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Berberine: New Research on Mechanisms Via Which This Alkaloid May Impact Metabolic and Cardiovascular Health
http://www.townsendletter.com/May2018/berberine0518.html
Berberine, an orangish-yellow alkaloid found at high levels in the bark and root structures of plants including Oregon grape (Mahonia aquifolium), goldenseal (Hydrastis canadensis), barberry (Berberis vulgaris), and Chinese goldthread (Coptis chinensis), has a broad and wide history of use. Oregon grape, a North American source of this alkaloid, was used by the native inhabitants and European colonists in the Pacific Northwest as a blood toner, an antimicrobial, and to ease digestive distress.1 As a bitter tonic, the extract from the roots and bark of these herbs was used to stimulate digestion, while its antimicrobial properties were taken advantage of both topically and internally.2 Chinese goldthread, known as duǎn è huánglián, is one of the 50 fundamental herbs in traditional Chinese medicine,3 where its bitter and cold properties are used to influence conditions of the Heart, Large Intestine, Liver, and Stomach.
Berberine
In the digestive system, berberine exerts a multitude of actions. Berberine acts as an antimicrobial, having both a direct bactericidal effect as well as decreasing bacterial adherence to mucosal epithelial surfaces.4,5 Berberine also directly influences intestinal permeability, improving tight junction integrity.6,7 Berberine has evidence of exerting a tonifying effect on gastrointestinal motility – increasing motility and contractility in states of hypofunction, and relaxing the system when it is in an excessively contractile state.8 Berberine has an antinociceptive effect, which may be in part due to its impact on contractility, or mediated via its interactions with the endogenous opioid system,9 or via nitric oxide synthesis.10 Berberine increases the gut production of short chain fatty acids (SCFAs), in particular butyrate.11 Butyrate has an anti-inflammatory effect in the colon, which may play a role not only in digestive disorders, but neurological and metabolic conditions as well.12
Because of its low bioavailability in its non-transformed state,13 much of the research surrounding berberine has looked at the impact on the gut. The gut microbiota also plays a significant role in the absorption of berberine, as it transforms it to dihydroberberine, which has a five-fold increase in absorption over that of berberine.14 Dihydroberberine then oxidizes back to berberine in the intestinal tissue and enters the blood. One cautionary note which must be remembered in practice is that berberine, at commonly used doses, moderately inhibits cytochrome P450 3A4 (CYP3A4), CYP2D6, and CYP2C9,15,16 which may lead to increased levels of commonly used medications including lovastatin, clarithromycin, sildenafil, losartan, venlafaxine, and metoprolol, as well as many others.
Klaire LabsMetabolic Balance and Healthy Cardiovascular Function: An Akkermansia Effect?
One type of bacteria in the gut that has been shown to impact metabolic balance and cardiovascular health is Akkermansia muciniphila.This gram-negative bacteria feeds on mucin, as well as certain sugars including N-acetylglucosamine, N-acetyl-galac-to-samine, and glucose.17 Although A. muciniphila represents only a small fraction (3 to 5 percent) of the bacteria in the gut, the impact it may have on metabolism is significant. Reduced levels of A. muciniphila have been observed in patients with impaired glucose metabolism and obesity,18,19 while higher levels of the genus Akkermansia have been found in athletes and individuals with a low body mass index (BMI).20
In mice, supplementation with A. muciniphila reduced weight gain and fat mass, and improved glucose tolerance and insulin sensitivity.21 In one mouse study, excess weight due to high fat diet (HFD) feeding was reduced by more than half when supplemented with this bacterium. A. muciniphila may have this impact on metabolism by the reduction of chronic low-grade inflammation, as these changes were observed in conjunction with decreased lipopolysaccharide (LPS) signalling and increased anti-inflammatory factors such as α-tocopherol and β-sitosterol. Administration of A. muciniphila also has been shown to increase the intestinal levels of endocannabinoids, the endogenous cannabinoids produced by the body, which play a role in controlling inflammation, the gut barrier, and gut peptide secretion.22 A. muciniphila also was shown to reduce the development of atherosclerosis, improving gut tight junction integrity, and attenuating LPS-induced inflammation.23
Both metformin and berberine have been shown to increase levels of Akkermansia spp., with both treatments increasing the number of mucin-producing goblet cells that produce the substrate (mucin) that serves as food for this bacterium.24,25 Along with this finding, berberine was shown to improve HFD-induced atherosclerosis in the standard mouse model where development of atherosclerotic disease is inevitable, reducing inflammation systemically and in the atherosclerotic lesions.
Berberine and Blood Vessel Function
Endothelial dysfunction is one contributing factor that leads to increased blood pressure and cardiovascular disease. There are many different facets of dysfunction which include diminished vasodilation in response to stimulation, increased leukocyte (white blood cell) adhesion, and frequently, increased platelet activation.26 Collectively, these factors contribute to atherosclerosis and cardiovascular disease in addition to an increase in blood pressure. Endothelial dysfunction has also been observed in polycystic ovarian syndrome, migraines, and the vascular complications associated with diabetes.27-29 Increased proinflammatory cytokines and decreased adiponectin (a hormone produced by adipose tissue) levels both contribute to altered endothelial homeostasis.30
Methylation SummitBerberine increases activation of adenosine monophosphate–activated protein kinase (AMPK), a fuel-sensing enzyme that is present in all mammalian cells. When activated, AMPK stimulates energy-generating processes within the cell such as glucose uptake and decreases energy consuming processes such as lipid synthesis, reducing blood sugar and cholesterol production.31,32 AMPK is also present in the endothelial cells of the blood vessels, and promotes normal function via anticontractile, anti-inflammatory, and antiatherogenic actions.33 Consumption of a HFD contributes to endothelial dysfunction in part via downregulation of the AMPK pathway.34
Although hyperglycemia leads to endothelial dysfunction, berberine has been observed to alleviate this negative effect and promote normal vasodilation via the AMPK pathway.35 Via activation of AMPK, berberine reduces the pro-inflammatory response of macrophage foam cells, a cellular responder of the immune system which plays a role in the development of atherosclerotic plaques, to stimuli including hydrogen peroxide and LPS.36 Berberine also inhibits the release of platelet-derived growth factor (PDGF) from vascular smooth muscle cells as well as smooth muscle hypertrophy via activation of the AMPK pathway. By doing so, berberine promotes normal endothelial function and the reduction of stenosis, that is, the narrowing of blood vessels.37
Berberine also induces vaso-relaxation via endothelial-independent mechanisms similar to a calcium-channel blocker, decreasing mean blood pressure and pulse pressure in the mouse model of atherosclerotic disease.38 Endothelium-dependent relaxation has also been observed with berberine treatment, mediated by the endothelial release of nitric oxide.39
One additional mechanism via which berberine may improve cardiovascular system function and hemodynamics is via the inhibition of clot formation. In platelet aggregation assays, berberine was observed to inhibit thrombin-induced platelet aggregation.40 Thrombin is a key enzyme in the blood coagulation cascade that converts fibrinogen to fibrin during blood coagulation. Berberine has been shown to have neuroprotective effects in animal models of stroke;41 this may be one mechanism by which these benefits are seen.
Berberine and Dyslipidemia
In addition to improving lipid dysregulation via activation of AMPK,42 there are several additional mechanisms via which berberine acts to restore cholesterol balance.43 Berberine inhibits cholesterol absorption and promotes its excretion via the bile.44,45 Berberine increases the expression of LDL receptors in the liver, which promotes bile formation and secretion.46 In animals, oral supplementation with berberine was observed to reduce total cholesterol and non-HDL cholesterol levels by 29 to 33 percent and 31 to 41 percent respectfully, also reducing the absorption of dietary cholesterol by 40 to 51 percent.47
Berberine also alters the expression of genes related to cholesterol metabolism via interaction with the bile acid farnesoid X receptor (FXR) in the intestinal epithelial cells.48 Interaction with FXR increases excretion of conjugated bile acids in the feces and reduces the accumulation of hepatic triglycerides and the development of HFD-associated obesity. Although the inhibition of HMG-CoA reductase is not the primary mechanism via which berberine reduces cholesterol, in the setting of hyperhomocysteinemia (common in cardiovascular disease, also contributing to increased hepatic cholesterol synthesis and lipid accumulation), berberine was observed to inhibit HMG-CoA reductase activity and reduce hepatic cholesterol content.49
Clearly, berberine has a broad range of effects on metabolism and the function of many systems of the body, some of which may be mediated via interactions with the microbes in the gut, and others which occur at a cellular and genetic level. Research continues to elucidate the mechanisms via which this botanical has such a broad impact on physiology. For our many predecessors and the pioneers of herbal medicine, this only serves to reinforce that which they already observed.
http://www.townsendletter.com/May2018/berberine0518.html
Berberine, an orangish-yellow alkaloid found at high levels in the bark and root structures of plants including Oregon grape (Mahonia aquifolium), goldenseal (Hydrastis canadensis), barberry (Berberis vulgaris), and Chinese goldthread (Coptis chinensis), has a broad and wide history of use. Oregon grape, a North American source of this alkaloid, was used by the native inhabitants and European colonists in the Pacific Northwest as a blood toner, an antimicrobial, and to ease digestive distress.1 As a bitter tonic, the extract from the roots and bark of these herbs was used to stimulate digestion, while its antimicrobial properties were taken advantage of both topically and internally.2 Chinese goldthread, known as duǎn è huánglián, is one of the 50 fundamental herbs in traditional Chinese medicine,3 where its bitter and cold properties are used to influence conditions of the Heart, Large Intestine, Liver, and Stomach.
Berberine
In the digestive system, berberine exerts a multitude of actions. Berberine acts as an antimicrobial, having both a direct bactericidal effect as well as decreasing bacterial adherence to mucosal epithelial surfaces.4,5 Berberine also directly influences intestinal permeability, improving tight junction integrity.6,7 Berberine has evidence of exerting a tonifying effect on gastrointestinal motility – increasing motility and contractility in states of hypofunction, and relaxing the system when it is in an excessively contractile state.8 Berberine has an antinociceptive effect, which may be in part due to its impact on contractility, or mediated via its interactions with the endogenous opioid system,9 or via nitric oxide synthesis.10 Berberine increases the gut production of short chain fatty acids (SCFAs), in particular butyrate.11 Butyrate has an anti-inflammatory effect in the colon, which may play a role not only in digestive disorders, but neurological and metabolic conditions as well.12
Because of its low bioavailability in its non-transformed state,13 much of the research surrounding berberine has looked at the impact on the gut. The gut microbiota also plays a significant role in the absorption of berberine, as it transforms it to dihydroberberine, which has a five-fold increase in absorption over that of berberine.14 Dihydroberberine then oxidizes back to berberine in the intestinal tissue and enters the blood. One cautionary note which must be remembered in practice is that berberine, at commonly used doses, moderately inhibits cytochrome P450 3A4 (CYP3A4), CYP2D6, and CYP2C9,15,16 which may lead to increased levels of commonly used medications including lovastatin, clarithromycin, sildenafil, losartan, venlafaxine, and metoprolol, as well as many others.
Klaire LabsMetabolic Balance and Healthy Cardiovascular Function: An Akkermansia Effect?
One type of bacteria in the gut that has been shown to impact metabolic balance and cardiovascular health is Akkermansia muciniphila.This gram-negative bacteria feeds on mucin, as well as certain sugars including N-acetylglucosamine, N-acetyl-galac-to-samine, and glucose.17 Although A. muciniphila represents only a small fraction (3 to 5 percent) of the bacteria in the gut, the impact it may have on metabolism is significant. Reduced levels of A. muciniphila have been observed in patients with impaired glucose metabolism and obesity,18,19 while higher levels of the genus Akkermansia have been found in athletes and individuals with a low body mass index (BMI).20
In mice, supplementation with A. muciniphila reduced weight gain and fat mass, and improved glucose tolerance and insulin sensitivity.21 In one mouse study, excess weight due to high fat diet (HFD) feeding was reduced by more than half when supplemented with this bacterium. A. muciniphila may have this impact on metabolism by the reduction of chronic low-grade inflammation, as these changes were observed in conjunction with decreased lipopolysaccharide (LPS) signalling and increased anti-inflammatory factors such as α-tocopherol and β-sitosterol. Administration of A. muciniphila also has been shown to increase the intestinal levels of endocannabinoids, the endogenous cannabinoids produced by the body, which play a role in controlling inflammation, the gut barrier, and gut peptide secretion.22 A. muciniphila also was shown to reduce the development of atherosclerosis, improving gut tight junction integrity, and attenuating LPS-induced inflammation.23
Both metformin and berberine have been shown to increase levels of Akkermansia spp., with both treatments increasing the number of mucin-producing goblet cells that produce the substrate (mucin) that serves as food for this bacterium.24,25 Along with this finding, berberine was shown to improve HFD-induced atherosclerosis in the standard mouse model where development of atherosclerotic disease is inevitable, reducing inflammation systemically and in the atherosclerotic lesions.
Berberine and Blood Vessel Function
Endothelial dysfunction is one contributing factor that leads to increased blood pressure and cardiovascular disease. There are many different facets of dysfunction which include diminished vasodilation in response to stimulation, increased leukocyte (white blood cell) adhesion, and frequently, increased platelet activation.26 Collectively, these factors contribute to atherosclerosis and cardiovascular disease in addition to an increase in blood pressure. Endothelial dysfunction has also been observed in polycystic ovarian syndrome, migraines, and the vascular complications associated with diabetes.27-29 Increased proinflammatory cytokines and decreased adiponectin (a hormone produced by adipose tissue) levels both contribute to altered endothelial homeostasis.30
Methylation SummitBerberine increases activation of adenosine monophosphate–activated protein kinase (AMPK), a fuel-sensing enzyme that is present in all mammalian cells. When activated, AMPK stimulates energy-generating processes within the cell such as glucose uptake and decreases energy consuming processes such as lipid synthesis, reducing blood sugar and cholesterol production.31,32 AMPK is also present in the endothelial cells of the blood vessels, and promotes normal function via anticontractile, anti-inflammatory, and antiatherogenic actions.33 Consumption of a HFD contributes to endothelial dysfunction in part via downregulation of the AMPK pathway.34
Although hyperglycemia leads to endothelial dysfunction, berberine has been observed to alleviate this negative effect and promote normal vasodilation via the AMPK pathway.35 Via activation of AMPK, berberine reduces the pro-inflammatory response of macrophage foam cells, a cellular responder of the immune system which plays a role in the development of atherosclerotic plaques, to stimuli including hydrogen peroxide and LPS.36 Berberine also inhibits the release of platelet-derived growth factor (PDGF) from vascular smooth muscle cells as well as smooth muscle hypertrophy via activation of the AMPK pathway. By doing so, berberine promotes normal endothelial function and the reduction of stenosis, that is, the narrowing of blood vessels.37
Berberine also induces vaso-relaxation via endothelial-independent mechanisms similar to a calcium-channel blocker, decreasing mean blood pressure and pulse pressure in the mouse model of atherosclerotic disease.38 Endothelium-dependent relaxation has also been observed with berberine treatment, mediated by the endothelial release of nitric oxide.39
One additional mechanism via which berberine may improve cardiovascular system function and hemodynamics is via the inhibition of clot formation. In platelet aggregation assays, berberine was observed to inhibit thrombin-induced platelet aggregation.40 Thrombin is a key enzyme in the blood coagulation cascade that converts fibrinogen to fibrin during blood coagulation. Berberine has been shown to have neuroprotective effects in animal models of stroke;41 this may be one mechanism by which these benefits are seen.
Berberine and Dyslipidemia
In addition to improving lipid dysregulation via activation of AMPK,42 there are several additional mechanisms via which berberine acts to restore cholesterol balance.43 Berberine inhibits cholesterol absorption and promotes its excretion via the bile.44,45 Berberine increases the expression of LDL receptors in the liver, which promotes bile formation and secretion.46 In animals, oral supplementation with berberine was observed to reduce total cholesterol and non-HDL cholesterol levels by 29 to 33 percent and 31 to 41 percent respectfully, also reducing the absorption of dietary cholesterol by 40 to 51 percent.47
Berberine also alters the expression of genes related to cholesterol metabolism via interaction with the bile acid farnesoid X receptor (FXR) in the intestinal epithelial cells.48 Interaction with FXR increases excretion of conjugated bile acids in the feces and reduces the accumulation of hepatic triglycerides and the development of HFD-associated obesity. Although the inhibition of HMG-CoA reductase is not the primary mechanism via which berberine reduces cholesterol, in the setting of hyperhomocysteinemia (common in cardiovascular disease, also contributing to increased hepatic cholesterol synthesis and lipid accumulation), berberine was observed to inhibit HMG-CoA reductase activity and reduce hepatic cholesterol content.49
Clearly, berberine has a broad range of effects on metabolism and the function of many systems of the body, some of which may be mediated via interactions with the microbes in the gut, and others which occur at a cellular and genetic level. Research continues to elucidate the mechanisms via which this botanical has such a broad impact on physiology. For our many predecessors and the pioneers of herbal medicine, this only serves to reinforce that which they already observed.
