|Year : 2018 | Volume
| Issue : 3 | Page : 207-214
Probiotic use in the management of hypertension: A new era of therapeutic management
Swapnil Purushottam Borse1, Devendra Pratap Singh1, Dilawar Upadhyay2, Vipin Sharma3, Manish A Nivsarkar3
1 Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development Centre; Department of Pharmacology and Toxicology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
2 Sun Pharma Advanced Research Company Ltd., Vadodara, Gujarat, India
3 Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development Centre, Ahmedabad, Gujarat, India
|Date of Web Publication||25-Sep-2018|
Dr. Manish A Nivsarkar
B. V. Patel Pharmaceutical Education and Research Development Centre, S. G. Highway, Thaltej, Ahmedabad - 380 054, Gujarat
Source of Support: None, Conflict of Interest: None
Hypertension (HTN) has become a common chronic medical condition which affects ≥20% of adult population worldwide. HTN is assumed to be a major contributing factor for increasing complication of metabolic syndrome by adding one or more comorbidities such as heart disease, stroke, chronic renal failure, myocardial infarction, blindness, and dementia. HTN is also considered as a lifestyle disorder, and there are mainly two types of HTN, namely primary and secondary. Primary HTN is about 90%–95% of all cases of HTN and it is defined as high blood pressure due to genetic factors and nonspecific lifestyle, while secondary HTN is due to an identifiable cause such as Cushing's syndrome, obesity, and glucose intolerance. However, the exact cause and pathophysiology of HTN is still not clear. On the other hand, human body acts as a host and around 100 trillion bacteria are present in the body which is 10 times more than the number of cells in the human body. Many studies have published the role of microbiome in health and disease. Recent findings have shed light on the important role of microbiota in HTN and its treatment with probiotics (beneficial microbiota to host). Considering this, here, we have summarized and focused on possible interplays between the HTN microbiota, pharmacotherapeutic use of probiotics in HTN, and prospects to increase the degree of therapeutic personalization.
Keywords: Gut microbiota, hypertension, metabolic syndrome, probiotics
|How to cite this article:|
Borse SP, Singh DP, Upadhyay D, Sharma V, Nivsarkar MA. Probiotic use in the management of hypertension: A new era of therapeutic management. Indian J Health Sci Biomed Res 2018;11:207-14
|How to cite this URL:|
Borse SP, Singh DP, Upadhyay D, Sharma V, Nivsarkar MA. Probiotic use in the management of hypertension: A new era of therapeutic management. Indian J Health Sci Biomed Res [serial online] 2018 [cited 2018 Oct 15];11:207-14. Available from: http://www.ijournalhs.org/text.asp?2018/11/3/207/242043
| Introduction|| |
Hypertension (HTN) is also known as high blood pressure (BP), where blood exerts more pressure than normal against wall of the blood vessels. It has been classified as primary (essential) or secondary HTN. Primary HTN encompasses about 90%–95% of all the reported cases of HTN, whose exact cause is not known and assumed to be due to nonspecific lifestyle and genetic factors, while secondary HTN is due to an identifiable cause such as Cushing's syndrome, obesity, glucose intolerance, moon face, and a hump of fat behind the neck or shoulder. This heterogeneous disease affects a large number of population causing severe health and economic burden. It is estimated that, by 2025, the total number of HTN patients is expected to increase to 1.56 billion globally. In 2015, countries such as China, India, Russia, Indonesia, and the US accounted for more than half of the global disability-adjusted life years related to systolic BP of at least 110–115 mmHg. Elevated BP is estimated to cause approximately 13% of all deaths worldwide in the past years. Despite the current therapeutic strategies, HTN progresses with or without additional comorbidity(s) in an individual. HTN is a major contributor in the development of renal failure, cardiovascular disease, and stroke. Therefore, this is the call for united efforts to treat HTN by all the possible means. In recent days, the research on gut microbiota has shown its significant role in the development and progression of HTN. HTN is mainly a disease of lifestyle and dietary habits, while on the other hand, gut microbiota is highly sensitive to lifestyle and dietary habits; hence, there is a link between the management of HTN with or without probiotics. Here, in this review, we have summarized the etiopathogenic importance of gut microbiome and how probiotics can start a new era in the therapeutic management of HTN.
| Gut Microbiota of Healthy-Versus-Hypertensive Patients|| |
From the classic work in ecology, we know that the initial assembly, or primary succession, of any community is usually important in determining its future composition and function. Similarly, the host–microbiota interaction, their roles, and the possible associated mechanisms/symbiotic association in maintaining healthy condition seem to be established and choreographed during the earliest days of life. The gastrointestinal tract (GIT) is sterile until an infant ingests vaginal and fecal microflora at delivery. The infant microbiota is further enriched by breastfeeding. In bottle-fed infants, Bifidobacteria does not predominate, while in case of breastfed infant, a colon population is of 90% Bifidobacteria with some Enterobacteriaceae and Enterococci present, but virtually no Bacteroides, Staphylococci, Lactobacilli, or Clostridia. After switching to cow's milk or solid foods, Bifidobacteria, Clostridia, Lactobacilli, Bacteroides, Streptococci, and enterics colonize. The type and number of indigenous microflora increases distally along the length of the GIT., The relatively sparse flora of the upper intestine generally numbers <105 colony-forming unit (CFU)/mL of contents, until the mid-ileum where the population increases to 107 CFU/mL of contents, indicating a shift toward the flora that heavily populates the colon. Various experiments have been done to explore the host–microbiota interactions., For instance, Charbonneau et.al. had explored the importance and symbiotic association between 6-month Malawian infants' gut microbiota and mother's milk. They found that sialylated milk oligosaccharides promote microbiota-dependent growth in malnourished infants. Such symbiotic interactions are important to create a beneficial impact on various organ systems and maintaining homeostasis in liver, muscle, and brain metabolism. The role of gut microbiota has also been well accepted in the inhibition of pathogens, development of enteric protection and immune system, metabolism, bacterial–epithelial cross talk, and signaling of gut–brain axis, leading to significant changes in phenotypic characters. However, alteration in gut microbiota can hamper the development of an individual as well as normal body homeostasis to maintain the healthy condition., Around 100 trillion bacteria are present in the body which is 10 times more than the number of cells in the human body. This includes both beneficial and harmful bacteria and ideally they should be around 85% and 15%, respectively, to maintain the healthy condition of an individual. Therefore, there is always a question whether whom to call beneficial or harmful among these species as the healthy state may get altered with respect to the alteration in the ratio of gut microbiota., In a normal individual, the Firmicutes/Bacteroidetes (F/B) ratio evolves during different life phases., In infants, adults, and elderly individuals, the observed F/B ratio is around 0.4, 10.9, and 0.6, respectively. In a normal individual, the balanced F/B ratio helps to maintain not only the acetate-butyrate production, but also fermentation of carbohydrates, thereby producing volatile fatty acids as an energy source to host., There are such n number of functional roles which are being continuously played by the balanced F/B ratio.,
It has been found that alteration in the gut microbiota may lead to diseased condition., An imbalance in gut microbiota is commonly known as dysbiosis. During HTN, microbial richness, diversity, and evenness decrease significantly, while F/B ratio increases. These changes are accompanied by decreases in acetate- and butyrate-producing bacteria. This is in alignment with human data, and a similar dysbiotic pattern has been observed. Similar changes in gut microbiota were observed in the chronic angiotensin II infusion rat model, most notably decreased microbial richness and an increased F/B ratio. When HTN was spontaneously induced in rats treated with oral minocycline, it not only rebalanced the dysbiotic HTN gut microbiota, but also attenuated high BP, by reducing the F/B ratio. These observations demonstrate that high BP is associated with gut microbiota dysbiosis, both in animal and human HTN., It has been suggested that F/B ratio can be used as a potential biomarker for pathological conditions. The F/B ratio increases in coronary artery disease patients. The F/B ratio is also altered in irritable bowel syndrome, adiposity, obesity, diabetes, metabolic syndrome, etc. Therefore, there are huge chances that this ratio may also have altered significantly in case of HTN, as HTN is one of the metabolic disorders sharing many common etiogenic/confounding factors with these diseases and thereby disturbing normal gut biota, leading to the development and progression of HTN to chronic complications.
| Pathogenesis of Hypertension and Gut Microbiota|| |
As discussed above, HTN is one of the features of metabolic syndrome and is also linked with other metabolic diseases such as obesity, adiposity, hypercholesterolemia, hyperglycemia, and insulin resistance. The sympathetic nervous system gets overactivated by the action of leptin that could alter lipid profiles and may cause peripheral vasoconstriction and increase renal tubular sodium reabsorption, thereby increasing BP. Insulin resistance also has the same effect on BP which is caused due to the weakening of endothelium-dependent vasodilatation. Oxidative stress is thought to be the key mechanism of these phenomena. It reflects an imbalance between oxidants and antioxidants leading to overproduction of reactive oxygen species and a decrease in antioxidant enzyme activities. Oxidative stress is implicated in various physiological processes. The decreased antioxidant capacity, reduced nitric oxide (NO) bioavailability, altered abnormal G protein-coupled receptors, and dysregulated renin–angiotensin–aldosterone system lead to vascular endothelial injury, hormone abnormalities related to nutrient metabolism, and chronic systemic inflammation, ultimately resulting in the initiation and progression of HTN. As discussed above, alteration in normal gut microbiota can lead to disease condition., The exact molecular mechanism for the gut microbiota as a potential confounding factor and/or inducer of HTN is still unknown. Many preclinical and clinical studies have been done and are well summarized to check the association between human microbiome, health, and HTN.,,
Obesity and lipid-fat metabolism
Elevated levels in the cholesterol and free fatty acid levels is one of the major factor in atherosclerosis and related complications leading to HTN/cardiovascular disease (CVD). Gut microbiota plays a vital role in the maintenance of energy homeostasis and balance in serum cholesterol and its subtypes along with fat depositions and adiposity. Obesity/adiposity has been assumed to be one of the major contributing factors in metabolic disorders including HTN. It has been found that the levels of Staphylococcus and Enterobacteriaceae, Faecalibacterium prausnitzii, and Escherichia More Details coli are increased in obesity, while those in Bacteroides are decreased in obesity. The proportions of Bacteroides-Prevotella group increase after weight loss in obese adolescents. It has been reported that intestinal flora regulates the expression of farnesoid X receptor, thus suppressing the rate-limiting enzyme CYP7A1 in bile acid synthesis from cholesterol, which reduces the production level of bile acid and elevates the serum cholesterol level that play an atherogenic role in the manifestation and development of CVD. Abnormal small-bowel motility and small intestinal bacterial overgrowth are common in patients with liver cirrhosis with concomitant portal HTN. It is also interesting to note that the F/B ratio is increased in obesity and related with the occurrence of comorbidities and vice versa. On the other hand, opposite results have been observed with increased Akkermansia numbers in feces when obese patients are subjected to standard 52-week weight-loss program.
Oxidative stress and inflammation
Oxidative stress plays an important role in the pathophysiology of vascular abnormalities and HTN. Researchers have shown that microbial diversity influences metabolic pathways through generating oxidative stress and endotoxin, resulting in metabolic disorders. Qiao et al. have shown that alterations in gut microbiota in high-fat diet (HFD) fed mice are strongly linked to oxidative stress. The increased serum levels of uric acid are a risk factor for cardiovascular disease where oxidative stress plays a key role in the pathophysiology. Studies indicated that patients with coronary heart disease have an imbalance of intestinal flora with an increased amount of Streptococcus, Helicobacter pylori, and E. coli and a decreased number of Lactobacillus and Bifidobacterium. The decomposition activity of uric acid facilitated by gut microbiota positively correlates with the contents of E. coli. Therefore, the alteration of gut microbiota results in the increased excretion of uric acid through the intestinal tract and an elevated serum uric acid, leading to oxidative stress. Further, clinical studies have suggested that uric acid could play a contributory role in the pathogenesis of elevated BP. Therefore, the alteration of uric acid mediated by oxidative stress may link intestinal microflora to HTN. Increased oxidative stress also participates in the damage of cell membranes via peroxidation and results in increased intestinal permeability to endotoxin and local or systemic inflammatory reactions. Intestinal microbiota acts as a convertible bond factor to drive inflammatory response and/or oxidative stress, leading to the increase in risk for CVD, including high BP.
Inflammation is yet one more factor studied in efforts to better understand the biological underpinnings of the risk of HTN, atherosclerosis, insulin resistance, obesity, and diabetes. Alterations in intestinal permeability are potential triggers of inflammation in various metabolic and CVDs. Articles are published on the associations among inflammation, gut microbiota, and diseases. The dysbiosis of gut microbiota and bacteria has long been known to activate inflammatory pathways. Kim et al. demonstrated that HFD might cause inflammation in the intestinal lumen and plasma by altering the composition of gut microbiota and increasing its intestinal permeability through the induction of toll-like receptors, thereby accelerating the development of obesity and associated diseases. The effect of minocycline on lowering BP is most likely associated with improving gut microbial homeostasis and contributes to inhibiting the expression of pro-inflammatory cytokines, relieving intestinal damage and reducing mucositis of the intestine.
Endotoxin derived from gut might be a critical factor in chronic inflammation, glucose intolerance, and oxidative stress, which are responsible for an increase in the onset of metabolic diseases. It has been suggested that microbial diversity influences metabolic pathways through generating endotoxins. It has also been shown that endotoxin is positively correlated with total cholesterol, diastolic BP, waist-to-hip ratio, and body mass index, and that it has a negative correlation with high-density lipoprotein cholesterol, leading to the increased risk of CVDs. Many articles proved that the link between the development of systemic low-grade inflammation and CVD is mediated through a lipopolysaccharide receptor-dependent mechanism which finally causes metabolic endotoxemia.
Angiotensin II, an intermediate component in renin–angiotensin system (RAS), works to restore BP by inducing constriction of peripheral vessels. Oral minocycline treatment results in the decrease of high BP and produces positive effects in resisting dysbiosis in chronic angiotensin II infusion HTN in rat models, which suggests that angiotensin II is also a factor that links intestinal microflora and BP. However, the knowledge of this subject is very limited and cannot fully reveal the possible mechanisms of gut microbiota underlying HTN. Renin, one component of RAS that encircles the arterioles at the entrance to the glomeruli of the kidneys, plays a critical role in the regulation of body fluid volume and BP. It has been demonstrated that propionate, a single chain fatty acid (SCFA), could induce vasodilation and produce an acute hypotensive response in wild-type mice, and that the disruption of olfr78, an olfactory receptor expressed in smooth muscle cells of the vasculature, is differentially modulated in this process. Olfr78 plays a role in renin secretion via gut microbiota-derived signals, which means that it can contribute to the control of BP. SCFA receptors take part in nutrient metabolism, adiposity, inflammatory responses, and many other physiological processes via mediating SCFA in responding to microorganisms. Angiotensin-converting enzyme 2 (ACE2) was identified as an enzyme that negatively regulates the RAS by converting angiotensin II. It has also been shown that ACE2 modulates innate immunity and influences the composition of the gut microbiota.,
In addition, the previous studies indicate that microorganism-fermented dairy products may contain ACE inhibitors, which suppress the angiotensin II production and play an important role in regulating the RAS, leading to the reduction of BP.
Resistance to insulin is linked with HTN. Preclinical and clinical studies have shown that with insulin resistance, the stimulatory effect of insulin on glucose uptake in adipocytes, mediated via insulin receptor substrate (IRS) 1, was severely diminished, and its effect on salt reabsorption in the kidney's proximal tubule, mediated via IRS2, was preserved. There can be a condition of salt overload and HTN due to compensatory hyperinsulinemia in individuals with insulin resistance that may enhance salt absorption in the proximal tubule. There are a number of clinical and/or preclinical evidences for the association between insulin resistance and microbiome, indicating their pathogenic as well as therapeutic importance in metabolic syndrome.
The relationship between sodium absorption from the intestine and HTN has been well reviewed by Afsar et al. Alteration in the intestinal structure and function (gut hormone, gut–brain axis, RAS system, etc.) can affect the development and progression of HTN. It is said that SCFAs are energy sources for colonocytes and are involved in the regulation of colonic sodium absorption. They play an important role in allowing the colon to adapt to chronic changes in dietary carbohydrate and sodium loads. High levels of sodium are one of the most important factors in the risk of HTN. Therefore, sodium metabolism may be one possible link between intestinal microflora and BP regulation. However, no evidence has been found to confirm this hypothesis.
Cross talk between transient receptor potential and Ca2+ signaling
The impaired endothelial dysfunction is a coupling with transient receptor potential (TRP)-associated calcium channels in the progression of HTN; due to deregulation of TRP channels, the NO availability is decreased in vascular smooth muscle. This imbalance causes deformities of TRP channels and affects Ca2+ entry, leading to critical vascular physiological dysfunction and HTN.
| Probiotics|| |
Probiotics are the live bacteria and yeast having symbiotic relationship with host and play an important role in maintaining healthy gut. The World Health Organization has considered probiotics as a next-most important immune defense system when commonly prescribed antibiotics are rendered useless by antibiotic resistance. The use of probiotics in antibiotic resistance is termed as microbial interference therapy. With increasing understanding that beneficial microbes are required for health, probiotics are now becoming a common therapeutic tool to be used by health-care practitioners and even many guidelines are also recommending them as a part of potential therapeutic regimen with highest safety. Many probiotics have been screened to check their effect on HTN patients which include but may not be limited to yogurt, sour milk, milk, and rose-hip drink containing Lactobacillus.
Mechanism of action
Probiotics exerts multimodal action in the prevention and treatment of diseases. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression, steric hindrance, and through competitive inhibition. Probiotics mainly acts by decreasing luminal pH; secreting antimicrobial peptides; inhibiting bacterial invasion; blocking the bacterial adhesion to the epithelial cell by increased expression of MUC2 and MUC3 intestinal mucins; enhancing mucous secretion; activating cytokine cascades and immune modulation; and inhibiting/reducing the concentration of myeloperoxidase, tumor necrosis factor-alpha, nuclear factor-kappa B, epidermal growth factor receptor, etc.,,, Probiotics also acts by increasing GI barrier integrity by tightening mucosal barrier and upregulation of growth factors and receptor sites. This occurs through bacterial–epithelial cross talk and helps to maintain the portal HTN., Through the SCFA production, probiotics fosters the growth of nonpathogenic commensal bacteria. Probiotics also gives protective effects through production of H2O2 and benzoic acid, which inhibit many pathogenic, acid-sensitive bacteria.,, SCFA also have anti-inflammatory impact on both colony epithelium and immune cells., SCFA modulates immune signaling through G-protein coupled receptor. SCFA-olfactory78 receptor, which is a type of G-protein coupled receptor involved in odorant sensing, is also expressed in smooth muscle cells of the kidney vasculature, including the glomerular afferent arteriole, where it binds acetate and propionate to regulate glomerular filtration rate and renin release and regulates BP. Both butyrate and propionate cause colonic artery dilation and thereby causes anti-hypertensive activity. The SCFA also works through its receptors Gpr41 and Gpr43 (also called free fatty acid receptor 3 or FFAR3 and FFAR2, respectively) which are involved in BP regulation. The application of probiotics in gastrointestinal motility disorders has been well studied. Therefore, more information of the role of probiotics in the signaling cascade will improve our understanding and helps us to provide new site of biomarkers, which could open a door for other types of regulatory pathways used in HTN cross talk. Probiotics helps to produce so many enzymes, co-factors, metabolites, vitamins, and minerals that are modulating our health. HTN caused by endothelial dysfunction affects NO levels. In a study performed on common bile duct ligation in rats showed prevention of endothelial dysfunction, after ingestion of probiotics. Based on these findings, it was also believed that in vascular smooth muscle cells, probiotic intake has been increased (intracellular calcium) (Ca2+)i in endothelial cells to produce NO which ultimately causes vasodilatation and prevents the contractility of blood vessels. Hence, it is believed that the probiotics has inferable work in HTN. Beyond these findings, another mechanism was postulated that involvement of TRP channels has also linked with Ca2+ entry pathways in HTN because HTN is associated with profound alterations in Ca2+ homeostasis in smooth muscle cell, which plays a major role in hypertensive disease states. However, more studies are required for a better understanding of cross talk between TRP channel-associated calcium entries in the presence of probiotics for controlling the HTN. As HTN is interlinked with other metabolic disorders, it is necessary to examine the outcomes at microscopic level to get a clear picture of probiotic action against CVD.,,,, [Figure 1] depicts the probable mechanism of actions and rationale behind the use of probiotics in the management of HTN.
To exert good pharmacotherapeutic action, probiotics should have the following characteristics: (1) acid and bile resistant; (2) metabolically active in the GIT; (3) able to adhere to the GIT; (4) possess antimicrobial activity toward pathogenic bacteria; and (5) reduce colon pH.,, For pharmacological use, the mostly studied probiotics in case of HTN are: Enterococcus faecium, Bifidobacterium infantis, Bifidobacterium animalis Saccharomyces cerevisiae, Streptococcus thermophilus, and Lactobacillus (Lactobacillus helveticus, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei, and Lactobacillus plantarum), while others are Lactobacillus GG, Bifidobacterium lactis haromyces boulardii, Lactobacillus agilis, and yeast Saccharomyces boulardii. Several clinical trials have been conducted evaluating the use of probiotics and its effects on BP regulation. A meta-analysis of nine randomized trials showed a significant decrease in both systolic BP (SBP) and diastolic BP in HTN patients. A synergistic effect has been observed when multiple species of probiotics were used. Conclusion drawn from this meta-analysis is that consuming probiotics may improve BP by a modest degree, with a potentially greater effect when baseline BP is elevated, multiple species of probiotics are consumed, the duration of intervention is ≥8 weeks, or daily consumption dose is ≥1011 CFUs. A meta-analysis on the effect of probiotics-fermented milk on HTN has shown that Japanese population showed better results than their European counterparts. The reduction in HTN in Japanese versus European population for both SBP and diastolic BP was −6.12 versus −2.08 mmHg and −3.45 versus −0.52 mmHg, respectively.,,
Drug–disease–microbiome interactions need to be taken into consideration while use probiotics which may affect the pharmacotherapeutics, safety, efficacy, and potency of its own but also of concomitantly administered drug., For instance, several medications are commonly prescribed to patients with metabolic syndrome, including the antidiabetic drug metformin and the lipid-lowering drug simvastatin, which were suggested to be modulated by the gut microbiome. Epidemiological data show that HTN patients are more prone to periodontitis caused by periodontitis-causing bacteria, including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola., Microbiota gets altered and involved in the development and progression of several diseases including but not limited to diabetes, cancer, obesity, gastroenteropathy, and inflammatory bowel disease.,,,, Therefore, such factors also need to be taken seriously, especially when dealing with drug of narrow therapeutic window, higher plasma protein binding, and less Vd (volume of distribution).
| Controversies|| |
Various meta-analysis and systematic reviews ,,, so far have supported the use of probiotics for the management of HTN except one contradicting case study which has been discussed below.
Goeser et al. had conflicting conclusion from their study in a recurrent Clostridium difficile-infected hypertensive patient treated by fecal microbiota transplantation (FMT). They concluded that “hypertensive episodes may occur shortly after FMT and reflect a potentially hitherto unknown side effect of FMT resulting from interference of the 'new' intestinal microbiome with BP-regulating factors.” One cannot directly reject this interpretation, but this conclusion cannot be completely supported and seems to be overemphasized. Because, the patient in their study was with multiple problems including geriatric condition, tetraplegia, and had experienced repeated aspiration episodes (due to stroke) complicated by subsequent pneumonias, chronic hepatitis C infection, peripheral artery occlusion and coronary heart disease with a previous history of myocardial infarction, type 1 diabetes, and arterial HTN. The role of disease–disease interaction is also well accepted in scientific fraternity and, according to us, this also may have played role for posttreatment arterial HTN., Therefore, increased arterial HTN cannot be calmed as a side effect of FMT, which may be overemphasizing the claim. However, it was worth to note that the highly resistive recurrent Clostridium difficile infection was totally cured by the FMT treatment in this complex case of HTN with comorbidities.,
| Future Perspective|| |
Personalized probiotic antihypertensive treatment
Microbiome of an individual can vary with respect to patient-related factors including but not limited to hygiene-related habits, genetics, sex, age, disease, individualized nutritional status, diet, lifestyle, and environmental-geographical condition. Therefore, it is also important to incorporate/consider these aspects while designing the clinical studies. Predictive tools may be a futuristic approach to offer help in this regard. Apart from this, it is also important to focus on drug–disease–microbiome interplay in order to ensure higher degree of personalization in HTN management.
| Discussion and Conclusion|| |
Metabolic disorders such as HTN involve many pathways and feedback loops for the maintenance of normal homeostatic balance. One has to take all the possible efforts to prevent HTN and/or halt the progression of HTN so that other related comorbidities do not develop. For instance, it is interesting to note the findings of a Heart Outcomes Prevention Evaluation study, which showed that even modest reductions of SBP and diastolic BP by 3.3 and 1.4 mmHg, respectively, were associated with a 22% reduction in the relative risk of cardiovascular mortality, myocardial infarction, or stroke. Therefore, pharmacotherapeutic measures which are helpful to ensure the maintenance of normal homeostatic balance, have potential to prevent as well as treat the disease with minimal or no side effects, have the highest nutritional and/or pharmacotherapeutic value, and probiotics are the best examples of the same. Today is the world of personalization and hence personalized medicine is gaining more and more importance. Considering the same, even population-based/country-specific approaches for the pharmacotherapeutic use of probiotics need to be developed.,,
Guandalini has well said that “the probiotics have now left the field of ''alternative'' medicine and popular remedies, and have entered at full title that of mainstream medicine. Clearly, there is more to come!” In other words, although scientific fraternity has well accepted the importance/role of gut microbiota in the maintenance of healthy condition and probiotics are being used as a potential pharmacotherapeutic agent, we need to do more strategic researches in order to develop proper clinical guidelines for the use of probiotics as a both preventative/nutritional and pharmacotherapeutic agent.
The authors are thankful to B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre and NIRMA University, Ahmedabad, India, for providing all the facilities for the successful completion of the work. Authors are also thankful to Ms. Pallavi Rane for her timely help.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, et al.
Global burden of hypertension and systolic blood pressure of at least 110 to 115 mm hg, 1990-2015. JAMA 2017;317:165-82.
Sun J, Xu W, Wang G. The role of intestinal microflora and its possible mechanisms in hypertension. Lipid Cardiovasc Res 2016;2:8-16.
Relman DA. Gut microbiota: How to build healthy growth-promoting gut communities. Nat Rev Gastroenterol Hepatol 2016;13:379-80.
Levy J. The effects of antibiotic use on gastrointestinal function. Am J Gastroenterol 2000;95:S8-10.
Putignani L. Human gut microbiota: onset and shaping through life stages and perturbations. Frontiers 2013;2:1-2.
Charbonneau MR, O'Donnell D, Blanton LV, Totten SM, Davis JC, Barratt MJ, et al.
Sialylated milk oligosaccharides promote microbiota-dependent growth in models of infant undernutrition. Cell 2016;164:859-71.
Hemaiswarya S, Raja R, Ravikumar R, Carvalho IS. Mechanism of action of probiotics. Braz Arch Biol Technol 2013;56:113-9.
Wexler HM. Bacteroides: The good, the bad, and the nitty-gritty. Clin Microbiol Rev 2007;20:593-621.
D'Argenio V, Salvatore F. The role of the gut microbiome in the healthy adult status. Clin Chim Acta 2015;451:97-102.
Mariat D, Firmesse O, Levenez F, Guimarăes V, Sokol H, Doré J, et al.
The firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 2009;9:123.
Pevsner-Fischer M, Blacher E, Tatirovsky E, Ben-Dov IZ, Elinav E. The gut microbiome and hypertension. Curr Opin Nephrol Hypertens 2017;26:1-8.
Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr 2002;22:283-307.
Yang T, Santisteban MM, Rodriguez V, Li E, Ahmari N, Carvajal JM, et al.
Gut dysbiosis is linked to hypertension. Hypertension 2015;65:1331-40.
Emoto T, Yamashita T, Sasaki N, Hirota Y, Hayashi T, So A, et al.
Analysis of gut microbiota in coronary artery disease patients: A possible link between gut microbiota and coronary artery disease. J Atheroscler Thromb 2016;23:908-21.
Rahmouni K. Obesity-associated hypertension: Recent progress in deciphering the pathogenesis. Hypertension 2014;64:215.
Guo S. Insulin signaling, resistance, and the metabolic syndrome: Insights from mouse models into disease mechanisms. J Endocrinol 2014;220:T1-T23.
Sies H. Role of metabolic H2O2 generation: Redox signaling and oxidative stress. J Biol Chem 2014;289:8735-41.
Samuel BS, Shaito A, Motoike T, Rey FE, Backhed F, Manchester JK, et al.
Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, gpr41. Proc Natl Acad Sci U S A 2008;105:16767-72.
Li S, Zhang C, Gu Y, Chen L, Ou S, Wang Y, et al.
Lean rats gained more body weight than obese ones from a high-fibre diet. Br J Nutr 2015;114:1188-94.
Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, et al.
Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013;17:225-35.
Louis S, Tappu RM, Damms-Machado A, Huson DH, Bischoff SC. Characterization of the gut microbial community of obese patients following a weight-loss intervention using whole metagenome shotgun sequencing. PLoS One 2016;11:e0149564.
Qiao Y, Sun J, Ding Y, Le G, Shi Y. Alterations of the gut microbiota in high-fat diet mice is strongly linked to oxidative stress. Appl Microbiol Biotechnol 2013;97:1689-97.
Mazzali M, Kanbay M, Segal MS, Shafiu M, Jalal D, Feig DI, et al.
Uric acid and hypertension: Cause or effect? Curr Rheumatol Rep 2010;12:108-17.
Muccioli GG, Naslain D, Bäckhed F, Reigstad CS, Lambert DM, Delzenne NM, et al.
The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 2010;6:392.
Kim KA, Gu W, Lee IA, Joh EH, Kim DH. High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 2012;7:e47713.
Garrido-Mesa N, Utrilla P, Comalada M, Zorrilla P, Garrido-Mesa J, Zarzuelo A, et al.
The association of minocycline and the probiotic escherichia coli
nissle 1917 results in an additive beneficial effect in a DSS model of reactivated colitis in mice. Biochem Pharmacol 2011;82:1891-900.
Sorbara S. Gut bacteria and their influence on metabolic disorders. Biology Undergraduate Publications. 2014;1:BI-399.
Stoll LL, Denning GM, Weintraub NL. Endotoxin, TLR4 signaling and vascular inflammation: Potential therapeutic targets in cardiovascular disease. Curr Pharm Des 2006;12:4229-45.
Varagic J, Ahmad S, VonCannon JL, Moniwa N, Brosnihan KB, Wysocki J, et al.
Predominance of AT1 blockade over mas–mediated angiotensin-(1–7) mechanisms in the regulation of blood pressure and renin–angiotensin system in mRen2. Lewis rats. Am J Hypertens 2013;26:583-90.
Siragy HM, Carey RM. Role of the intrarenal renin-angiotensin-aldosterone system in chronic kidney disease. Am J Nephrol 2010;31:541-50.
Afsar B, Vaziri ND, Aslan G, Tarim K, Kanbay M. Gut hormones and gut microbiota: Implications for kidney function and hypertension. J Am Soc Hypertens 2016;10:954-61.
Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y. Effect of powdered fermented milk with lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension. J Am Coll Nutr 2005;24:257-65.
Pietri P, Vlachopoulos C, Tousoulis D. Inflammation and arterial hypertension: From pathophysiological links to risk prediction. Curr Med Chem 2015;22:2754-61.
Musch MW, Bookstein C, Xie Y, Sellin JH, Chang EB. SCFA increase intestinal Na absorption by induction of NHE3 in rat colon and human intestinal C2/bbe cells. Am J Physiol Gastrointest Liver Physiol 2001;280:G687-G93.
Félétou M, Köhler R, Vanhoutte PM. Endothelium-derived vasoactive factors and hypertension: Possible roles in pathogenesis and as treatment targets. Curr Hypertens Rep 2010;12:267-75.
Bengmark S. Colonic food: Pre- and probiotics. Am J Gastroenterol 2000;95:S5-7.
Kawase M, Hashimoto H, Hosoda M, Morita H, Hosono A. Effect of administration of fermented milk containing whey protein concentrate to rats and healthy men on serum lipids and blood pressure. J Dairy Sci 2000;83:255-63.
Drisko JA, Giles CK, Bischoff BJ. Probiotics in health maintenance and disease prevention. Altern Med Rev 2003;8:143-55.
Sekirov I, Russell SL, Antunes LC, Finlay BB. Gut microbiota in health and disease. Physiol Rev 2010;90:859-904.
Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 2009;9:313-23.
Giofré MR, Meduri G, Pallio S, Calandra S, Magnano A, Niceforo D, et al.
Gastric permeability to sucrose is increased in portal hypertensive gastropathy. Eur J Gastroenterol Hepatol 2000;12:529-33.
Gionchetti P, Rizzello F, Venturi A, Campieri M. Probiotics in infective diarrhoea and inflammatory bowel diseases. J Gastroenterol Hepatol 2000;15:489-93.
Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, et al.
Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009;461:1282-6.
Bär F, Von Koschitzky H, Roblick U, Bruch HP, Schulze L, Sonnenborn U, et al.
Cell-free supernatants of escherichia coli
nissle 1917 modulate human colonic motility: Evidence from an in vitro
organ bath study. Neurogastroenterol Motil 2009;21:559-66, e16-7.
Dubey V, Ghosh AR. Probiotics cross talk with multi cell signaling in colon carcinogenesis. J Prob Health 2013;1:2-5.
Rashid SK, Khodja NI, Auger C, Alhosin M, Boehm N, Oswald-Mammosser M, et al.
Probiotics (VSL# 3) prevent endothelial dysfunction in rats with portal hypertension: Role of the angiotensin system. PLoS One 2014;9:e97458.
Sobol C, Korotkov S, Belostotskaya G, Nesterov V. The influence of probiotics and probiotic product on respiration of mitochondria and intracellular calcium signal in cells of cardiovascular system. Biochem (Moscow) Suppl Ser A Membr Cell Biol 2013;7:294-301.
Firth AL, Remillard CV, Yuan JX. TRP channels in hypertension. Biochim Biophys Acta 2007;1772:895-906.
Guandalini S. Probiotics for children with diarrhea: An update. J Clin Gastroenterol 2008;42 Suppl 2:S53-7.
Khalesi S, Sun J, Buys N, Jayasinghe R. Effect of probiotics on blood pressure: A systematic review and meta-analysis of randomized, controlled trials. Hypertension 2014;64:897-903.
Dong JY, Szeto IM, Makinen K, Gao Q, Wang J, Qin LQ, et al.
Effect of probiotic fermented milk on blood pressure: A meta-analysis of randomised controlled trials. Br J Nutr 2013;110:1188-94.
Menche J, Sharma A, Kitsak M, Ghiassian SD, Vidal M, Loscalzo J, et al.
Disease networks. Uncovering disease-disease relationships through the incomplete interactome. Science 2015;347:1257601.
Kaddurah-Daouk R, Baillie RA, Zhu H, Zeng ZB, Wiest MM, Nguyen UT, et al.
Enteric microbiome metabolites correlate with response to simvastatin treatment. PLoS One 2011;6:e25482.
Desvarieux M, Demmer RT, Jacobs DR Jr., Rundek T, Boden-Albala B, Sacco RL, et al.
Periodontal bacteria and hypertension: The oral infections and vascular disease epidemiology study (INVEST). J Hypertens 2010;28:1413-21.
Faujdar SS, Mehrishi P, Bishnoi S, Sharma A. Role of probiotics in human health and disease: An update. Int J Curr Microbiol App Sci 2016;5:328-44.
Singh SP, Nivsarkar M. A Novel Model for NSAID Induced Gastroenteropathy and the Proposed Role of TNF-α: Way Forward for the Discovery of Futuristic Therapeutic Interventions. 3rd
Nirma Institute of Pharmacy International Conference-NIPiCON 2016 “Global Challenges in Drug Discovery, Development and Regulatory Affairs”; Ahmedabad; 2016.
Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: Basic principles and practical applications. Br J Clin Pharmacol 2004;57:6-14.
Goeser F, Schlabe S, Ruiner CE, Kramer L, Strassburg CP, Spengler U, et al.
Non-invasive fecal microbiota transplantation for recurrent clostridium difficile infection in a patient presenting with hypertensive disorder post interventionem. Z Gastroenterol 2016;54:1143-6.
Linghu B, Snitkin ES, Hu Z, Xia Y, DeLisi C. Genome-wide prioritization of disease genes and identification of disease-disease associations from an integrated human functional linkage network. Genome Biol 2009;10:R91.
Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J, et al.
Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet 2001;358:2130-1.