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Modulating the Gut Microbiome in Multiple Sclerosis Management: A Systematic Review of Current Interventions.
Tsogka, A, Kitsos, DK, Stavrogianni, K, Giannopapas, V, Chasiotis, A, Christouli, N, Tsivgoulis, G, Tzartos, JS, Giannopoulos, S
Journal of clinical medicine. 2023;12(24)
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Multiple sclerosis (MS) is an autoimmune disease caused by the altered immune system mistakenly attacking the central nervous system. While genetics play a leading causative role in the manifestation of this disease, other contributing environmental factors can also exist, such as a disruption in the intestinal microbial composition. Previous research has shown that the bidirectional communication between the brain's and gut's health, also known as the gut-brain axis, may contribute to the prognosis of MS. Modulating gut microbial composition can be a therapeutic strategy in MS patients to manage symptoms and prevent disease progression. This systematic review assessed different protocols for modulating gut microbial composition, including dietary modifications, probiotic use, intermittent fasting, and faecal microbial transplantation. The review included thirteen studies that compared the effects of the above gut microbial modulation intervention protocols in MS patients with healthy participants. While different dietary modification strategies improved MS symptoms, probiotic supplementations and intermittent fasting reduced inflammation, and faecal microbial transplantation showed promising positive effects in a few reports. Due to the methodological limitations of the included studies, further robust studies are required to evaluate the beneficial effects of gut microbial modulation strategies in reducing the symptoms of MS patients. However, healthcare professionals can use the results of this study to understand the benefits of gut microbial modulation in MS patients.
Abstract
This review attempted to explore all recent clinical studies that have investigated the clinical and autoimmune impact of gut microbiota interventions in multiple sclerosis (MS), including dietary protocols, probiotics, fecal microbiota transplantation (FMT), and intermittent fasting (IF). Methods: Thirteen studies were held between 2011 and 2023 this demonstrated interventions in gut microbiome among patients with MS and their impact the clinical parameters of the disease. These included specialized dietary interventions, the supply of probiotic mixtures, FMT, and IF. Results: Dietary interventions positively affected various aspects of MS, including relapse rates, EDSS disability scores, MS-related fatigue, and metabolic features. Probiotic mixtures showed promising results on MS-related fatigue, EDSS parameters, inflammation; meanwhile, FMT-though a limited number of studies was included-indicated some clinical improvement in similar variables. IF showed reductions in EDSS scores and significant improvement in patients' emotional statuses. Conclusions: In dietary protocols, clinical MS parameters, including relapse rate, EDSS, MFIS, FSS, and MSQoL54 scales, were significantly improved through the application of a specific diet each time. Probiotic nutritional mixtures promote a shift in inflammation towards an anti-inflammatory cytokine profile in patients with MS. The administration of such mixtures affected disability, mood levels, and quality of life among patients with MS. FMT protocols possibly demonstrate a therapeutic effect in some case reports. IF protocols were found to ameliorate EDSS and FAMS scores. All interventional means of gut microbiome modulation provided significant conclusions on several clinical aspects of MS and highlight the complexity in the relationship between MS and the gut microbiome.
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Absence of Effects of L-Arginine and L-Citrulline on Inflammatory Biomarkers and Oxidative Stress in Response to Physical Exercise: A Systematic Review with Meta-Analysis.
Porto, AA, Gonzaga, LA, Benjamim, CJR, Valenti, VE
Nutrients. 2023;15(8)
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L-citrulline is a non-essential amino acid that acts as a precursor to L-arginine. L-arginine is a semi-essential amino acid used for nitric oxide production which is crucial for maintaining physiological function and immune regulation. Previous research has shown that L-citrulline and L-arginine supplementation may offer antioxidant and anti-inflammatory benefits in reducing exercise-related oxidative stress and inflammation. This systematic review and meta-analysis included seven randomised controlled trials to investigate the effect of L-citrulline and L-arginine on antioxidants, oxidative stress, and inflammatory and anti-inflammatory markers. This systematic review and meta-analysis showed no significant improvements in oxidative stress and inflammation followed by the supplementation of L-citrulline and L-arginine before exercise. However, further robust studies that include different dosages and exercise intensities are required to assess the beneficial effects of L-citrulline and L-arginine supplements to support physical exercise-induced oxidative stress and inflammation due to the heterogeneity of the included studies. Healthcare professionals can use the results of this study to understand the potential benefits of L-citrulline and L-arginine supplementation in people prone to producing proinflammatory cytokines.
Abstract
The repercussions on oxidative and inflammatory stress markers under the effects of arginine and citrulline in response to exercise are not fully reached. We completed a systematic review to investigate the effects of L-Citrulline or L-Arginine on oxidative stress and inflammatory biomarkers following exercise. EMBASE, MEDLINE (PubMed), Cochrane Library, CINAHL, LILACS, and Web of Science databases were used to record the trials. This study includes randomized controlled trials (RCTs) and non-RCTs with subjects over 18 years old. Those under the intervention protocol consumed L-Citrulline or L-Arginine, and the controls ingested placebo. We recognized 1080 studies, but only 7 were included (7 studies in meta-analysis). We observed no difference between pre- vs. post-exercise for oxidative stress (subtotal = -0.21 [CI: -0.56, 0.14], p = 0.24, and heterogeneity = 0%. In the sub-group "L-Arginine" we found a subtotal = -0.29 [-0.71, 0.12], p = 0.16, and heterogeneity = 0%. For the "L-Citrulline" subgroup we observed a subtotal = 0.00 [-0.67, 0.67], p = 1.00, and heterogeneity was not applicable. No differences were observed between groups (p = 0.47), and I² = 0%) or in antioxidant activity (subtotal = -0.28 [-1.65, 1.08], p = 0.68, and heterogeneity = 0%). In the "L-Arginine" sub-group, we found a subtotal = -3.90 [-14.18, 6.38], p = 0.46, and heterogeneity was not applicable. For the "L-Citrulline" subgroup, we reported a subtotal = -0.22 [-1.60, 1.16], p = 0.75, and heterogeneity was not applicable. No differences were observed between groups (p = 0.49), and I² = 0%), inflammatory markers (subtotal = 8.38 [-0.02, 16.78], p = 0.05, and heterogeneity = 93%. Tests for subgroup differences were not applicable, and anti-inflammatory markers (subtotal = -0.38 [-1.15, 0.39], p = 0.34 and heterogeneity = 15%; testing for subgroup differences was not applicable). In conclusion, our systematic review and meta-analysis found that L-Citrulline and L-Arginine did not influence inflammatory biomarkers and oxidative stress after exercise.
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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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A Review of Dietary (Phyto)Nutrients for Glutathione Support.
Minich, DM, Brown, BI
Nutrients. 2019;11(9)
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Glutathione is made up of 3 amino acids (cysteine, glutamic acid and glycine) and plays important roles in the body, including oxidative stress reduction, supporting the immune system and contributing to detoxification processes. Evidence suggests that it is an important marker and target for treatment in many chronic, age-related diseases. This review article explores the evidence of nutritional strategies to improve glutathione status. The authors examine the evidence for supplementation of the precursors of glutathione as well as with various forms of supplemental glutathione itself, and the impacts on glutathione status and clinical impacts. Crucially, the review article provides information on dietary sources of precursors of glutathione and glutathione itself, which will provide Nutrition Practitioners with compelling information for use in clinic. Lean protein, brassica vegetables, polyphenol-rich fruits and vegetables, green tea, herbs and spices and omega-3 rich foods are all discussed in detail.
Abstract
Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse roles of glutathione in physiology are relevant to a considerable body of evidence suggesting that glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Yet, proper personalized balance in the individual is key as well as a better understanding of antioxidants and redox balance. Optimizing glutathione levels has been proposed as a strategy for health promotion and disease prevention, although clear, causal relationships between glutathione status and disease risk or treatment remain to be clarified. Nonetheless, human clinical research suggests that nutritional interventions, including amino acids, vitamins, minerals, phytochemicals, and foods can have important effects on circulating glutathione which may translate to clinical benefit. Importantly, genetic variation is a modifier of glutathione status and influences response to nutritional factors that impact glutathione levels. This narrative review explores clinical evidence for nutritional strategies that could be used to improve glutathione status.
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Vitamin D Supplementation in Central Nervous System Demyelinating Disease-Enough Is Enough.
Häusler, D, Weber, MS
International journal of molecular sciences. 2019;20(1)
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Vitamin D is associated with a reduced risk and severity of multiple sclerosis (MS). However, whether supplementing vitamin D level alters disease severity, is a matter of ongoing debate. This review looks at both clinical and pre-clinical evidence for supplementing vitamin D in people with MS. In vitro experiments show that vitamin D and its metabolites can alter function of various immune cells, mostly via interaction with vitamin D receptors (VDR). Results from human clinical trials, however, are mixed. Preclinical evidence suggests that high dose vitamin D supplementation, when leading to hypercalcaemia, a potentially serious side effect of excessive vitamin D intake, may worsen MS. The authors also review research which suggests mechanisms by which sun exposure can improve MS symptoms independent of vitamin D production. The authors conclude that moderate sun exposure, combined with adequate dietary intake of vitamin D, and in conjunction with a regular assessment of vitamin D serum levels (to avoid hypercalcaemia), might be the best strategy for patients with MS.
Abstract
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS.
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The Effect of Bifidobacterium animalis ssp. lactis HN019 on Cellular Immune Function in Healthy Elderly Subjects: Systematic Review and Meta-Analysis.
Miller, LE, Lehtoranta, L, Lehtinen, MJ
Nutrients. 2017;9(3)
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Elderly individuals are more susceptible to infections and cancer, due to lowered immune system function. The gut bacteria play a key role in human immune system function and there is an interest in a potential role for probiotics in strengthening the immune system through manipulation of the microbiome. This systematic review and meta-analysis of 4 randomised controlled trials aimed to examine the efficacy of Bifidobacterium animalis lactis HN019 on the cellular immune activity of healthy elderly adults age 60-70 years. The authors concluded that supplementation with this bacterial strain at a range of potencies for 3-6 weeks duration had a significant positive impact on the part of the immune system that is responsible for removing pathogens and cell debris (phagocytosis) and a lesser but nevertheless significant impact on natural killer cells responsible for tumour destruction.
Abstract
Elderly people have increased susceptibility to infections and cancer that are associated with decline in cellular immune function. The objective of this work was to determine the efficacy of Bifidobacterium (B.) animalis ssp. lactis HN019 (HN019) supplementation on cellular immune activity in healthy elderly subjects. We conducted a systematic review of Medline and Embase for controlled trials that reported polymorphonuclear (PMN) cell phagocytic capacity or natural killer (NK) cell tumoricidal activity following B. lactis HN019 consumption in the elderly. A random effects meta-analysis was performed with standardized mean difference (SMD) and 95% confidence interval between probiotic and control groups for each outcome. A total of four clinical trials were included in this analysis. B. lactis HN019 supplementation was highly efficacious in increasing PMN phagocytic capacity with an SMD of 0.74 (95% confidence interval: 0.38 to 1.11, p < 0.001) and moderately efficacious in increasing NK cell tumoricidal activity with an SMD of 0.43 (95% confidence interval: 0.08 to 0.78, p = 0.02). The main limitations of this research were the small number of included studies, short-term follow-up, and assessment of a single probiotic strain. In conclusion, daily consumption of B. lactis HN019 enhances NK cell and PMN function in healthy elderly adults.
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The microbiome: A key regulator of stress and neuroinflammation.
Rea, K, Dinan, TG, Cryan, JF
Neurobiology of stress. 2016;4:23-33
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This study discusses the concept of intestinal microbiota as the key regulator involved in energy regulation, gut barrier function, protection from pathogens, and immune system function amongst others. The gut microbiota is the complex community of microorganisms that lives in the digestive tracts of humans. The main aim of this study is to summarise the role of gastrointestinal microbiota in fundamental physiological and pathophysiological processes and thereafter to understand and treat a range of stress and immune-related disorders. This review outlines the numerous complex relationships between gastrointestinal microbiota, stress and immune responses at the three critical stages of life The authors concluded that the evidence from this study suggests that resilience to stress and immune-related disorders and dysfunction of stress and immune systems may be dependent on the diversity and complexity of gastrointestinal microbiota. However, gut microbiota mediated relationship to stress and neuro-inflammation is still unconfirmed as previous studies mostly, have largely been, preclinical and further studies are warranted.
Abstract
There is a growing emphasis on the relationship between the complexity and diversity of the microorganisms that inhabit our gut (human gastrointestinal microbiota) and health/disease, including brain health and disorders of the central nervous system. The microbiota-gut-brain axis is a dynamic matrix of tissues and organs including the brain, glands, gut, immune cells and gastrointestinal microbiota that communicate in a complex multidirectional manner to maintain homeostasis. Changes in this environment can lead to a broad spectrum of physiological and behavioural effects including hypothalamic-pituitary-adrenal (HPA) axis activation, and altered activity of neurotransmitter systems and immune function. While an appropriate, co-ordinated physiological response, such as an immune or stress response are necessary for survival, a dysfunctional response can be detrimental to the host contributing to the development of a number of CNS disorders. In this review, the involvement of the gastrointestinal microbiota in stress-mediated and immune-mediated modulation of neuroendocrine, immune and neurotransmitter systems and the consequential behaviour is considered. We also focus on the mechanisms by which commensal gut microbiota can regulate neuroinflammation and further aim to exploit our understanding of their role in stress-related disorders as a consequence of neuroinflammatory processes.
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Effect of Flavonoids on Upper Respiratory Tract Infections and Immune Function: A Systematic Review and Meta-Analysis.
Somerville, VS, Braakhuis, AJ, Hopkins, WG
Advances in nutrition (Bethesda, Md.). 2016;7(3):488-97
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Upper respiratory tract infections (URTIs) are common and include sinusitis, tonsillitis, pharyngitis, otitis media, laryngitis, and the “common cold”. More than 90% of URTIs are cause by viruses. Flavonoids are found in many plant foods and have a range of physiologic effects in humans, including antiviral, anti-inflammatory, cytotoxic, antimicrobial, and antioxidant. The purpose of this systematic review and meta-analysis of 14 randomised controlled trials was to investigate the efficacy of flavonoids on URTIs and immune function. The authors found that flavonoids decrease URTI incidence by 33% compared with controls with no increase in adverse effects. There was also a non-significant decrease in URTI severity and duration with the flavonoid intervention. The meta-analysis demonstrated that differences between flavonoids and control for all immune biomarkers were clinically irrelevant. The authors therefore suggest that flavonoids do not attenuate URTI incidence by altering immune function but by an antiviral mechanism. They call for further research to establish the optimal dose and type of flavonoids.
Abstract
Previous research on animals indicates flavonoid compounds have immunomodulatory properties; however, human research remains inconclusive. The aim of this systematic review was to assess the efficacy of dietary flavonoids on upper respiratory tract infections (URTIs) and immune function in healthy adults. A created search strategy was run against Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and EMBASE classic, CINAHL, and AMED. The returned studies were initially screened, and 2 reviewers independently assessed the remaining studies for eligibility against prespecified criteria. Fourteen studies, of 387 initially identified, were included in this review, and the primary outcome measure was the effect of flavonoids on URTI incidence, duration, and severity. Of the included studies, flavonoid supplementation ranged from 0.2 to 1.2 g/d. Overall, flavonoid supplementation decreased URTI incidence by 33% (95% CI: 31%, 36%) compared with control, with no apparent adverse effects. Sick-day count was decreased by 40% with flavonoid supplementation, although unclear. Differences in bio-immune markers (e.g., interleukin-6, tumor necrosis factor-α, interferon-γ, neutrophils) were trivial between the intervention and control groups during the intervention and after exercise when a postintervention exercise bout was included. These findings suggest that flavonoids are a viable supplement to decrease URTI incidence in an otherwise healthy population.
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Effects of Probiotics and Synbiotics on Obesity, Insulin Resistance Syndrome, Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease: A Review of Human Clinical Trials.
Sáez-Lara, MJ, Robles-Sanchez, C, Ruiz-Ojeda, FJ, Plaza-Diaz, J, Gil, A
International journal of molecular sciences. 2016;17(6)
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The microbiome influences human physiology and affects metabolism. The aim of this review was to investigate the effectiveness of probiotics and synbiotics (a combination of probiotics and prebiotics) in the prevention and treatment of obesity, metabolic syndrome, type 2 diabetes mellitus (T2DM) and non-alcoholic liver disease (NAFLD) in human clinical trials. Supplementation of selected probiotics was found to have beneficial effects on body mass index (BMI), waist circumference, visceral (abdominal) fat and hip circumference in overweight or obese people. Some probiotic strains also appear to have positive effects on glucose metabolism and insulin sensitivity in patients with metabolic syndrome, obesity and/or T2DM. Increased antioxidant status, reduced inflammation and improved lipid metabolism were observed in these patient groups. Specific pro- and synbiotics also led to improvements in NAFLD. However, there were also studies which showed no benefits of probiotic/synbiotic supplementation. The authors state that this may be due to study design, choice of probiotic strains or too small number of trial subjects, and call for more research.
Abstract
The use of probiotics and synbiotics in the prevention and treatment of different disorders has dramatically increased over the last decade. Both probiotics and synbiotics are well known ingredients of functional foods and nutraceuticals and may provide beneficial health effects because they can influence the intestinal microbial ecology and immunity. The present study reviews the effects of probiotics and synbiotics on obesity, insulin resistance syndrome (IRS), type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) in human randomized clinical trials. Select probiotics and synbiotics provided beneficial effects in patients with obesity, mainly affecting the body mass index and fat mass. Some probiotics had beneficial effects on IRS, decreasing the cell adhesion molecule-1 levels, and the synbiotics decreased the insulin resistance and plasma lipid levels. Moreover, select probiotics improved the carbohydrate metabolism, fasting blood glucose, insulin sensitivity and antioxidant status and also reduced metabolic stress in subjects with T2D. Some probiotics and synbiotics improved the liver and metabolic parameters in patients with NAFLD. The oral intake of probiotics and synbiotics as co-adjuvants for the prevention and treatment of obesity, IRS, T2D and NAFLD is partially supported by the data shown in the present review. However, further studies are required to understand the precise mechanism of how probiotics and synbiotics affect these metabolic disorders.
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Garlic: a review of potential therapeutic effects.
Bayan, L, Koulivand, PH, Gorji, A
Avicenna journal of phytomedicine. 2014;4(1):1-14
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Garlic has been used throughout history, across many different cultures, for its therapeutic effects in supporting cardiovascular diseases, blood glucose dysregulation, and for anti-tumour and anti-microbial properties. Garlic (Allium sativum L.) use is thought to date as far back as the sixth century BC and has subsequently popped up in ancient Greek, Egyptian, Indian and Chinese medicines. This 2013 review looked at evidence to support the therapeutic effects of garlic, and its principal bioactive compound allicin. The authors reviewed clinical studies from the 1960’s through to 2012 and garlic was shown to reduce systolic blood pressure, prevent atherosclerosis, reduce serum cholesterol, LDL and triglycerides in doses ranging from 200 - 960 mg daily. The allylsulfide derivatives in garlic are attributed to its anti-cancer properties with studies showing garlic has a variety of anti-tumour effects, including tumour cell growth inhibition and chemopreventive effects. Garlic has also been shown to have therapeutic effect at reducing fasting blood glucose levels in diabetic patients. Garlic’s antimicrobial uses date back to Louis Pasteur when it was shown to be effective against multiple bacterial strains including Salmonella, Escherichia coli, Klebsiella, and Helicobacter as it is capable of inhibiting sulfhydryl enzymes. Garlic also displays some anti-fungal and anti-viral properties however there are few studies which explore these mechanisms. Anecdotal evidence suggests it reduces the duration of the common cold and aids respiration. The review offers little evidence of dosing or therapeutic efficacy.
Abstract
Throughout history, many different cultures have recognized the potential use of garlic for prevention and treatment of different diseases. Recent studies support the effects of garlic and its extracts in a wide range of applications. These studies raised the possibility of revival of garlic therapeutic values in different diseases. Different compounds in garlic are thought to reduce the risk for cardiovascular diseases, have anti-tumor and anti-microbial effects, and show benefit on high blood glucose concentration. However, the exact mechanism of all ingredients and their long-term effects are not fully understood. Further studies are needed to elucidate the pathophysiological mechanisms of action of garlic as well as its efficacy and safety in treatment of various diseases.