes and the proinflammatory phenotype of microglia in a dose-dependent manner. Activated astrocytes and microglia are known to play important roles in MS pathophysiology, especially in the progressive phase. It is possible that reduced signaling through bile acid receptors is associated with increased neuroinflammation. Supplementation with TUDCA in an animal model of MS improved signs of neuropathology and reduced disease severity.30
Markers for dopaminergic function, neuroinflammation, oxidative stress and autophagy were assessed in a progressive mouse model of Parkinson’s disease. Pretreatment with TUDCA alleviated dopaminergic neuronal damage, attenuated microglial and astroglial activation, and prevented dopamine and DOPAC (3-4-dihydroxyphenulacetic acid – a metabolite of dopamine31) reductions, and reduced protein oxidation and autophagy.32
Bile acids can be absorbed into circulation and have systemic effects.2 TUDCA has extensive therapeutic benefits beyond the hepatobiliary system in, for example, inflammatory metabolic disorders such as atherosclerosis, diabetes, and renal disease.33
Although considered a vascular disease, reports of diabetic retinopathy have shown that retinal neurons are also affected. TUDCA was shown to notably reduce cell death in cultured retinal neural cells affected by increased glucose concentration, prevented mitochondrial and nuclear release of apoptosis-inducing factor (AIF), and reduced oxidative stress biomarkers.34
Tail vein injection of TUDCA-treated CKD-hMSCs in a CKD murine hindlimb ischemia model led to improvements in blood perfusion ratio, blood vessel formation, kidney recovery, and limb salvage, suggesting a promising new intervention that addresses cardiovascular problems and CKD in patients.35
Orally ingested TUDCA is able to cross the blood-brain barrier to reach neuronal tissue and to prevent cell death.36Â Though further human studies need to be conducted, evidence continues to mount in support of its potential clinical application as part of a therapeutic approach to the treatment of neuroinflammatory and neurodegenerative conditions.
Dr. Elizabeth (Liz) Sutherland began her undergraduate degree at the University of Cambridge in Classics and finished it at Tufts University with a BS in Biopsychology. She earned her doctorate in naturopathic medicine (ND) from National University of Natural Medicine (NUNM), in Portland, OR, after which she completed post-doctoral research fellowships at the Kaiser Permanente Northwest (KPNW) Center for Health Research (where she subsequently became the first KPNW Research Associate to hold an ND degree) and the University of Arizona College of Medicine. She also earned a Certificate in Human Investigations for clinical trials at Oregon Health and Science University. Dr. Sutherland has served as co-investigator on a number of NIH-funded studies and is primary author or co-author on multiple peer-reviewed publications. She was Chair of the Institutional Review Board at NUNM, and also taught and redesigned the Mind-Body medicine curriculum. Currently, Dr. Sutherland serves as Vice President of Continuing Education Compliance for AARM, and editor in chief of the Journal of Restorative Medicine. In addition, she helps physicians and scientists from several wellness and medical disciplines write grant proposals, books, and manuscripts for submission to academic journals.
Dr. Miles is a clinician who provides integrative and natural approaches to kidney function, cardiovascular health, digestion, autoimmunity, and prevention. She graduated from Sonoran University of Health Sciences (previously Southwest College of Naturopathic Medicine) in Arizona. She enjoys educating patients via social media, webinars, and in-person presentations and has been interviewed in various podcasts and radio shows. Dr. Miles has also launched an online course sharing natural support for kidney and blood pressure health. She is a medical writer and has written for traditional, integrative, naturopathic, and functional medicine sources. Dr. Miles is a Medical Advisor for Restorative Formulations.
References
It is a long established fact that a reader will be distracted by the readable content of a page when looking at its layout. The point of using Lorem Ipsum is that it has a more-or-less normal distribution of letters, as opposed to using ‘Content here, content here’, making it look like readable English. Many desktop publishing packages and web page editors now use Lorem Ipsum as their default model text, and a search for ‘lorem ipsum’ will uncover many web sites still in their infancy.
It is a long established fact that a reader will be distracted by the readable content of a page when looking at its layout. The point of using Lorem Ipsum is that it has a more-or-less normal distribution of letters, as opposed to using ‘Content here, content here’, making it look like readable English. Many desktop publishing packages and web page editors now use Lorem Ipsum as their default model text, and a search for ‘lorem ipsum’ will uncover many web sites still in their infancy.
The point of using Lorem Ipsum is that it has a more-or-less normal distribution of letters, as opposed to using ‘Content here, content here’, making
The point of using Lorem Ipsum is that it has a more-or-less normal distribution of letters, as opposed to using ‘Content here, content here’, making it look like readable English. Many desktop publishing packages and web page editors now use Lorem Ipsum as their default model text, and a search for ‘lorem ipsum’ will uncover many web sites still in their infancy.
It is a long established fact that a reader will be distracted by the readable content of a page when looking at its layout. The point of using Lorem Ipsum is that it has a more-or-less normal distribution
Copyright BlazeThemes. 2023
