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Serum, Urine, and Fecal Metabolome Alterations in the Gut Microbiota in Response to Lifestyle Interventions in Pediatric Obesity: A Non-Randomized Clinical Trial.
Lee, Y, Cho, JY, Cho, KY
Nutrients. 2023;15(9)
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Paediatric obesity is linked to an increased risk of type 2 diabetes, hypertension, dyslipidaemia, and metabolic syndrome. Diverse evidence suggests that obesity is associated with alterations in the gut microbiota and its metabolites. The aim of this study was to understand the metabolic pathways underlying paediatric obesity and the effect of intervention, which could provide guidance for the treatment of obesity. This study was a non-randomised clinical trial which enrolled 50 children with obesity and 22 normal-weight children aged 7–18 years. Results showed that imbalances in microbiota and metabolites were associated with both obesity and response to the intervention. The most distinct metabolic alterations in the obese group were branched-chain amino acid and purine changes. Authors conclude that the findings of their study could be valuable for identifying novel targets and biomarkers for the treatment of obesity.
Abstract
Pediatric obesity is associated with alterations in the gut microbiota and its metabolites. However, how they influence obesity and the effect of lifestyle interventions remains unknown.. In this non-randomized clinical trial, we analyzed metabolomes and microbial features to understand the associated metabolic pathways and the effect of lifestyle interventions on pediatric obesity. Anthropometric/biochemical data and fasting serum, urine, and fecal samples were collected at baseline and after an eight-week, weight-reduction lifestyle modification program. Post-intervention, children with obesity were classified into responder and non-responder groups based on changes in total body fat. At baseline, serum L-isoleucine and uric acid levels were significantly higher in children with obesity compared with those in normal-weight children and were positively correlated with obesogenic genera. Taurodeoxycholic and tauromuricholic α + β acid levels decreased significantly with obesity and were negatively correlated with obesogenic genera. Branched-chain amino acid and purine metabolisms were distinguished metabolic pathways in the obese group. Post-intervention, urinary myristic acid levels decreased significantly in the responder group, showing a significant positive correlation with Bacteroides. Fatty acid biosynthesis decreased significantly in the responder group. Thus, lifestyle intervention with weight loss is associated with changes in fatty acid biosynthesis, and myristic acid is a possible therapeutic target for pediatric obesity.
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Defecation status, intestinal microbiota, and habitual diet are associated with the fecal bile acid composition: a cross-sectional study in community-dwelling young participants.
Saito, Y, Sagae, T
European journal of nutrition. 2023;62(5):2015-2026
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Primary bile acids (priBAs) are synthesised from cholesterol in the human liver, conjugated with either taurine or glycine [amino acids], and secreted into the intestinal tract, where they dissolve dietary lipids. Diet is a modifiable factor that can influence defecation status, BAs, and intestinal microbiota. The aim of this study was to identify associations among defecation status, intestinal microbiota, and diet by examining faecal BA composition in community-dwelling young participants. This study was a cross-sectional study which enrolled 70 students. Results showed that 20.9% of the participants had high faecal BA levels with predominantly priBAs. This cluster was associated with an increased relative abundance of Clostridium subcluster XIVa [bacteria], increased frequency of normal faeces, and decreased relative abundance of Bacteroides and Clostridium cluster IV [bacteria]. Conversely, high levels of cytotoxic [toxic to cells] secondary BA (secBA) were associated with low normal defecation frequency, low insoluble fibre intake, and high animal fat intake. Authors concluded that among community-dwelling young adults, secBA production is affected by both dietary and lifestyle related factors. Thus, their findings may inform novel strategies for preventing colorectal cancer and cholelithiasis.
Abstract
PURPOSE Bile acid (BA) metabolism by intestinal bacteria is associated with the risk of gastrointestinal diseases; additionally, its control has become a modern strategy for treating metabolic diseases. This cross-sectional study investigated the influence of defecation status, intestinal microbiota, and habitual diet on fecal BA composition in 67 community-dwelling young participants. METHODS Feces were collected for intestinal microbiota and BA analyses; data about defecation status and dietary habits were collected using the Bristol stool form scales and a brief-type self-administered diet history questionnaire, respectively. The participants were categorized into four clusters based on their fecal BA composition, according to cluster analysis, and tertiles based on deoxycholic acid (DCA) and lithocholic acid (LCA) levels. RESULTS The high primary BA (priBA) cluster with high fecal cholic acid (CA) and chenodeoxycholic acid (CDCA) levels had the highest frequency of normal feces, whereas the second BA (secBA) cluster with high levels of fecal DCA and LCA had the lowest. Alternately, the high-priBA cluster had a distinct intestinal microbiota, with higher Clostridium subcluster XIVa and lower Clostridium cluster IV and Bacteroides. The low-secBA cluster with low fecal DCA and LCA levels had the lowest animal fat intake. Nevertheless, the insoluble fiber intake of the high-priBA cluster was significantly higher than that of the high-secBA cluster. CONCLUSION High fecal CA and CDCA levels were associated with distinct intestinal microbiota. Conversely, high levels of cytotoxic DCA and LCA were associated with increased animal fat intake and decreased frequency of normal feces and insoluble fiber intake. CLINICAL TRIAL REGISTRY University Hospital Medical Information Network (UMIN) Center system (UMIN000045639); date of registration: 15/11/2019.
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The role of gut microbiome in inflammatory skin disorders: A systematic review.
Widhiati, S, Purnomosari, D, Wibawa, T, Soebono, H
Dermatology reports. 2022;14(1):9188
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Gut-skin axis refers to the complex cross-talk between gut bacteria and skin. Although the exact mechanism underlying chronic inflammatory skin conditions is unknown, imbalances in the composition of gut microbes are believed to play a role. Twenty-three studies were included in this systematic review to assess whether gut microbial imbalance may contribute to inflammatory skin conditions such as Psoriasis, Acne Vulgaris, Atopic Dermatitis, and Urticaria. According to this systematic review, immune stimulation, inflammation, and disruption of bacterial composition are common mechanisms in all these skin disorders. A western diet and environmental exposures are found to be contributing to the disruption of bacteria and the pathology of these skin disorders. It has been observed that friendly gut bacteria such as Bifidobacterium are reduced in people with inflammatory skin conditions, whereas elevated levels of pathogenic bacteria such as E. coli and Proteobacteria are present in the gut of patients with inflammatory skin conditions. The abundance of anti-inflammatory bacteria such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Clostridium leptum, Lactobacillus, and Bifidobacterium may protect against inflammatory skin conditions. Further robust studies are required to evaluate the pathogenesis behind inflammatory skin conditions as well as the involvement of gut bacteria in the development and progression of the disease. Healthcare professionals can gain a deeper understanding of gut bacteria that contribute to the pathology of inflammatory diseases as well as how clinically using anti-inflammatory bacterial species may improve the condition of individuals suffering from inflammatory skin conditions.
Abstract
The close relationship between the intestine and the skin has been widely stated, seen from gastrointestinal (GI) disorders often accompanied by skin manifestations. Exactly how the gut microbiome is related to skin inflammation and influences the pathophysiology mechanism of skin disorders are still unclear. Many studies have shown a two-way relationship between gut and skin associated with GI health and skin homeostasis and allostasis. This systematic review aimed to explore the associations between the gut microbiome with inflammatory skin disorders, such as acne, psoriasis, atopic dermatitis, and urticaria, and to discover the advanced concept of this relationship. The literature search was limited to any articles published up to December 2020 using PubMed and EBSCOHost. The review followed the PRISMA guidelines for conducting a systematic review. Of the 319 articles screened based on title and abstract, 111 articles underwent full-text screening. Of these, 23 articles met our inclusion criteria, comprising 13 atopic dermatitis (AD), three psoriasis, four acne vulgaris, and four chronic urticaria articles. Acne vulgaris, atopic dermatitis, psoriasis, and chronic urticaria are inflammation skin disorders that were studied recently to ascertain the relationship of these disorders with dysbiosis of the GI microbiome. All acne vulgaris, psoriasis, and chronic urticaria studies stated the association of gut microbiome with skin manifestations. However, the results in atopic dermatitis are still conflicting. Most of the articles agree that Bifidobacterium plays an essential role as anti-inflammation bacteria, and Proteobacteria and Enterobacteria impact inflammation in inflammatory skin disorders.
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Impact of Blueberry Consumption on the Human Fecal Bileacidome: A Pilot Study of Bile Acid Modulation by Freeze-Dried Blueberry.
Gagnon, W, Garneau, V, Trottier, J, Verreault, M, Couillard, C, Roy, D, Marette, A, Drouin-Chartier, JP, Vohl, MC, Barbier, O
Nutrients. 2022;14(18)
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Primary bile acids (BAs) are made in the liver from cholesterol. They are released into the small intestine, where they aid fat digestion and absorption. Most BAs are reabsorbed from the gut, yet a small amount gets modified by the gut bacteria, forming secondary BAs destined for faecal excretion. Excess secondary BAs have negative health consequences. The different types of primary BAs influence many physiological functions. Such as glucose regulation, fat metabolism and absorption, intestinal inflammation and immunity, as well as gut bacteria diversity. For optimal BA metabolism, they are tightly regulated by the body, as minimal changes in BA pool and composition can have a significant impact on overall health. The composition of the BA pool can be influenced by gut bacteria, metabolic disorders, pathologies of the liver and gut, and diet. Dietary polyphenols, a plant-based compound, have been of particular interest here. This study sought to investigate the impact of supplementary freeze-dried blueberry powder (BBP), a rich polyphenol source, on the faecal BA pool composition in people at risk of metabolic syndrome. For this 11 men and 13 women were supplemented for 8 weeks. When compared to the data before the intervention, no significant changes in total BAs were observed. However, the composition of the BA pool changed leading to the accumulation of particular BAs and a reduction in secondary BA levels. This suggested that the consumption of blueberries can be considered a potential clinical intervention to aid the elimination of toxic secondary BAs. As the mechanisms leading to such modifications and their consequences for human health are complex, the authors advocate for investigation in larger population groups and also alert that such changes may be subject to interindividual variability and health status.
Abstract
Cholesterol-derived bile acids (BAs) affect numerous physiological functions such as glucose homeostasis, lipid metabolism and absorption, intestinal inflammation and immunity, as well as intestinal microbiota diversity. Diet influences the composition of the BA pool. In the present study, we analyzed the impact of a dietary supplementation with a freeze-dried blueberry powder (BBP) on the fecal BA pool composition. The diet of 11 men and 13 women at risk of metabolic syndrome was supplemented with 50 g/day of BBP for 8 weeks, and feces were harvested before (pre) and after (post) BBP consumption. BAs were profiled using liquid chromatography coupled with tandem mass spectrometry. No significant changes in total BAs were detected when comparing pre- vs. post-BBP consumption samples. However, post-BBP consumption samples exhibited significant accumulations of glycine-conjugated BAs (p = 0.04), glycochenodeoxycholic (p = 0.01), and glycoursodeoxycholic (p = 0.01) acids, as well as a significant reduction (p = 0.03) in the secondary BA levels compared with pre-BBP feces. In conclusion, the fecal bileacidome is significantly altered after the consumption of BBP for 8 weeks. While additional studies are needed to fully understand the underlying mechanisms and physiological implications of these changes, our data suggest that the consumption of blueberries can modulate toxic BA elimination.
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The Gut Microbiota (Microbiome) in Cardiovascular Disease and Its Therapeutic Regulation.
Rahman, MM, Islam, F, -Or-Rashid, MH, Mamun, AA, Rahaman, MS, Islam, MM, Meem, AFK, Sutradhar, PR, Mitra, S, Mimi, AA, et al
Frontiers in cellular and infection microbiology. 2022;12:903570
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Cardiovascular disease (CVD) accounts for 31% of all-cause mortality worldwide. Irregularities in the composition of intestinal microbial composition, genetic factors, nutrition, metabolic irregularities, and smoking are among the potential causes of CVD. Intestinal permeability and translocation of endotoxins and bacterial metabolites to systemic circulation may trigger an immune response and inflammation, which may increase the risk of CVD. Synthesis of bacterial metabolites such as trimethylamine N-oxide (TMAO) by choline-inducing gut bacteria and reduced consumption of dietary TMAO precursors may elevate the CVD risk. This review explores the latest research on the role of gut microbiota in the development of atherosclerosis and CVD, as well as potential strategies to prevent CVD by targeting TMAO-producing gut bacteria. Elevated levels of TMAO in the bloodstream can lead to the buildup of cholesterol and ultimately result in atherosclerosis. However, consuming probiotics and fibre-rich foods can help regulate gut bacteria, reduce inflammation, and improve lipid profiles, all of which contribute to better cardiovascular health. More future robust studies are required to examine the mechanistic insights and confirm whether TMAO can serve as a biomarker for preventing CVD through the therapeutic modulation of intestinal bacteria.
Abstract
In the last two decades, considerable interest has been shown in understanding the development of the gut microbiota and its internal and external effects on the intestine, as well as the risk factors for cardiovascular diseases (CVDs) such as metabolic syndrome. The intestinal microbiota plays a pivotal role in human health and disease. Recent studies revealed that the gut microbiota can affect the host body. CVDs are a leading cause of morbidity and mortality, and patients favor death over chronic kidney disease. For the function of gut microbiota in the host, molecules have to penetrate the intestinal epithelium or the surface cells of the host. Gut microbiota can utilize trimethylamine, N-oxide, short-chain fatty acids, and primary and secondary bile acid pathways. By affecting these living cells, the gut microbiota can cause heart failure, atherosclerosis, hypertension, myocardial fibrosis, myocardial infarction, and coronary artery disease. Previous studies of the gut microbiota and its relation to stroke pathogenesis and its consequences can provide new therapeutic prospects. This review highlights the interplay between the microbiota and its metabolites and addresses related interventions for the treatment of CVDs.
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Gut Microbiota-Derived Metabolites and Cardiovascular Disease Risk: A Systematic Review of Prospective Cohort Studies.
Sanchez-Gimenez, R, Ahmed-Khodja, W, Molina, Y, Peiró, OM, Bonet, G, Carrasquer, A, Fragkiadakis, GA, Bulló, M, Bardaji, A, Papandreou, C
Nutrients. 2022;14(13)
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Cardiovascular disease (CVD) remains a major public health issue. Identification of circulating biomarkers with prognostic value may help to both identify pathophysiological processes relevant to CVD development and improve preventive cardiovascular risk reduction efforts. The aim of this study was to identify the association of circulating levels of microbial metabolites with CVD incidence. This study is a systematic review of twenty-one studies of which 19 were prospective cohort studies, one study included one nested case-control study and one study included two nested case–control studies. Results show that: - associations of trimethylamine N-oxide (TMAO) [molecular metabolite derived from the gut flora] and subsequent risk of CV outcomes were supported by some but not all prospective studies. - inconsistent results were also obtained for secondary bile acids in relation to CVD and related outcomes, and CVD/all-cause mortality. - with regards to branched-chain amino acids (BCAAs), their associations with CV outcomes were robust amongst most of the studies. Authors conclude that their findings show inconsistent results for TMAO and bile acids but robust ones for the relationships between BCAAs and CVD. Thus, further studies are needed to investigate whether circulating microbial metabolites could be an intervention target for CVD.
Abstract
Gut microbiota-derived metabolites have recently attracted considerable attention due to their role in host-microbial crosstalk and their link with cardiovascular health. The MEDLINE-PubMed and Elsevier's Scopus databases were searched up to June 2022 for studies evaluating the association of baseline circulating levels of trimethylamine N-oxide (TMAO), secondary bile acids, short-chain fatty acids (SCFAs), branched-chain amino acids (BCAAs), tryptophan and indole derivatives, with risk of cardiovascular disease (CVD). A total of twenty-one studies were included in the systematic review after evaluating 1210 non-duplicate records. There were nineteen of the twenty-one studies that were cohort studies and two studies had a nested case-control design. All of the included studies were of high quality according to the "Newcastle-Ottawa Scale". TMAO was positively associated with adverse cardiovascular events and CVD/all-cause mortality in some, but not all of the included studies. Bile acids were associated with atrial fibrillation and CVD/all-cause mortality, but not with CVD. Positive associations were found between BCAAs and CVD, and between indole derivatives and major adverse cardiovascular events, while a negative association was reported between tryptophan and all-cause mortality. No studies examining the relationship between SCFAs and CVD risk were identified. Evidence from prospective studies included in the systematic review supports a role of microbial metabolites in CVD.
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Vegan diet in young children remodels metabolism and challenges the statuses of essential nutrients.
Hovinen, T, Korkalo, L, Freese, R, Skaffari, E, Isohanni, P, Niemi, M, Nevalainen, J, Gylling, H, Zamboni, N, Erkkola, M, et al
EMBO molecular medicine. 2021;13(2):e13492
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As vegan diets gain popularity amongst families, there is little known about the impact of strict plant-based diets on metabolism and micronutrient status in children, apart from reduced average growth within the norm. This small study looked at 40 Finnish children from one day centre, and compared children following an omnivore or vegetarian diet to those raised on a vegan diet. The diets were analysed, and biomarkers and metabolites were measured. The metabolic profile and nutrient status of children who followed a vegan diet from birth were distinctively different to other diet patterns, including vegetarians. The authors suggest that little animal source foods are enough to shift the metabolism of children. Dietary analysis showed that vegan children had higher folate consumption and lower protein and saturated fats intake. Despite intake appearing adequate, serum markers for fat-soluble vitamins A and D were low. While the fatty acid ALA was higher compared to omnivores, DHA and overall cholesterol were decreased. The authors concluded that the bodies own cholesterol production does not seem to compensate for a lack of dietary cholesterol in this case and it remains to be established whether lower cholesterol in vegan children are negative to health. Furthermore, the circulating amino acids pool was decreased in vegan children, particularly branch chained amino acids. The most distinct difference, however, was seen in the variance of bile acid patterns. The physiological functions of bile acids go beyond digestion, yet the consequences of diverging bile acid profiles in children’s health are unknown. In conclusion, the data shows that a strict vegan diet affects the metabolism of healthy children, but much of the long-term impact on health is currently still unclear. This article highlights some of the differences, risks and uncertainties that come with raising young children on a strictly vegan diet.
Abstract
Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant-based diets on metabolism and micronutrient status of children are unknown. We recruited 40 Finnish children with a median age 3.5 years-vegans, vegetarians, or omnivores from same daycare centers-for a cross-sectional study. They enjoyed nutritionist-planned vegan or omnivore meals in daycare, and the full diets were analyzed with questionnaires and food records. Detailed analysis of serum metabolomics and biomarkers indicated vitamin A insufficiency and border-line sufficient vitamin D in all vegan participants. Their serum total, HDL and LDL cholesterol, essential amino acid, and docosahexaenoic n-3 fatty acid (DHA) levels were markedly low and primary bile acid biosynthesis, and phospholipid balance was distinct from omnivores. Possible combination of low vitamin A and DHA status raise concern for their visual health. Our evidence indicates that (i) vitamin A and D status of vegan children requires special attention; (ii) dietary recommendations for children cannot be extrapolated from adult vegan studies; and (iii) longitudinal studies on infant-onset vegan diets are warranted.
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Type 2 diabetes preventive effects with a 12-months sardine-enriched diet in elderly population with prediabetes: An interventional, randomized and controlled trial.
Díaz-Rizzolo, DA, Serra, A, Colungo, C, Sala-Vila, A, Sisó-Almirall, A, Gomis, R
Clinical nutrition (Edinburgh, Scotland). 2021;40(5):2587-2598
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Older people have a higher risk of developing Type 2 diabetes (T2D) due to the possibility of β-cell dysfunction due to ageing. Sardines are believed to be protective against the development of T2D. Therefore, this randomised controlled trial evaluated the preventative effects of a sardine-rich diet in elderly prediabetic patients. For one year, both the sardine group (SG) and control group (CG) followed a T2D prevention diet, with the SG consuming 200 g of sardines each week. Both groups improved body weight, BMI, waist and hip circumference, and body composition. Taurine, EPA, DHA, omega-3 fatty acid, calcium, iodine, zinc, phosphorous and fluoride, vitamin B12 and D, and lycopene and tocopherols were found to be higher in the SG than the CG, indicating the sardines were protective against T2D. In SG, HDL cholesterol and adiponectin levels were significantly increased, and blood pressure and triglycerides were decreased, signalling a reduced risk of T2D and cardiovascular disease. In addition, SG showed a reduction in HOMA-IR and an Omega-3 fatty acid was substituted for Omega-6 fatty acids in the erythrocyte membrane, suggesting a reduced risk of T2D. Further robust research is required to confirm the protective effect of a sardine-enriched diet against T2D. It may be useful to healthcare providers to comprehend how a sardine-enriched diet could improve obesity, T2D and CVD markers in pre-diabetic elderly patients.
Abstract
BACKGROUND Fish could play a role in preventing type 2 diabetes (T2D) but there has been little specification about the type of fish and the preventive mechanism involved in its health claim. The sardine is a source of omega-3 and taurine that, in isolation or in synergy, would produce T2D-delaying through different molecular mechanism. HYPOTHESIS The consumption of twice a week of sardine, during one year would reduce T2D-developing risk in a population with prediabetes (preDM) and old age. DESIGN 152 subjects with fasting glucose between 100-124 mg/dL aged ≥65 yo were recruited from three primary care centers in Barcelona and were randomly distributed among two interventional groups: control group (CG) and sardine group (SG). Both groups received same T2D-prevention nutritional during a year but only SG had to add 200 g of sardine per week. All variables were collected before to start and at the end of the diet. (ClinicalTrials.gov: NCT03557541). RESULTS 152 people were randomized into CG (n=77) and SG (n=75) with 18 and 12 drop outs respectively. Subjects in SG, significantly compared to CG, decreased percentage classified-individuals in a very high risk group to develop T2D according to FINDRISC (p=0.035). In addition to increasing HDL-cholesterol and adiponectin and decreasing triglycerides (p<0.05) and blood pressure (<0.05), SG showed a lower HOMA-IR (p=0.032). The consumption of sardine characteristics nutrients as omega-3, EPA and DHA, vitamin D, fluorine and taurine were higher for SG (p<0.05). These results agreed with the increased of taurine, fatty acid (FA) omega-3 and bile acids circulating metabolites (p<0.05). Changes erythrocyte membrane FA were detected only in SG with a decrease of 5 omega-6 FA (p<0.001) and an increase of 3 omega-3 FA types (p<0.001). CONCLUSION We conclude that a year T2D-prevention diet with sardine supplementation has a greater protective effect against developing T2D and CV events.
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The Gut Microbiota and Its Implication in the Development of Atherosclerosis and Related Cardiovascular Diseases.
Sanchez-Rodriguez, E, Egea-Zorrilla, A, Plaza-Díaz, J, Aragón-Vela, J, Muñoz-Quezada, S, Tercedor-Sánchez, L, Abadia-Molina, F
Nutrients. 2020;12(3)
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Cardiovascular disease (CVD) is the leading non-communicable disease and cause of death worldwide. The human microbiome can exert direct influences on bodily functions and in recent years much attention has been drawn to the significance of these microorganisms and their role in disease development. Divergences of microbiome patterns are also implicated in the progression and pathogenesis of CVD. This review describes the connection between host microbiota and CVD development. Elaborated are some of the potential mechanisms by which the microbiota and their associated metabolites can directly influence vascular tone and contribute to high blood pressure. More indirect processes, such as microbiota-mediated inflammation, insulin resistance and obesity are also accounted for. Furthermore, the authors discuss modulation of the microbiome composition as potential target for therapeutic interventions. Known influences that alter the microbiome are diet patterns, specific compounds such as probiotics, fish oils and polyphenols, physical activity and novel technologies like faecal transplants. This review outlines the many ways in which the microbiome can contribute to the development of CVD. Summarised are key points to consider in clinical practice, when navigating CVD and its microbiome associated risks factors.
Abstract
The importance of gut microbiota in health and disease is being highlighted by numerous research groups worldwide. Atherosclerosis, the leading cause of heart disease and stroke, is responsible for about 50% of all cardiovascular deaths. Recently, gut dysbiosis has been identified as a remarkable factor to be considered in the pathogenesis of cardiovascular diseases (CVDs). In this review, we briefly discuss how external factors such as dietary and physical activity habits influence host-microbiota and atherogenesis, the potential mechanisms of the influence of gut microbiota in host blood pressure and the alterations in the prevalence of those bacterial genera affecting vascular tone and the development of hypertension. We will also be examining the microbiota as a therapeutic target in the prevention of CVDs and the beneficial mechanisms of probiotic administration related to cardiovascular risks. All these new insights might lead to novel analysis and CVD therapeutics based on the microbiota.
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Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study).
Zhang, Y, Gu, Y, Ren, H, Wang, S, Zhong, H, Zhao, X, Ma, J, Gu, X, Xue, Y, Huang, S, et al
Nature communications. 2020;11(1):5015
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Berberine, which is a naturally occurring alkaloid found in plants, has been traditionally used as a remedy to protect against Type 2 diabetes and other metabolic disorders. It is important to study how berberine affects the human gut microbiome, specifically in regard to its impact on short-chain fatty acid and bile acid metabolism, due to its low oral bioavailability. The PREMOTE study investigated the glycaemic lowering effects of individual and combination of berberine and probiotics in newly diagnosed Type 2 Diabetes patients. This randomised, double-blinded, placebo-controlled trial included four hundred and nine Type 2 diabetic patients and randomly assigned them (1:1:1:1 ratio) to receive berberine alone, berberine combined with probiotics, probiotics alone or a placebo for twelve weeks. A combination of berberine plus probiotics and berberine alone significantly improved glycated haemoglobin levels compared to the placebo and probiotics alone treatment. The antidiabetic effects of berberine could be due to the Ruminococcus bromii abundance followed by the berberine treatment and its ability to inhibit deoxycholic acid biotransformation. Further robust studies are required to consider the therapeutic application of berberine and probiotics in a general population due to the limitations of the present study. However, healthcare professionals can use the results of this trial to understand the mechanism behind the anti-diabetic effects of berberine and probiotics.
Expert Review
Conflicts of interest:
None
Take Home Message:
- The use of berberine, as a specific antimicrobial agent, along with high strength probiotics may be beneficial for managing blood glucose and potentially other metabolic health markers alongside diet and lifestyle modifications
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
Dysbiosis of the human gut microbiome has been associated with the development of type 2 diabetes (T2D). Research has found that, in part, mechanisms of action for the antidiabetic medications, Metformin and Acarbose, include alterations in the gut microbiome as well as the inhibition of bile acid (BA) metabolism and signalling. Remedies targeting the gut microbiota for treatment of T2D and other metabolic diseases have therefore been investigated.
Berberine (BBR) has been used in Indian Ayurvedic and Traditional Chinese Medicine to treat metabolic conditions for hundreds of years. Probiotics have also been extensively researched for their potential metabolic benefits. This randomised, double-blind, placebo-controlled trial aimed to investigate whether BBR and probiotics may be effective in managing T2D.
Methods
A total of 409 participants aged 42-61 years were recruited from 20 medical centres in China. All patients were newly diagnosed (<12 months) with T2D and had no previous antidiabetic medication history. Participants were randomised into 4 groups; Probiotics and BBR, BBR only, probiotics only or a placebo for 12 weeks. Subgroup analysis was also completed for those aged >50 and >54.
Dosage of BBR was 0.6 g prior to a meal, twice daily. 4 g of powdered multi-strain probiotics including 9 strains of lactic acid bacteria were taken at bedtime. All participants were given a 7-day broad-spectrum antibiotic treatment immediately prior to baseline. 391 people completed the trial. The primary outcome measurement was glycaemic haemoglobin (HbA1c). Secondary evaluations of additional metabolic markers included fasting and post-load plasma glucose (FPG, PPG), homeostasis assessment model index for insulin resistance (HOMA-IR), total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c) and serum triglycerides (TG).
Results
Results showed a reduction in glycaemic haemoglobin (HbA1c) for both the BBR plus probiotics group (least squares mean [95% CI] -1.04 [-1-19, -0.89]% ) and the BBR only group (-.99 [-1.16, 0.83]%). The results for these groups were significantly greater than the probiotics alone (-0.53 {-068, -0.37]%) and the placebo groups (0.59 [-0.75, -0.44]%).
Secondary metabolic evaluations for FPG and PPG, TC, LDL -c and TGs also showed similar improvements in the BBR and BBR plus probiotic groups only. Additionally, in the >50 and >54 subgroups BBR and probiotics marginally improved the HOMA-IR.
Metagenomic and metabolomic analysis of the gut microbiome was also undertaken after a one-week pre-treatment with antibiotics immediately prior to the trial and at week 13. These results showed that the blood glucose lowering effects of BBR may be due to decreased deoxycholic acid species (DCA) biotransformation by ruminococcus bromii.
Higher levels of adverse gastrointestinal side effects were reported in the BBR treatment groups, however, the authors reported that this did not affect glycemic control outcomes.
Conclusion
This study found that BBR had an antidiabetic effect through microbial alterations in the human gut microbiome
The authors declare no conflicts of interest.
Clinical practice applications:
- 600mg of BBR twice daily prior to a meal plus a multi-strain (lactic acid) probiotic of >50 billion colony forming units (CFU) for 12 weeks may be effective in lowering HbA1c in T2D clients diagnosed within the previous 12 months
- Further research is needed for clients with longer term T2D diagnosis
- Insulin resistance may be marginally improved in clients >50
- Practitioners should be aware that in this study, adverse gastrointestinal side effects were more likely to be be experienced with the use of BBR
Considerations for future research:
The authors reported several limitations to this study:
- A population of Chinese people living in China may not be generalisable to other ethnic/racial populations
- The study was over a short duration. Longer studies are needed to confirm the results
- Participants had newly diagnosed T2D and had not received any previous medications. Future studies should include patients with a longer diagnosis time
- Records should be kept of any additional lifestyle changes made by the participants
- Adverse reactions were experienced in the BBR groups, in this study. It was reported that the gut microbiome and anti-diabetic effects were not affected, however, this may be something to be considered in longer trials.
Abstract
Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], -1.04[-1.19, -0.89]%) and BBR-alone group (-0.99[-1.16, -0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (-0.59[-0.75, -0.44]%, -0.53[-0.68, -0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).