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Modulatory Effects of Triphala and Manjistha Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study.
Peterson, CT, Pourang, A, Dhaliwal, S, Kohn, JN, Uchitel, S, Singh, H, Mills, PJ, Peterson, SN, Sivamani, RK
Journal of alternative and complementary medicine (New York, N.Y.). 2020;(11):1015-1024
Abstract
Objectives: Triphala (which contains Emblica officinalis, Terminalia bellerica, and Terminalia chebula) and manjistha (Rubia cordifolia), have received increased clinical attention. The aim of the study was to evaluate the effects of triphala, manjistha, or placebo dietary supplementation on gut microbiota as such studies in humans are lacking. Design: This was a 4-week randomized, double-blind, placebo-controlled pilot trial. Setting: This trial was conducted at the University of California Davis, Department of Dermatology. Subjects: A total of 31 healthy human subjects were randomized to 3 groups. Interventions: The 3 groups were instructed to take 2,000 mg of either triphala, manjistha or placebo daily for 4 weeks. Outcome Measures: The impact of treatment on gut microbiota composition was evaluated following a 4-week dietary intervention by profiling fecal communities with 16S rRNA profiling in triphala (n = 9), manjistha (n = 9), or placebo (n = 11) treated subjects that completed the intervention. Results: An average of 336 phylotypes were detected in each sample (range: 161 to 648). The analysis of gut microbiota in placebo control and herb-supplemented participants indicated that responses were highly personalized, and no taxa were uniformly altered by the medicinal herb supplementation protocol. Subjects in both treatment groups displayed a trend toward decreased Firmicutes to Bacteroidetes ratio and increased relative abundance of Akkermansia muciniphila. Both medicinal herb treatments reduced the relative abundance of Rikenellaceae, primarily reflecting changes in Alistipes spp. Conclusions: Dietary supplementation with medicinal herbs altered fecal microbial communities. Despite the lack of a clear response signature, a group of bacterial taxa were identified that were more commonly altered in herb-supplemented participants compared to placebo controls. Clinicaltrials.gov identifier NCT03477825.
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Effects of Caloric Intake and Aerobic Activity in Individuals with Prehypertension and Hypertension on Levels of Inflammatory, Adhesion and Prothrombotic Biomarkers-Secondary Analysis of a Randomized Controlled Trial.
Wagner, EN, Hong, S, Wilson, KL, Calfas, KJ, Rock, CL, Redwine, LS, von Känel, R, Mills, PJ
Journal of clinical medicine. 2020;(3)
Abstract
BACKGROUND Cardiopulmonary fitness and low calorie diets have been shown to reduce inflammation but few studies have been conducted in individuals with elevated blood pressure (BP) in a randomized intervention setting. Thereby, adhesion biomarkers, e.g., soluble intercellular adhesion molecule (sICAM)-3, have not been examined so far. METHODS Sixty-eight sedentary prehypertensive and mildly hypertensive individuals (mean age ± SEM: 45 ± 1 years; mean BP: 141/84 ± 1/1 mmHg) were randomized to one of three 12-week intervention groups: cardio training and caloric reduction, cardio training alone, or wait-list control group. Plasma levels of inflammatory, adhesion and prothrombotic biomarkers were assessed. In a second step, intervention groups were combined to one sample and multivariate regression analyses were applied in order to account for exercise and diet behavior changes. RESULTS There were no significant differences among the intervention groups. In the combined sample, greater caloric reduction was associated with a larger increase of sICAM-3 (p = 0.026) and decrease of C-reactive protein (p = 0.018) as a result of the interventions. More cardio training was associated with increases of sICAM-3 (p = 0.046) as well as interleukin-6 (p = 0.004) and a decrease of tumor necrosis factor- (p = 0.017) levels. Higher BP predicted higher plasminogen activator inhibitor (PAI)-1 (p = 0.001), and greater fitness predicted lower PAI-1 levels (p = 0.006) after the intervention. CONCLUSIONS In prehypertensive and hypertensive patients, plasma levels of the adhesion molecule sICAM-3 and inflammatory biomarkers have different response patterns to cardio training with and without caloric reduction. Such anti-inflammatory and anti-thrombotic effects may have implications for the prevention of atherothrombotic cardiovascular disease among individuals at increased risk.
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Prebiotic Potential of Herbal Medicines Used in Digestive Health and Disease.
Peterson, CT, Sharma, V, Uchitel, S, Denniston, K, Chopra, D, Mills, PJ, Peterson, SN
Journal of alternative and complementary medicine (New York, N.Y.). 2018;24(7):656-665
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Triphala, licorice and slippery elm are key treatments for gastrointestinal health and disease in traditional systems of medicine. Prebiotics are defined as undigested dietary carbohydrates that alter the gut microbiota and promote human health. They reach the site of action in the colon mostly unmetabolized and are broken down by enzymes. The aim of the study was to find out whether the complex carbohydrates present in herbal medicine may be strong drivers to modulate gut microbiota composition. The study recruited 12 healthy men and women, aged between 30-60 years who had previously followed a vegan or vegetarian diet for more than 1 year, to donate a single stool sample. Results show that both the sugar and protein content of these herbal medicines drive alterations in gut microbiota profiles. Each of these herbal medicines studied, uniquely altered gut bacteria communities. Authors conclude that the health benefits of these herbs are mostly due to their ability to alter the gut microbiota in a manner that is predicted to improve colonic epithelium function, reduce inflammation, and promote protection from bacterial pathogenic infection.
Abstract
INTRODUCTION The prebiotic potential of herbal medicines has been scarcely studied. METHODS The authors therefore used anaerobic human fecal cultivation to investigate whether three herbal medicines commonly used in gastrointestinal health and disease in Ayurveda alter the growth and abundance of specific bacterial species. RESULTS Profiling of cultures supplemented with Glycyrrhiza glabra, Ulmus rubra, or triphala formulation by 16S rDNA sequencing revealed profound changes in diverse taxa in human gut microbiota. Principal coordinate analysis highlights that each herbal medicine drives the formation of unique microbial communities. The relative abundance of approximately one-third of the 299 species profiled was altered by all 3 medicines, whereas additional species displayed herb-specific alterations. Herb supplementation increased the abundance of many bacteria known to promote human health, including Bifidobacterium spp., Lactobacillus spp., and Bacteroides spp. Herb supplementation resulted in the reduced relative abundance of many species, including potential pathogens such as Citrobacter freundii and Klebsiella pneumoniae. Herbal medicines induced blooms of butyrate- and propionate-producing species. U. rubra and triphala significantly increased the relative abundance of butyrate-producing bacteria, whereas G. glabra induced the largest increase in propionate-producing species. To achieve greater insight into the mechanisms through which herbal medicines alter microbial communities, the authors assessed the shifts in abundance of glycosyl hydrolase families induced by each herbal medicine. Herb supplementation, particularly G. glabra, significantly increased the representation and potential expression of several glycosyl hydrolase families. DISCUSSION These studies are novel in highlighting the significant prebiotic potential of medicinal herbs and suggest that the health benefits of these herbs are due, at least in part, to their ability to modulate the gut microbiota in a manner predicted to improve colonic epithelium function, reduce inflammation, and protect from opportunistic infection. Forthcoming studies in human clinical trials will test the concordance of the results generated in vitro and the predictions made by genome analyses.
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Effects of Turmeric and Curcumin Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study.
Peterson, CT, Vaughn, AR, Sharma, V, Chopra, D, Mills, PJ, Peterson, SN, Sivamani, RK
Journal of evidence-based integrative medicine. 2018;:2515690X18790725
Abstract
BACKGROUND Curcuma longa (common name: turmeric) and one of its biologically active constituents, curcumin, have received increased clinical attention. Insufficient data exist on the effects of curcumin and turmeric on the gut microbiota and such studies in humans are lacking. METHODS Turmeric tablets with extract of piperine (Bioperine) (n = 6), curcumin with Bioperine tablets (n = 5), or placebo tablets (n = 3) were provided to healthy human subjects and subsequent changes in the gut microbiota were determined by 16S rDNA sequencing. RESULTS The number of taxa detected ranged from 172 to 325 bacterial species. The placebo group displayed an overall reduction in species by 15%, whereas turmeric-treated subjects displayed a modest 7% increase in observed species posttreatment. Subjects taking curcumin displayed an average increase of 69% in detected species. The gut microbiota response to treatment was highly personalized, thus leading to responders and nonresponders displaying response concordance. These "responsive" subjects defined a signature involving uniform increases in most Clostridium spp., Bacteroides spp., Citrobacter spp., Cronobacter spp., Enterobacter spp., Enterococcus spp., Klebsiella spp., Parabacteroides spp., and Pseudomonas spp. Common to these subjects was the reduced relative abundance of several Blautia spp. and most Ruminococcus spp. CONCLUSIONS All participants' microbiota displayed significant variation over time and individualized response to treatment. Among the responsive participants, both turmeric and curcumin altered the gut microbiota in a highly similar manner, suggesting that curcumin may drive the majority of observed changes observed in turmeric-treated subjects.
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Identification of Altered Metabolomic Profiles Following a Panchakarma-based Ayurvedic Intervention in Healthy Subjects: The Self-Directed Biological Transformation Initiative (SBTI).
Peterson, CT, Lucas, J, John-Williams, LS, Thompson, JW, Moseley, MA, Patel, S, Peterson, SN, Porter, V, Schadt, EE, Mills, PJ, et al
Scientific reports. 2016;:32609
Abstract
The effects of integrative medicine practices such as meditation and Ayurveda on human physiology are not fully understood. The aim of this study was to identify altered metabolomic profiles following an Ayurveda-based intervention. In the experimental group, 65 healthy male and female subjects participated in a 6-day Panchakarma-based Ayurvedic intervention which included herbs, vegetarian diet, meditation, yoga, and massage. A set of 12 plasma phosphatidylcholines decreased (adjusted p < 0.01) post-intervention in the experimental (n = 65) compared to control group (n = 54) after Bonferroni correction for multiple testing; within these compounds, the phosphatidylcholine with the greatest decrease in abundance was PC ae C36:4 (delta = -0.34). Application of a 10% FDR revealed an additional 57 metabolites that were differentially abundant between groups. Pathway analysis suggests that the intervention results in changes in metabolites across many pathways such as phospholipid biosynthesis, choline metabolism, and lipoprotein metabolism. The observed plasma metabolomic alterations may reflect a Panchakarma-induced modulation of metabotypes. Panchakarma promoted statistically significant changes in plasma levels of phosphatidylcholines, sphingomyelins and others in just 6 days. Forthcoming studies that integrate metabolomics with genomic, microbiome and physiological parameters may facilitate a broader systems-level understanding and mechanistic insights into these integrative practices that are employed to promote health and well-being.
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The Self-Directed Biological Transformation Initiative and Well-Being.
Mills, PJ, Wilson, KL, Pung, MA, Weiss, L, Patel, S, Doraiswamy, PM, Peterson, CT, Porter, V, Schadt, E, Chopra, D, et al
Journal of alternative and complementary medicine (New York, N.Y.). 2016;(8):627-34
Abstract
OBJECTIVE To examine the effects of a comprehensive residential mind-body program on well-being. DESIGN The Self-Directed Biological Transformation Initiative was a quasi-randomized trial comparing the effects of participation in a 6-day Ayurvedic system of medicine-based comprehensive residential program with a 6-day residential vacation at the same retreat location. SETTING Retreat setting. PARTICIPANTS 69 healthy women (n = 58) and men (n = 11) (mean age ± standard deviation, 53.6 ± 12 years). INTERVENTION The Ayurvedic intervention addressed physical and emotional well-being through group meditation and yoga, massage, diet, adaptogenic herbs, lectures, and journaling. OUTCOME MEASURES A battery of standardized questionnaires. RESULTS Participants in the Ayurvedic program showed significant and sustained increases in ratings of spirituality (p < 0.01) and gratitude (p < 0.05) compared with the vacation group, which showed no change. The Ayurvedic participants also showed increased ratings for self-compassion (p < 0.01) as well as less anxiety at the 1-month follow-up (p < 0.05). CONCLUSIONS Findings suggest that a short-term intensive program providing holistic instruction and experience in mind-body healing practices can lead to significant and sustained increases in perceived well-being and that relaxation alone is not enough to improve certain aspects of well-being.
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Statin Effects on Aggression: Results from the UCSD Statin Study, a Randomized Control Trial.
Golomb, BA, Dimsdale, JE, Koslik, HJ, Evans, MA, Lu, X, Rossi, S, Mills, PJ, White, HL, Criqui, MH
PloS one. 2015;(7):e0124451
Abstract
BACKGROUND Low/ered cholesterol is linked to aggression in some study designs. Cases/series have reported reproducible aggression increases on statins, but statins also bear mechanisms that could reduce aggression. Usual statin effects on aggression have not been characterized. METHODS 1016 adults (692 men, 324 postmenopausal women) underwent double-blind sex-stratified randomization to placebo, simvastatin 20mg, or pravastatin 40mg (6 months). The Overt-Aggression-Scale-Modified-Aggression-Subscale (OASMa) assessed behavioral aggression. A significant sex-statin interaction was deemed to dictate sex-stratified analysis. Exploratory analyses assessed the influence of baseline-aggression, testosterone-change (men), sleep and age. RESULTS The sex-statin interaction was significant (P=0.008). In men, statins tended to decrease aggression, significantly so on pravastatin: difference=-1.0(SE=0.49)P=0.038. Three marked outliers (OASMa-change ≥40 points) offset otherwise strong significance-vs-placebo: statins:-1.3(SE=0.38)P=0.0007; simvastatin:-1.4(SE=0.43)P=0.0011; pravastatin:-1.2(SE=0.45)P=0.0083. Age≤40 predicted greater aggression-decline on statins: difference=-1.4(SE=0.64)P=0.026. Aggression-protection was emphasized in those with low baseline aggression: age<40-and-low-baseline-aggression (N=40) statin-difference-vs-placebo=-2.4(SE=0.71)P=0.0016. Statins (especially simvastatin) lowered testosterone, and increased sleep problems. Testosterone-drop on statins predicted aggression-decline: β=0.64(SE=0.30)P=0.034, particularly on simvastatin: β=1.29(SE=0.49)P=0.009. Sleep-worsening on statins significantly predicted aggression-increase: β=2.2(SE=0.55)P<0.001, particularly on simvastatin (potentially explaining two of the outliers): β=3.3(SE=0.83)P<0.001. Among (postmenopausal) women, a borderline aggression-increase on statins became significant with exclusion of one younger, surgically-menopausal woman (N=310) β=0.70(SE=0.34)P=0.039. The increase was significant, without exclusions, for women of more typical postmenopausal age (≥45): (N=304) β=0.68(SE=0.34)P=0.048 - retaining significance with modified age-cutoffs (≥50 or ≥55). Significance was observed separately for simvastatin. The aggression-increase in women on statins was stronger in those with low baseline aggression (N=175) β=0.84(SE=0.30)P=0.006. No statin effect on whole blood serotonin was observed; and serotonin-change did not predict aggression-change. CONCLUSION Statin effects on aggression differed by sex and age: Statins generally decreased aggression in men; and generally increased aggression in women. Both findings were selectively prominent in participants with low baseline aggression - bearing lower change-variance, rendering an effect more readily evident. TRIAL REGISTRATION Clinicaltrials.gov NCT00330980.
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Individual and neighborhood socioeconomic status and inflammation in Mexican American women: what is the role of obesity?
Gallo, LC, Fortmann, AL, de Los Monteros, KE, Mills, PJ, Barrett-Connor, E, Roesch, SC, Matthews, KA
Psychosomatic medicine. 2012;(5):535-42
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OBJECTIVE Inflammation may represent a biological mechanism underlying associations of socioeconomic status (SES) with cardiovascular disease. We examined relationships of individual and neighborhood SES with inflammatory markers in Mexican American women and evaluated contributions of obesity and related heath behaviors to these associations. METHODS Two hundred eighty-four Mexican American women (mean age = 49.74 years) were recruited from socioeconomically diverse South San Diego communities. Women completed measures of sociodemographic characteristics and health behaviors, and underwent a physical examination with fasting blood draw for assay of plasma C-reactive protein (CRP), interleukin 6 (IL-6), and soluble intercellular adhesion molecule 1 (sICAM-1). Neighborhood SES was extracted from the US Census Bureau 2000 database. RESULTS In multilevel models, a 1-standard deviation higher individual or neighborhood SES related to a 27.35% and 23.56% lower CRP level (p values < .01), a 7.04% and 5.32% lower sICAM-1 level (p values < .05), and a 10.46% (p < .05) and 2.40% lower IL-6 level (not significant), respectively. Controlling for individual SES, a 1-standard deviation higher neighborhood SES related to a 18.05% lower CRP level (p = .07). Differences in body mass index, waist circumference, and dietary fat consumption contributed significantly to SES-inflammation associations. CONCLUSIONS The findings support a link between SES and inflammatory markers in Mexican American women and implicate obesity and dietary fat in these associations. Additional effects of neighborhood SES were not statistically significant; however, these findings should be viewed tentatively due to the small sample size to evaluate contextual effects. Trial Registration ClinicalTrials.gov identifier: NCT00387166.
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Effects on blood pressure and autonomic nervous system function of a 12-week exercise or exercise plus DASH-diet intervention in individuals with elevated blood pressure.
Edwards, KM, Wilson, KL, Sadja, J, Ziegler, MG, Mills, PJ
Acta physiologica (Oxford, England). 2011;(3):343-50
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AIM: Hypertension is related to abnormalities in autonomic nervous system (ANS) function, with increased sympathetic output and decreased parasympathetic tone. Lifestyle interventions are the first line of treatment in hypertension, and decreased blood pressure (BP) effects may be related to changes in ANS function. Using heart rate recovery (HRR) from exercise as an index of parasympathetic tone and plasma noradrenaline as an index of sympathetic tone, we investigated the effects of lifestyle interventions on ANS function in patients with elevated BP. METHODS Sedentary participants with elevated BP were randomly assigned to either an exercise only (N = 25), exercise plus dietary approaches to stop hypertension (DASH) diet (N = 12), or waitlist control (N = 15) 12-week intervention. Plasma noradrenaline was measured at rest and participants performed a peak exercise test before and after the intervention. HRR was calculated as peak heart rate (HR) minus HR at 1 min post-exercise. RESULTS Heart rate recovery showed a significant group by time interaction; both intervention groups showed increases in HRR from pre- to post-intervention, while waitlist showed no change. Similarly, both exercise plus diet and exercise groups, but not waitlist, showed significant reductions in BP from pre- to post-intervention. Linear regression revealed that BP post-intervention was significantly predicted by change in HRR when controlling for pre-BP, age, gender and BMI. CONCLUSIONS Lifestyle interventions induced training-reduced BP and altered autonomic tone, indexed by HRR. This study indicates the importance of behavioural modification in hypertension and that increased parasympathetic function is associated with success in reduction of BP.
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Effects of a weight loss intervention on body mass, fitness, and inflammatory biomarkers in overweight or obese breast cancer survivors.
Pakiz, B, Flatt, SW, Bardwell, WA, Rock, CL, Mills, PJ
International journal of behavioral medicine. 2011;(4):333-41
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BACKGROUND Obesity is characterized by chronic mild inflammation and may influence the risk and progression of cancer. PURPOSE The current study is an exploratory analysis of the effect of a weight loss intervention that emphasized increased physical activity on inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], interleukin-8 [IL-8], and vascular endothelial growth factor [VEGF]) at the end of the 16-week intervention period in overweight breast cancer survivors. METHODS Study participants averaged 56 years of age (N=68). Intervention participants (n=44 vs. 24 controls) participated in a cognitive behavioral therapy-based weight management program as part of an exploratory randomized trial. The intervention incorporated strategies to promote increased physical activity and diet modification. Baseline and 16-week data included height, weight, body composition, physical activity level, and biomarkers IL-6, IL-8, TNF-α, and VEGF. RESULTS Weight loss was significantly greater in the intervention group than controls (-5.7 [3.5] vs. 0.2 [4.1] kg, P<0.001). Paired t tests noted favorable changes in physical activity level (P<0.001 intervention, P=0.70 control), marginally lower IL-6 levels (P=0.06 intervention, P=0.25 control) at 16 weeks for participants in the intervention group, and lower TNF-α levels for participants in the intervention (P<0.05) and control groups (P<0.001). Increased physical activity was associated with favorable changes in IL-6 for participants in the intervention group (R(2) =0.18; P<0.03). CONCLUSION Favorable changes in cytokine levels were observed in association with weight loss in this exploratory study with overweight breast cancer survivors.