Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease?

G Model

ARTICLE IN PRESS

YPHRS-3806; No. of Pages 12

Pharmacological Research xxx (2018) xxx–xxx

Contents lists available at ScienceDirect

Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs

Review

Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Marinaldo Pacífico Cavalcanti Neto a , Jailane de Souza Aquino b , Larissa de Fátima Romão da Silva b , Ruanniere de Oliveira Silva b , Keyth Sulamitta de Lima Guimarães b , Yohanna de Oliveira b , Evandro Leite de Souza b , Marciane Magnani c , Hubert Vidal d , José Luiz de Brito Alves b,d,∗ a

Laboratory of Cell Signaling Metabolic Modulation, Institute of Health Biotechnology, Federal University of Amazonas, Coari, Brazil Department of Nutrition, Health Sciences Center, Federal University of Paraiba, Joao Pessoa, Brazil Department of Food Engineering, Technology Center, Federal University of Paraiba, Joao Pessoa, Brazil d Univ-Lyon, CarMeN (Cardio, Metabolism, Diabetes and Nutrition) Laboratory, INSERM U1060, INRA U1397, Université Claude Bernard Lyon 1, INSA Lyon, Oullins, France b c

a r t i c l e

i n f o

Article history: Received 31 August 2017 Received in revised form 24 January 2018 Accepted 29 January 2018 Available online xxx Keywords: Probiotics Gut dysbiosis Cardiometabolic disorders Chronic kidney disease Oxidative stress Inflammation

a b s t r a c t The gut microbiota plays an important role in host metabolism and its dysregulation have been related to cardiometabolic disorders (CMD), such as type 2 diabetes mellitus (T2D), dyslipidemia and arterial hypertension, as well as to chronic kidney diseases (CKD). The implication of the gut microbiota on systemic disorders has been associated with changes in its composition (dysbiosis) as a result of the oxidative unbalance in the body. This alteration may be the result of the adoption of unhealthy lifestyle behavior, including lack of physical activity and fat- or sugar-rich diets, which are largely associated with increased incidence of CMD and CKD. In last years, a number of clinical trials and experimental studies have demonstrated that probiotics can modulate the host metabolism, resulting in amelioration of systemic disease phenotypes by the improvement of dyslipidemia, glycemic profile and blood pressure or CKD parameters. The beneficial effects of probiotics consumption have been associated with their anti-inflammatory, antioxidant and gut-modulating properties. Despite of some mechanistic evidence, these effects are not totally elucidated. The present review summarizes and clarifies the effects of probiotics administration on CMD and CKD using combined evidence from clinical and experimental studies. Considering that the microbiota dysregulation has been associated with inflammation and oxidative stress and consequently with CMD and CKD, supplementation with probiotics is discussed as a strategy for management of CMD and CKD. © 2018 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Gut microbiota as a potential therapeutic target for probiotic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Dyslipidemias, gut microbiota and probiotic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 3.1. Experimental findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Abbreviations: HMG-CoA, 3-hydroxy-3-methyl glutaryl-coenzyme A; BUN, Blood urea-nitrogen; BMI, Body mass index; BCAAs, Branched-chain amino acids; CMD, Cardiometabolic disorders; CD, Cardiovascular disease; CKD, Chronic kidney diseases; CRP, C reactive protein; DMA, Dimethylamine; GPCRs, G protein coupled receptors; GLP1, Glucagon-like peptide 1; GSH-Px, Glutathione peroxidase; GR, Glutathione reductase; HbA1C, Glycosylated hemoglobin; HDL-c, High-density lipoprotein cholesterol; indS, Indoxyl sulfate; ICAM-1, Intercellular adhesion molecule 1; LAB, Lactic acid bacteria; LPS, Lipopolysaccharides; LDL-c, Low-density lipoprotein cholesterol; MDA, Malondialdehyde; Ox-LDL, Oxidized low-density lipoprotein; PCS, P-cresyl sulfate; PYY, Peptide YY; ROS, Reactive oxygen species; SCFA, Short chain fatty acids; SOD, Superoxide dismutase; TAC, Total antioxidant capacity; TC, Total cholesterol; GSH, Total gluthatione; TG, Triglycerides; TMAO, Trimethylamine-N-oxide; TNF-␣, Tumor necrosis factor alpha; T2D, Type 2 diabetes mellitus; VCAM, Vascular cell adhesion molecule. ∗ Corresponding author at: Federal University of Paraiba, Department of Nutrition, Campus I − Jd. Cidade Universitária, João Pessoa, PB, CEP: 58051-900, Brazil. E-mail address: jose luiz [email protected] (J.L. de Brito Alves). https://doi.org/10.1016/j.phrs.2018.01.020 1043-6618/© 2018 Elsevier Ltd. All rights reserved.

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

2

3.2. Clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Type 2 diabetes, gut microbiota and probiotic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. Experimental findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. Clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5. Chronic kidney disease, gut microbiota and probiotic intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.1. Experimental findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2. Clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6. Additional aspects considering the use of probiotics in CD and CKD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 7. Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Financial support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.

1. Introduction Most of cardiometabolic disorders (CMD), such as type 2 diabetes mellitus (T2DM), dyslipidemia and arterial hypertension, are main risk factors for the development of cardiovascular disease (CD) and chronic kidney diseases (CKD). These disorders are considered primary causes of premature death and disability in under, middle and highly developed countries [1–3]. The increase of CMD and CKD worldwide, in part, has been associated with unhealthy lifestyle behavior, diet rich in calories, sugar, saturated fatty acids and cholesterol and lack of physical activity [4]. This lifestyle is an important risk factor for oxidative unbalance among pro-oxidant factors and anti-oxidant enzymes, high level of pro-inflammatory markers and change in gut microbial composition [5]. Alteration in gut-microbiota homeostasis, including a low survival of lactic acid bacteria (LAB) and gut dysbiosis, has been associated with facilitated passage of lipopolysaccharide (LPS) from intestinal barriers to systemic circulation. LPS stimulates the production of pro-inflammatory cytokines, which are implicated in many systemic disorders [6–8]. Excessive free radicals and pro-inflammatory cytokines have been associated with several metabolic pathways dysregulation in pancreas, kidney, adipose tissue, skeletal muscle, liver and blood vessels (Fig. 1), causing the development of CD and CKD [9,10]. These findings reveal the complexity and multi-factorial nature of non-communicable diseases and indicate gut microbiota intervention as a potential therapeutic target for the management of these diseases. Increasing experimental and clinical evidence demonstrates that probiotic consumption promotes beneficial effects on cardiometabolic and kidney parameters, such as i) improvement of dyslipidemia; ii) improvement of glycemic profile; iii) attenuation of blood pressure in hypertensive conditions; and iv) improvement of CKD. Although there is evidence demonstrating that probiotics consumption alleviates CMD and CKD, the underlying mechanisms are not still totally understood. Some studies have suggested that the benefits of probiotics consumption may be related to their antiinflammatory [11,12], antioxidant [13–17] and gut-modulating properties [18]. In order to highlight these new insights, this review will approach firstly the gut microbiota as a potential therapeutic target for probiotics intervention. Lastly, we will focus on the findings of experimental and clinical studies on the possible benefits of probiotic consumption on dyslipidemia, T2DM and CKD. We highlight our recently published review approaching on the potential beneficial effects of probiotics for the management of arterial hypertension, showing how probiotic supplementation helped blood pressure control in experimental and clinical studies [19]. To the best of our knowledge, due to the lack of new original articles published in the last years about the effects of probiotic on arterial hypertension, the referred research topics has not been included in the present review.

2. Gut microbiota as a potential therapeutic target for probiotic intervention The gut microbiota forms a complex and highly dynamic ecosystem in host. The initial colonization of the gastrointestinal tract is established between birth and 4 years. At about 70 years, a new modification in composition of gut microbiota is characterized by reduced population of Bifidobacterium (B.) and increased population of Clostridium. Different microbial ecosystems colonize the different gut compartments. The microbial population increases along the gastrointestinal tract, from 102 –104 cells in the stomach and duodenum, 104 –108 in the jejunum and ileum, to 1010 –1012 cells in the colon and faeces. The colon is the most densely colonized part of the gastrointestinal tract containing approximately 500–1000 different bacterial species, each with its own range of metabolic activities. This bacterial diversity makes the colon the most metabolically active organ in the human body [20,21]. Although most of the microorganisms forming the human gut microbiota are bacteria, several species of archae, protozoa and fungi are found in this environment. The most dominant archaeal groups are methane-producing species [22]. For the fungi, the majority belong to the phyla Ascomycota (including the genus Candida and Saccharomyces) and Basidiomycota [23]. Viruses are also important components of gut microbiota, leading to the recent concept of “gut virome” [24]. Regarding the bacteria, the predominant phyla are the Firmicutes (Gram + ) and the Bacteroidetes (Gram-). Among the other phyla, members of Actinobacteria (including genus Bifidobacterium), Verrucomicrobia (including genus Akkermansia) and Proteobacteria (including genus Escherichia) are known to influence human nutrition and metabolism, but several other phyla are represented in the human gut [25,26]. The Firmicutes include a large number of genera with prominent members in the human gut, e.g., Eubacterium, Roseburia, Ruminococcus, and to a lesser extent Lactobacillus (L.). The Bacteroidetes group includes bacteria belonging mainly to genera Bacteroides and Prevotella. While the distribution of these phyla varies across populations, a small number of broad patterns of gut microbiota composition, named enterotypes, which do not depend on the country or the continent of the subjects, are possible to be defined [27]. The gut microbiota exerts intense metabolic activity, maintaining a symbiotic interaction with the host [28]. These metabolic functions have important implications for human health and nutrition, although they depend on the gut microbiota composition and complex interactions of diet and host. The composition of gut microbiota may be influenced by age, gender, drugs, hormonal conditions, host genotype, phylogeny and environmental factors (e.g., diet, smoking, alcohol consumption and stress) [29]. The eating style is considered a key factor affecting the microbial composi-

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

3

Fig. 1. Schematic drawing showing the impact of gut microbiota dysbiosis on the inflammation, oxidative stress and systemic damage in several key tissues under cardiometabolic disorders (CMD) and chronic kidney disease (CKD). After probiotic intervention, the microbial diversity is potentially augmented. This contributes reducing gut dysbiosis, inflammation, oxidative stress and lastly metabolic and cariod-renal disorders. OS (oxidative stress); FFA (free fat acids); GFR (glomerular filtration rate).

tion and, eventually, causing a breakdown of the epithelial barrier [30]. As a living “organ”, the gut microbiota requires nutrients and energy to grow and maintain cellular processes. The composition and metabolism of the gut microbiota can be influenced by diet composition, mostly by the kind of carbohydrate, protein and fat. Bacteria use these substrates for the production of different molecules capable of influencing human health and metabolism (Table 1). During carbohydrate fermentation, colonic bacteria produce short chain fatty acids – SCFA (mainly acetate, propionate, and butyrate), lactate and gases (CO2 , H2 , and methane) [31]. These products exert a variety of functions in the intestinal tract, such as act as carbon and energy sources to other more specialized bacteria, stimulate the increase in epithelial cells proliferation, facilitate epithelial cell differentiation and regulate immune functions and gut hormones [32,33]. Protein fermentation leads to the production of branched-chain amino acids and a variety of phenolics and other metabolites potentially toxic to the host. These later are normally detoxified in the intestinal barrier and by the liver, but could exert harmful effects in some pathological situations [34]. Lastly, the role of the gut microbiota in the regulation of host lipid metabolism, especially cholesterol, has been suggested [35]. One mechanism relies on

the effect of fermentation-derived propionate on the activity of the enzyme 3-Hydroxy-3-Methyl Glutaryl-Coenzyme A synthase in the liver, leading to inhibition of cholesterol synthesis [36]. Furthermore, several gut bacteria, particularly lactobacilli, possess bile acid hydrolase activities and are able to hydrolyze bile salts [37]. This activity has an impact on the enterohepatic cycle of bile acids, causing increased fecal loss of bile salts and secondary reduction of serum cholesterol due to stimulation of bile acid synthesis in the liver [38]. The gut microbiota displays an intrinsic capacity to adapt to nutrient availability and changes in environmental conditions. However, exogenous factors (e.g., high dietary fat and sugar, nonsteroidal anti-infammatory drugs, antibiotics and oxidative stress) can induce gut dysbiosis [30], impairing the gut microbiota composition. An increased ratio of the phylum firmicutes to genus Bacteroides has been associated with dysbiosis condition [39]. An increasing number of diseases have been associated with disturbance of the normal gut microbiome or gut dysbiosis, such as obesity [6], dyslipidemias [40], insulin resistance and diabetes [41,42], liver cirrhosis [43], hypertension and CKD [10]. Strategies capable of recovering the community of commensal microbiota and controlling CMD and chronic kidney disease have recently attracted attention [39,44]. Probiotic, prebiotic or symbi-

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

4

Table 1 Metabolites produced by the intestinal microbiota and the health benefits of the host. Microorganisms involved Escherichia coli Bifidobacterium adolescentis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis, Bifidobacterium longum Streptococcus thermophilus and Bifidocateria Bacteroides, Bifidobacteria, Lactobacilli, Clostridia, Eubacteria, Fusobacteria, Butyrvibrio, Veillonella Peptostreptococci

Metabolites

Health benefits

Vitamin K Complex B vitamins

Folic acid Acetate

Clostridia, Fusobacteria, Butyrvibrio, Peptostreptococci, Eubacteria

Butyrate

Bacteroides, Propionbacteria, Veillonella

Propionate

otic intervention has been used in improvement of gut microbiota dysfunction and management of CMD and chronic kidney disease [45]. The term probiotic was first used to describe compounds produced by protozoa to stimulate the growth of other organisms [46]. Probiotics are currently defined as non-pathogenic microorganisms that, when consumed in adequate amounts, are able to reach the gut in sufficient amounts and confer health benefits to the host [47]. In part, the beneficial effects of probiotics could be due to their immunoregulatory properties. For example, probiotic strains have been shown to stimulate dendritic cell-induced T-regulatory cells to produce higher anti-inflammatory cytokine IL10 and attenuate IL-6 and TNF-␣ production [48,49]. Additionally, some probiotic strains could elicit antioxidant effects through the action of manganese superoxide dismutase, pseudo-catalase and peroxidase enzymes, protecting intestinal cells from the harmful effects of free radicals [17]. The human microbiome modulation could be favored by prebiotic compounds, defined as “non-digestible food components that induce the growth or activity of beneficial microorganisms in the gut, conferring benefits to host wellbeing and health” [20,50]. The combination of probiotic and prebiotic, named symbiotic, have gained growing attention due to a favourable interaction between probiotic strains and the prebiotic substrate, resulting in increased health benefits [45]. 3. Dyslipidemias, gut microbiota and probiotic intervention Multifactorial dyslipidemia, characterized by high levels of total cholesterol, triglycerides, low-density lipoprotein (LDL) or a decrease in high-density lipoprotein (HDL) are relevant risk factors for development of CD [51,52]. In part, modification in lipid metabolism is associated with type of fatty acids in diet. High intake of saturated, trans fatty acids and cholesterol has been associated with high serum levels of triglycerides, cholesterol, LDL-c and reduced HDL [53]. Additionally, a high fat diet has been shown to increase the population of E. coli and production of lipopolysaccharides, favoring inflammation and gut dysfunction [54]. Altered

Prevention of bleeding Prevention of diabetes Improvement of glucose, amino acids and fatty acids metabolism. Maintenance of the immune, nervous and circulatory system Increase in bone density and bone mineral content Possible increase in absorption of cc and magnesium, decrease of faecal loss of calcium and magnesium Decreased resistance in blood vessels Increased portal venous blood flow in the hepatic and colon Capacity to regulate appetite and body weight in mice (transported mainly to astrocytes in the hypothalamus) Decreased resistance in blood vessels Increased portal venous blood flow in the hepatic and colon Maintenance of mucosal integrity, repair of ulcerative colitis, proliferation of colonocytes Greater absorption of ions and fluids (prevention of diarrhea) Decreased resistance in blood vessels Increased s portal venous blood flow in the hepatic and colon Greater absorption of ions and fluids (prevention of diarrhea) Possible increase in absorption capacity Improvement of constipation problems

composition of microbiota and increased gut permeability, favoring higher translocation of dietetic lipids, cholesterol, inflammatory markers and ROS into the blood, have been related to dyslipidemia in both animal models and clinical trials [55]. These findings reinforce the gut microbiota modulation as part of a potential strategy to control dyslipidemia. Evidence supports the important role of gut microbiota in the development of dyslipidemias, with growing interest in the use of probiotic to prevent or treat dyslipidemia conditions [55–57]. In this section, the main experimental and clinical findings related to probiotic supplementation under dyslipidemias conditions will be discussed. 3.1. Experimental findings Preclinical studies have investigated the effects of probiotic strains administration on the lipid profile. In dyslipidemic mice, L. rhamnosus GG daily administration (1 × 108 CFU/mouse, for 13 weeks) effectively restored gut microbiota composition, improved hypertriglyceridemia, hypercholesterolemia and hepatic fat accumulation [57]. Interestingly, the improvement of hepatic steatosis has been associated with reduction in mRNA levels of lipogenic genes (notably PPAR␥, FAS and SREBP1c) and mRNA levels of proinflammatory cytokines, such as IL-6 and IL-12 [57]. Similarly, administration of L. rhamnosus hsryfm 1301 and milk fermented by this strain (109 CFU/mL, for 28 days) reduced cholesterol and triglycerides serum levels in a hyperlipidaemic rat model [58]. The daily supplementation of L. reuteri GMNL-263 at a dose of 5 × 108 CFU/kg or 2.5 × 109 CFU/kg for 8 weeks reduced the serum levels of cholesterol (approximately 15%), LDL-cholesterol (approximately 51%) and triglycerides (approximately 34%) in a hyperlipidaemic hamster model [59,60], causing improvement of the cardiovascular ejection fraction and fractional shortening. L. acidophilus strains have also been reported as potential probiotics with hypolipidaemic properties, acting directly on cholesterol assimilation [61] or through a bile salt-deconjugating activity [62] in the gastrointestinal tract. A long-term daily administration of L. acidophilus NS1 (1.0 × 108 CFU/mL, for 10 weeks) reduced the

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

plasma levels of cholesterol, LDL-cholesterol and triglycerides in diet-induced obese mice [63]. The treatment with two L. plantarum strains (CAI6 and SC4, 10 mL/kg of a solution 2.0 × 109 CFU/mL, for 28 days) caused a discrete reduction in serum levels of cholesterol (−10%/−7%) in hyperlipidaemic mice [64]. However, serum levels of LDLcholesterol (−17%/−15%) and triglycerides (−19%/−13%) were reduced after 28 days of intervention [64]. Interestingly, L. plantarum supplementation did not confer any beneficial effect on lipid parameters in healthy mice [64] Analyzing the effects of combined strains supplementation, the administration of two faecal-derived Lactobacillus strains (L. plantarum 9–41-A and L. fermentum M1-16) to rats fed a highcholesterol diet for six weeks showed hypocholesterolemic effects, which were associated with improved intestinal microbial balance [65]. The daily supplementation of a probiotic mixture containing B. longum, B. lactis, B. brevis, L. reuteri and L. plantarum in different doses (1.65 × 109 and 1.65 × 1010 CFU/kg for 8 weeks) reduced serum total cholesterol, triglycerides, LDL-cholesterol and inhibited hepatic steatosis in diet-induced hypercholesterolaemic rats [66]. Additionally, treatment for 5 weeks with a probiotic mixture containing L. acidophilus LA-5 and B. animalis subsp. lactis BB-12 exerted hypolipidaemic effects and reduced oxidative stress in the liver and myocardium [67]. Saccharomyces boulardii is the main nonpathogenic yeast used as a probiotic. The preventive and curative effects of S. boulardii supplementation (at 12 × 1010 CFU/kg (3 g/kg) twice a day, for 14 days) on lipid profile in hamsters fed a cholesterol-enriched diet resulted in reduction in serum levels of cholesterol and triglycerides [68]. 3.2. Clinical findings The beneficial effects of probiotic supplementation on lipid dysregulation have also been demonstrated in small-scale, double blind, placebo-controlled studies (Table 2). A double-blind randomized crossover placebo-controlled study performed with male and female hypercholesterolaemic volunteers (aged between 20 and 65 years) found no benefit of the supplementation with freeze-dried L. acidophilus for six weeks on serum lipids level [69]. Similarly, a 10 weeks-supplementation with L. fermentum did not improve serum lipid levels in hypercholesterolaemic volunteers [70]. Otherwise, in a randomized, double blind, controlled, crossover trial, the cholesterol-lowering capacity of a 12 weeksupplementation with L. plantarum CECT 7527, CECT 7528 and CECT 7529 in hypercholesterolaemic patients was demonstrated [71]. Two double-blind, placebo-controlled studies demonstrated that supplementation with L. acidophilus L1 [72] or with probiotic yogurt (fermented with a starter composed of L. acidophilus and B. lactis) [73] had a cholesterol-lowering effect in hypercholesterolaemic subjects. In a randomized double-blind clinical trial, the supplementation with L. curvatus and L. plantarum for 12 weeks reduced triglyceride serum levels, but did not alter TC, HDL and LDL-cholesterol serum levels in hypertriglyceridaemic subjects [74]. A recent meta-analysis including randomized clinical trials demonstrated that probiotic consumption from fermented milk products and probiotic preparations are effective to attenuate total cholesterol and LDL-cholesterol serum levels [75]. Similarly, another meta-analysis including randomized controlled trials demonstrated that consumption of probiotics is effective to reduce total-cholesterol and LDL-cholesterol in subjects with high, borderline high and normal cholesterol levels [76]. These data indicate the key role of gut microbiota in the regulation of lipid metabolism as well as the importance of dietary probiotic supplementation as a therapeutic tool for dyslipidemic disorders.

5

4. Type 2 diabetes, gut microbiota and probiotic intervention T2D is one of the most important metabolic disorders caused when the pancreatic ␤-cells do not produce sufficient insulin to maintain a normal blood glucose level or due to insulin resistance [77]. A combination of several risk factors, such as genetic susceptibility, age, obesity, physical inactivity, sedentary lifestyle and unhealthy eating habits (e.g., high consumption of glucose, fructose and fat) has been associated with elevated risk of T2D [78,79]. Additionally, growing evidence suggests that disruption of intestinal permeability could be also involved in the development of T2D [80–83]. This impaired intestinal permeability has been associated with inadequate microbial gut composition [80]. Studies have observed lower population of Firmicuts and butyrate-producing bacteria (Roseburia and Faecalibacterium prauznitzii) in patients with T2D [42,84]. Gut microbiota disruption might lead to chronic lowgrade inflammation, characterized by reduced levels of antiinflammatory cytokines, increased levels of pro-inflammatory cytokines and oxidative stress [85–87]. These changes cause destruction of pancreatic ␤-cells, impaired insulin resistance and T2D. Gut microbiota seems to play a key role in the development of T2D, and, therefore, become a potential intervention target, since gut microbiota dysregulation could have an important role in insulin sensibility and T2D control. A number of studies have demonstrated that probiotic supplementation can not only restore the microbial balance and gut permeability, but can also decrease pro-inflammatory markers, ROS and insulin resistance [88,89]. Below, the main experimental and clinical findings related to probiotic supplementation under T2D conditions will be discussed. 4.1. Experimental findings The hypoglycaemic, antioxidant and anti-inflammatory effects of probiotics have been examined under diabetes conditions. Supplementation with L. plantarum CCFM0236 (8 × 1010 CFU ml−1 ) improved blood levels of glucose, HbA1C and leptin in streptozotocin-induced T2D mice. Interestingly, these effects were associated with increased levels of glutathione peroxidase and reduced levels of malondialdehyde and TNF-␣ [90]. Long-term supplementation with L. reuteri, L. crispatus and Bacillus subtilis (0.1 g of lyophilized powder of each probiotic, 1010 CFU/mL/day, for 8 weeks) reduced the plasma levels of glucose and HbA1c, improved oral glucose tolerance test and up-regulated Glut-4 mRNA in adipose tissues in streptozotocin-induced diabetic rats [91]. Similarly, administration of a multi-strain probiotic mixture, containing L. casei, L. plantarum, L. rhamnosus, L. breve and L. plantarum CCFM36 (1.6 × 1010 CFU/day for 10 weeks), effectively reduced HbA1C and leptin levels, improved glucose tolerance and insulin resistance and protected against the impairment of pancreas in D2T mice [92]. These beneficial effects were associated with higher butyrate-production by probiotic strains and reduced pro-inflammatory cytokines [92]. Butyrate, besides represent an important energetic resource for intestinal cells, may promote the release of mediators, such as peptide YY and glucagon-like peptide 1 (GLP1), through interaction with specific G protein-coupled receptors (Gpr41 and Gpr43) expressed on colonic epithelial cells and enteroendocrine cells [32]. These effects could contribute to reduce food intake and protect against obesity and insulin resistance. Akkermansia muciniphila, a gram-negative specie and relatively sensitive to oxygen, is widely abundant in the gut and characterized as a mucin-utilizing bacterium [93]. Recent findings have shown

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model

ARTICLE IN PRESS

YPHRS-3806; No. of Pages 12

M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

6

Table 2 Summary of the major clinical studies investigating the relationship between probiotics or symbiotic intake and dyslipidemias. Type of study

Number of participants

Randomized, double-blind, placebo-controlled trial

49

Single-arm, open-label pilot study

12

Single-center, prospective, randomized, double-blind, placebo-controlled, parallel-group trial

60

Randomized, double-blind, placebo-controlled

92

Single center, double blind, placebo-controlled, randomized, parallel design trial Randomized, double-blind, placebo-controlled trial

46

80

Type and time of Intervention

Primary endpoint observed

Other parameters

CRP and fibrinogen levels not 200 mL of the Decreased TC, LDL-c, isoflavone-supplemented soy non-HDL-c and CT/HDL-c ratio improved product fermented with Enterococcus faecium CRL 183 and Lactobacillus helveticus 416 (108 and 109 CFU/mL) for 42 days Probiotic capsules containing Decreased remnant lipoprotein No significant changes in Saccharomyces boulardii particles serum levels of apo B-100, (5.6 × 1010 CFU) twice daily for lipoprotein-a, hs-CRP, insulin, 8weeks homocysteine and fibrinogen Decreased TC levels in L. No significant changes in Lactobacillus plantarum CECT 7527, CECT 7528 and CECT plantarum group and HDL-c levels and LDL-C:HDL-c 7529 (1.2 × 109 CFU/d) for 12 decreased TC, LDL-c and ratio between stratified groups OX-LDL levels in the high initial weeks values group according in a stratification of the patients Reduced TG serum levels, but 2 g including dual probiotic CRP and fibrinogen levels not strains containing Lactobacillus no change in TC, HDL and improved curvatus HY7601(5 × 109 cfu/d) LDL-cholesterol. and Lactobacillus plantarum KY1032 (5x109 cfu/d) for 12 weeks No significant changes in 2 capsules of Lactobacillus No significant effects on TC, fermentum (containing 2 x 109 LDL-c, HDL-c and TG serum levels of apo B-100, CFU) twice daily for 10 weeks lipoprotein-a, hs-CRP, insulin, homocysteine and fibrinogen 2 capsules of Lactobacillus No significant changes in No changes in serum lipids 10 acidophilus (3 x 10 CFU) three HDL-c levels and LDL-C:HDL-c times a day for 6 weeks ratio between stratified groups

References [150]

[151]

[71]

[74]

[70]

[69]

Apolipoprotein (Apo); Body mass index (BMI); C reactive protein (CRP); C-reactive protein, high sensitivity (CRP-hs); Glycated hemoglobin (HbA1C); High density lipoprotein (HDL); Interleukin 6 (IL-6); Low density lipoprotein (LDL); Malondyaldeide (MDA); Oxidized Low-Density Lipoprotein (OX-LDL); Total cholesterol (TC); Triglycerides (TG); Tumor Necrosis Factor-␣ (TNF- ␣).

that daily treatment with A. muciniphila (2.0 × 108 CFU, for 4 weeks) improved glucose tolerance and insulin resistance in diet-induced obese and diabetic mice [94–96].

4.2. Clinical findings The beneficial effects of probiotic supplementation on T2D have also been demonstrated in small-scale, double blind, placebocontrolled studies (Table 3). A 12-week randomized, double-blind, parallel-group, placebocontrolled trial carried out with 136 no insulin dependent diabetic patients divided into a placebo group (34 males and 34 females) and a probiotic group (37 males and 31 females) demonstrated that probiotic supplementation containing a 3 × 1010 CFU dose of six probiotics viable cell preparation (L. acidophilus, L. casei, L. lactis, B. bifidum, B. longum and B. infantis) improved serum levels of HbA1c and fasting insulin in both genders [97]. In agreement with these findings, a recent meta-analyses of randomized clinical trials demonstrated that probiotic supplementation is effectively associated with improved HbA1c and fasting insulin in T2D patients [98]. A randomized controlled clinical trial with 48 diabetic kidney disease patients demonstrated that 200 mL/day probiotic soy milk with L plantarum A7 for 8 weeks improved some oxidative stress factors, such as the levels of glutathione peroxidase and glutathione reductase [99]. Similarly, another randomized doubleblinded controlled clinical trial demonstrated that administration of a multispecies probiotic containing viable and freeze-dried strains [L. acidophilus (2 × 109 CFU), L. casei (7 × 109 CFU), L. rhamnosus (1.5 × 109 CFU), L. bulgaricus (2 × 108 CFU), B. breve (2 × 1010 CFU), B. longum (7 × 109 CFU), Streptococcus thermophilus (1.5 × 109 CFU)] associated with 100 mg fructo-oligosaccharide for 8 weeks

improved the total antioxidant capacity and GSH levels in Iranian diabetic patients [100]. Regarding inflammatory markers, an randomized doubleblinded parallel-group controlled clinical trial conducted with 40 T2D Iranian patients demonstrated that administrating 200 mL soy milk/day (containing 2 × 107 CFU/mL of L. plantarum A7, for 8 weeks) reduced LDL levels, although no effect was observed on TNF␣, CRP and adiponectin levels [101]. On the contrary, a randomized, double-blind, parallel-group, placebo-controlled trial performed on 45 Brazilian TD2 volunteers demonstrated that consuming 120 g/day of probiotic fermented goat milk containing 109 CFU of L. acidophilus La-5 combined with 109 CFU of B. animalis subsp. lactis Bb-12 for 6 weeks reduced fructosamine and HbA1c serum levels. These effects were associated with improvement of fasting plasma glucose, insulin concentrations or insulin resistance, which were evaluated by HOMA index [102]. In this study, although the primary outcomes have not been associated with improvement on markers of oxidative stress, the pro-inflammatory cytokines levels, notably TNF␣ and resistin, were reduced and positively correlated with lower HbA1c levels after probiotic supplementation [102]. A randomized controlled trial performed with overweight Australian men and women demonstrated that supplementation with L. acidophilus La-5 and B. animalis subsp. lactis Bb-12 (at a dose of 3.0 × 109 CFU/day in capsule or yogurt, for 6 weeks) did not improve biomarkers of glycaemic control, as well as having a slight detrimental effect [103]. Dyslipidemia is an aggravating factor for cardiovascular complications in T2D patients. A 6-weeks double-blind, randomized controlled clinical trial demonstrated that consuming 300 g daily of probiotic yogurt containing L. bulgaricus, B. lactis Bb-12 and L. acidophilus La-5 (106 CFU/g) decreased total cholesterol and LDL-c concentrations in the serum [104]. In contrast, another trial study

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model

ARTICLE IN PRESS

YPHRS-3806; No. of Pages 12

M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

7

Table 3 Summary of the major clinical studies investigating the relationship between probiotics or symbiotic intake and type 2 diabetes. Type of study

Number of participants

Type and time of Intervention

Primary endpoint observed

Other parameters

References

Randomized, double-blind, placebo-controlled trial

40

No significant alteration in Serum levels of adiponectin, TNF-␣, CRP and fasting glucose

Decreased significantly LDL and HDL

[101]

Randomized, double-blind, placebo-controlled trial

60

Decreased fasting blood glucose and HbA1C

No significant changes in serum levels of TG, TC, LDL and HDL

[152]

Randomized, double-blind, parallel-group, controlled trial

136

Effective decrease in HbA1c and fasting insulin

BMI, CRP-hs, lipid profile and blood pressure did not change

[97]

Randomized, double-blind, placebo-controlled trial

50

Reduction in fructosamine, HbA1c TNF-␣ and resistin serum levels

Fecal acetic acid, total phenolic content and antioxidant activity were augmented

[102]

Randomized, double-blind, placebo-controlled trial

156

No significant alteration in No significant effects in insulin Serum levels of adiponectin, and HbA1c levels TNF-␣, CRP and fasting glucose

[103]

Randomized, double-blind, placebo-controlled trial

54

Randomized, single-blind, placebo-controlled trial

34

Randomized, double-blind, placebo-controlled trial

60

200 ml/day of probiotic soy milk containing Lactobacillus planetarum A7 (2 x 107 cfu) for 8 weeks) 600 ml/d of probiotic fermented milk (kefir) containing Lactobacillus casei (2 × 106 CFU), Lactobacillus acidophilus (3 x 106 CFU) and Bifidobacterium lactis (0.5 × 106 CFU) for 8 weeks Multi-strain probiotics: Lactobacillus acidophilus, L. casei, L. lactis, Bifidobacterium bifidum, B. longum and B. infantis (1010 CFUs/each) for 12 weeks 120 g/d of fermented milk containing Lactobacillus acidophilus La-5 and Bifidobacterium animalis subsp lactis BB-12 (109 CFUs/each) for 6 weeks Probiotic yoghurt and probiotic capsules containing Lactobacillus acidophilus La5 and Bifidobacterium animalis subsp lactis Bb12 (3 × 109 CFU/d) for 6 weeks Multispecies probiotic supplement: Lactobacillus acidophilus (2 × 109 CFU), L. casei (7 × 109 CFU), L. rhamnosus (1.5 × 109 CFU), L. bulgaricus (2 108 CFU), Bifidobacterium breve (2 × 1010 CFU), B. longum (7 × 109 CFU), Streptococcus thermophilus (1.5 × 109 CFU) for 8 weeks Probiotic capsules containing L. acidophilus, L. bulgaricus, L. bifidum and L. casei (1500mg) twice daily for 6 weeks 300g/d of probiotic yogurt containing Lactobacillus acidophilus La5 (4.14 × 106 CFU/g) and Bifidobacterium lactis Bb12 (3.61 × 106 CFU/g) for 6 weeks

Prevented a rise in fasting plasma glucose

Decreased serum levels of hs-CRP and increased plasmatic glutathione

[100]

No modification in insulin, MDA, IL-6 and TG serum levels.

No modification in HDL-c and CRP levels.

[153]

Decreased TC, LDL-c, TC:HDL-c ratio, and LDL-c:HDL-c ratio

No significant changes in triglyceride and BMI.

[104]

Body mass index (BMI); C reactive protein (CRP); C-reactive protein, high sensitivity (CRP-hs); Glycated hemoglobin (HbA1C); High density lipoprotein (HDL); Interleukin 6 (IL-6); Low density lipoprotein (LDL); Malondyaldeide (MDA); Oxidized Low-Density Lipoprotein (OX-LDL); Total cholesterol (TC); Triglycerides (TG); Tumor Necrosis Factor-␣ (TNF- ␣).

carried out with diabetic patients observed increases in LDL-c serum levels and reduced HDL-levels after probiotic intervention [100].

5. Chronic kidney disease, gut microbiota and probiotic intervention Renal dysfunction can lead to CD through multiples mechanisms. Traditional risk factors, including hypertension, diabetes and dyslipidemia, as well as non-traditional factors, including hemodynamic and metabolic abnormalities, caused by renal dysfunction (e.g., inflammation and increased oxidative stress) can influence the pathogenesis of CD in chronic renal patients [105]. In recent years, the role of the intestinal microbiota has gained attention because of its impact on the regulation of host homeostasis through the modulation of metabolism and immune response [106,107]. The intestinal microbiota may influence host gene tran-

scription mechanisms by modulation of genes associated with metabolism, cell cycle and immune response [106]. Studies have associated disorders in intestinal microbiota with higher susceptibility to development of pathologies in different organs, including intestine, liver, brain and kidneys [108], with increased risk for obesity [109], diabetes [110], inflammatory diseases [111] and cancer [112]. However, information on the influence of intestinal microbiota on maintenance of kidney normal functions or pathophysiology of chronic kidney disease is still scarce. Previous studies have shown that microbiota composition is altered in patients with CKD and that communication between host and gut microbiota is an important event in CKD pathogenesis. This process probably involves a bi-directional communication; while uremia affects both the metabolism and composition of gut microbiota, important uremic toxins are generated from gut microbial metabolism. Elimination of these toxins is performed by kidneys, mainly, by tubular secretion and, therefore, they are con-

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

8

sidered uremic toxins [113]. The importance of toxins generated by intestinal microbial metabolism is increasingly recognized [114]. Approximately 10 g of proteins are daily degraded in the colon by intestinal bacteria, being converted into metabolites, such as amines, ammonium, phenols, thiols and indoles. These products are mostly eliminated by feces; however, part of their absorption and elimination is carried out by the kidneys. Impairment of renal function, as observed in CKD, causes the accumulation of these products [115,116]. During CKD, dietary restrictions and impairment of gastrointestinal function are closely related to changes in microbial metabolism, which are characterized by predominant proteolytic fermentation. Products from protein fermentation, such as indoxyl sulfate and p-cresyl sulfate, and microbial metabolites, such as trimethylamine-N-oxide, are important sources of uremic toxins [115]. Elevated serum concentrations of indoxyl sulfate and p-cresyl sulfate is associated with decreased kidney activity and considered an important factor for development of systemic inflammation, CD and mortality in CKD patients [117]. Both indoxyl sulfate and p-cresyl sulfate may also promote vascular abnormalities, such as aortic calcification, vascular stiffness [117], as well as induction of oxidative stress in endothelial cells [118], leading to increased cardiovascular mortality. The in vitro inhibitory effects of p-cresol, a metabolic precursor of p-cresyl, on cytokine-stimulated expression of endothelial adhesion molecules, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule (VCAM) have already been demonstrated [119]. Furthermore, gut microbiota disturbance promotes impairment of epithelial barrier integrity, which is associated with intestinal wall edema and gut ischemia, resulting in increased exposure of host tissues to endotoxins, including the kidneys [120]. Increased evidence demonstrating the role of intestinal microbiome and its potential action as a regulator of renal function, as well as its critical role in pathophysiological mechanisms of CKD [121], has stimulated the development of therapeutic strategies based on the modulation of the gut microbiota to reduce CDKrelated complications. New approaches have emerged to restore the symbiotic intestinal environment during CKD progression. The therapeutic potential of the administration or supplementation with probiotics, prebiotics or symbiotic is a promising alternative to attenuate CKD [122].

5.1. Experimental findings The oral administration of microencapsulated genetically engineered living cells from the urease-producing bacteria Escherichia coli-DH5 significantly reduced plasma urea levels in uremic rats [123]. Another study related that nephrectomized rats (a chronic renal failure model), fed a casein-based diet supplemented with probiotics Bacillus pasteurii (1 × 109 CFU/day), Sporlac (L. sporogenes, 1 × 108 CFU/day), kibow cocktail (containing L. acidophilus, S. thermophilus, L. bulgaricus, Bifidobacterium spp., L. casei and L. reuteri at 1 × 1010 CFU/day) or S. boulardii (1 × 109 CFU/day) for 16 weeks showed decreased blood urea-nitrogen (BUN) levels and prolonged life span [124]. The treatment of nephrectomized spontaneous hypertensive rats with L. acidophilus NT (1 × 1010 CFU/kg/day for 12 weeks) improved urinary protein excretion, serum levels of uremic toxins and systemic inflammation [125]. A daily treatment with Lactobacillus LB (1 mL, 109 CFU/mL, for 4 weeks) induced a progressive reduction in faecal metabolites (3-(3hydroxyphenyl) propionic acid, amebamide, benzopyrene, aspartyl glutamine, phenethylamine glucuronide and T2 toxin tetrol), which are typically increased in uremia condition in rats with chronic renal failure [126].

5.2. Clinical findings A pioneering study showed that patients on hemodialysis decreased plasma levels of dimethylamine (DMA) and nitrosodimethylamine, which are toxins produced in intestine, after oral administration of L. acidophilus [127]. In agreement with these findings, a randomized, double-blind pilot study using 46 patients in stage III or IV of CKD, who received supplementation with a mix of probiotics named KB (L. acidophilus KB27, B. longum KB31 and S. thermophilus KB19, a total of 109 CFU/day) for 6 months, observed that KB supplementation reduced the BUN and improved the quality of life of the patients [128]. A randomized double-blind clinical trial on 3–4 CKD stages observed that the supplementation with commercial lyophilized ® symbiotic (Probinul-neutro ), containing L. plantarum, L. casei subsp. rhamnosus, L. gasseri, B. infantis, B. longum, L. acidophilus, L. salivarius, L. sporogenes, Streptococcus thermophilus and the prebiotic inulin tapioca-resistant starch) recommended as 5 g three times a day for 4 weeks decreased the plasma level of p-cresol [129]. Another double-blind randomized controlled trial (SYNERGY Study) analyzed the efficacy of a symbiotic (inulin, fructooligosaccharides, galacto-oligosaccharides, Lactobacillus, Bifidobacteria and Streptococcus, 15 g for day) in nondialyzed CKD stage IV or V patients. The study found an attenuation in serum concentrations of uremic nephrovascular toxins and p-cresyl sulfate (PCS) after 6-weeks of treatment [130]. These data reinforce the need for further clinical studies and basic research to increase the available knowledge on the role of intestinal microbiota in the regulation and maintenance of tissue homeostasis and pathophysiological CKD course. Finally, the available literature indicates that therapeutic interventions capable of favoring the maintenance of symbiosis and preventing the production of harmful metabolites associated with microbial metabolism may slow down the progression of CKD, and, consequently, impact on better quality of life of the patients.

6. Additional aspects considering the use of probiotics in CD and CKD Health benefits or undesirable effects seem to be strain-specific during probiotic intervention. A precise identification of probiotic strains should be the first step conducted through in vitro studies. During the selection process of probiotic strains for potential applications, several aspects need to be considered. These include safety for the consumer (e.g., antibiotic susceptibility, hemolytic activity, and mucin degradation), beneficial physiological functionalities (e.g., acid and bile salt tolerance, bile salt deconjugation, cell surface hydrophobicity, autoaggregation, coaggregation with pathogens and antagonistic activity against pathogens) and be able to survive during gastrointestinal passage and food processing and storage [136,143]. Cellular adhesion is an important characteristic of probiotics strains, promoting gut colonization, contact between bacterial cell membranes, interaction with intestinal surfaces and enhanced antagonistic activity against pathogens. Complementarily, a better understanding of the metabolic characteristics of probiotic strains before pre-clinical or clinical intervention protocols could help to drive their successful use in specific pathophysiological conditions. This seems an important approach because not all probiotic strains are equipped with the optimal portfolio of enzymes and metabolic traits. Some particular features may be suggested as relevant for future investigations in CMD and CKD: i) free radical scavenging activity of probiotic strains [144]; ii) identification of butyrateproducing probiotic strains [145]; and iii) isolation of strains with capacity to produce conjugated linoleic acid (CLA) from free linoleic acid [146] and cholesterol-lowering properties [147].

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

Information of recent systematic reviews and meta-analyses of randomized trials allow to infer that: i) probiotic intervention in overweight or obese patients has a small or non-significant effect on body weight reduction [131]; ii) probiotic intervention has a modest effect in the reduction of blood pressure in hypertensive subjects, and these effects are mainly observed when the probiotics administration is conducted for more than 8 weeks and the consumption dose is higher than 1011 colony-forming units [132]; iii) probiotic supplementation is effective to reduce serum glucose, insulin and HbA1c levels in type 2 diabetes patients [89]; iv) probiotic supplementation reduce serum total cholesterol levels in normo and hypercholesterolaemic individuals and these effects are more pronounced in hypercholesterolaemic patients [75]; and v) probiotic administration exerts a very low to moderate effect on uremic toxin levels [133]. To the best of our knowledge, dyslipidaemic subjects seem to be the most responsive patients to probiotics intervention. Environmental factors, such as diet pattern, age, gender and residential area seem to exert impact on human gut microbiota and consequently affect the complex dynamics between probiotics and other microorganisms comprising the gut microbiota [28,134,135]. However, deeper studies on the investigation of the effects of probiotics in different populations, gender and age should be performed. Species of Lactobacillus, Bifidobacterium and Enterococcus are the microorganisms most studied as probiotics in clinical trials investigations. Nonetheless, there is a variety of other microorganisms that need to be better evaluated for safe and effective use as probiotics in further clinical trials. For example, E. coli Nissle 1917 has been recommended to treat constipation and inflammatory bowel disease [136], although no beneficial effect had been observed in streptomycin-treated mouse [137]. Some Bacillus species have shown to alleviate diarrhea and Helicobacter pylori infection [138]. Saccharomyces species, such as S. cerevisiae, S. bayanus and S. boulardii, are used as probiotics to treat diarrhea and ulcerative colitis [136]. Lactococcus species are sometimes recommended as probiotics to treat diarrhea [136]. Additional studies are needed to test the safe use of these strains and their effects on CMD and CKD. Recently, faecal microbiota transplantation (FMT) or fecal bacteriotherapy using capsules or colonoscopy has emerged as potential therapeutic strategies to restore intestinal microbiota in CMD and CKD [139,140], as well as has presented positive effects on nonalcoholic steatohepatitis and reduced portal hypertension, insulin resistance and endothelial dysfunction in a rat model [141]. Additionally, patients with metabolic syndrome that received FMT from lean donors improved insulin sensitivity [142]. FMT must be cautiously compared to probiotic supplementation because FMT that contains an undefined mixture of micro-organisms not meet the probiotic criteria. On the contrary, synthetic stool mixtures containing a well-defined mix of microbes meet the probiotic criteria [140], but there is a lack of studies investigating synthetic stool mixture on CMD and CKD conditions.

7. Conclusion and future perspectives It is important to recognize that without effective intervention, the increase of hypertension, T2D and dyslipidemias will aggravate the global epidemic of CD and CKD. The first choice against CMD should be performed through lifestyle modifications, including increased physical activity, maintenance of normal body weight, reduction of salt intake and adequate consumption of a diet high in fruit and vegetables, and low in saturated, trans and total fat. The role of gut microbiota in the development of hypertension is a relatively new field of study. Accumulating evidence from experimental and clinical discoveries demonstrated that disordered composition of gut microbiota and microbial products,

9

called gut dysbiois, are linked with CMD and CKD condition. In addition, the number of studies examining gut microbiota as a key target for probiotic intervention has been increasing in last years. Experimental and clinical studies retrieved in this review suggest that probiotic consumption is clinically feasible and could help in treatment of CMD and CKD (Fig. 1). Despite of these findings, there is still no consensus on the optimal dose, intervention time period and mechanism pathways underlying the efficacy of probiotics to improve CMD and CKD. Our research network has now conducted studies isolating cell strains with desirable features for probiotic use and determined their main metabolic trait (glucose and lipid metabolism), anti-oxidant and anti-inflammatory before pre-clinical protocols [148,149]. Future experimental and clinical studies will be developed in our laboratories to test the functional properties of probiotic strains under CMD and CKD conditions. Financial support The research was conducted in the absence of any financial support Acknowledgements The English text of this paper has been revised by Sidney Pratt, Canadian, MAT (The Johns Hopkins University), RSAdip – TESL (Cambridge University). References [1] K.T. Mills, J.D. Bundy, T.N. Kelly, J.E. Reed, P.M. Kearney, K. Reynolds, J. Chen, J. He, Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries, Circulation 134 (6) (2016) 441–450. [2] R.A. Nugent, S.F. Fathima, A.B. Feigl, D. Chyung, The burden of chronic kidney disease on developing nations: a 21 st century challenge in global health, Nephron. Clin. Pract. 118 (3) (2011) c269–77. [3] Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013, Lancet 386 (9995) (2015) 743–800. [4] P. Bjerregaard, Nutritional transition – where do we go from here? J. Hum. Nutr. Dietet. 23 (Suppl. 1) (2010) 1–2. [5] J. Cosnes, Smoking physical activity, nutrition and lifestyle: environmental factors and their impact on IBD, Dig. Dis. 28 (3) (2010) 411–417. [6] J. Pindjakova, C. Sartini, O. Lo Re, F. Rappa, B. Coupe, B. Lelouvier, V. Pazienza, M. Vinciguerra, Gut dysbiosis and adaptive immune response in diet-induced obesity vs. systemic inflammation, Front. Microbiol. 8 (2017) 1157. [7] K. Yoshioka, K. Kakihana, N. Doki, K. Ohashi, Gut microbiota and acute graft-versus-host disease, Pharmacol. Res. 122 (2017) 90–95. [8] L. Fernandez, S. Langa, V. Martin, A. Maldonado, E. Jimenez, R. Martin, J.M. Rodriguez, The human milk microbiota: origin and potential roles in health and disease, Pharmacol. Res. 69 (1) (2013) 1–10. [9] B. Ruiz-Nunez, D.A. Dijck-Brouwer, F.A. Muskiet, The relation of saturated fatty acids with low-grade inflammation and cardiovascular disease, J. Nutr. Biochem. 36 (2016) 1–20. [10] G.J. Weber, S. Pushpakumar, S.C. Tyagi, U. Sen, Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension, Pharmacol. Res. 113 (Pt. A) (2016) 300–312. [11] G. Traina, L. Menchetti, F. Rappa, P. Casagrande-Proietti, O. Barbato, L. Leonardi, F. Carini, F. Piro, G. Brecchia, Probiotic mixture supplementation in the preventive management of trinitrobenzenesulfonic acid-induced inflammation in a murine model, J. Biol. Regul. Homeost. Agents 30 (3) (2016) 895–901. [12] S. Resta-Lenert, K.E. Barrett, Probiotics and commensals reverse TNF-alphaand IFN-gamma-induced dysfunction in human intestinal epithelial cells, Gastroenterology 130 (3) (2006) 731–746. [13] L. Bouhafs, E.N. Moudilou, J.M. Exbrayat, M. Lahouel, T. Idoui, Protective effects of probiotic Lactobacillus plantarum BJ0021 on liver and kidney oxidative stress and apoptosis induced by endosulfan in pregnant rats, Ren. Fail. 37 (8) (2015) 1370–1378. [14] A. Amaretti, M. di Nunzio, A. Pompei, S. Raimondi, M. Rossi, A. Bordoni, Antioxidant properties of potentially probiotic bacteria: in vitro and in vivo activities, Appl. Microbiol. Biotechnol. 97 (2) (2013) 809–817.

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12 10

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

[15] Y. Wang, Y. Wu, H. Xu, X. Mei, D. Yu, W. Li, Antioxidant properties of probiotic bacteria, Nutrients 9 (5) (2017). [16] E. Kobatake, H. Nakagawa, T. Seki, T. Miyazaki, Protective effects and functional mechanisms of Lactobacillus gasseri SBT2055 against oxidative stress, PLoS One 12 (5) (2017) e0177106. [17] E. Calderini, H.U. Celebioglu, J. Villarroel, S. Jacobsen, B. Svensson, E. Pessione, Comparative proteomics of oxidative stress response of Lactobacillus acidophilus NCFM reveals effects on DNA repair and cysteine de novo synthesis, Proteomics 17 (5) (2017). [18] L.V. Thomas, K. Suzuki, J. Zhao, Probiotics: a proactive approach to health. A symposium report, Br. J. Nutr. 114 (Suppl. 1) (2015) S1–15. [19] J.L.B. d. Alves, V.P. d. Sousa, M.P.C. Neto, M. Magnani, V.A. d. Braga, J.H. d. Costa-Silva, C.G. Leandro, H. Vidal, L. Pirola, New insights on the use of dietary polyphenols or probiotics for the management of arterial hypertension, Front. Physiol. 7 (448) (2016) 8. [20] G.R. Gibson, H.M. Probert, J.V. Loo, R.A. Rastall, M.B. Roberfroid, Dietary modulation of the human colonic microbiota: updating the concept of prebiotics, Nutr. Res. Rev. 17 (2) (2004) 259–275. [21] J. Sun, E.B. Chang, Exploring gut microbes in human health and disease: pushing the envelope, Genes Dis. 1 (2) (2014) 132–139. [22] A. Salonen, J. Nikkila, J. Jalanka-Tuovinen, O. Immonen, M. Rajilic-Stojanovic, R.A. Kekkonen, A. Palva, W.M. de Vos, Comparative analysis of fecal DNA extraction methods with phylogenetic microarray: effective recovery of bacterial and archaeal DNA using mechanical cell lysis, J. Microbiol. Methods 81 (2) (2010) 127–134. [23] P.D. Scanlan, J.R. Marchesi, Micro-eukaryotic diversity of the human distal gut microbiota: qualitative assessment using culture-dependent and -independent analysis of faeces, ISME J. 2 (12) (2008) 1183–1193. [24] E. Scarpellini, G. Ianiro, F. Attili, C. Bassanelli, A. De Santis, A. Gasbarrini, The human gut microbiota and virome: potential therapeutic implications, Digest. Liver Dis. 47 (12) (2015) 1007–1012. [25] D. Mariat, O. Firmesse, F. Levenez, V. Guimaraes, H. Sokol, J. Dore, G. Corthier, J.P. Furet, The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age, BMC Microbiol. 9 (2009) 123. [26] M. Rajilic-Stojanovic, H. Smidt, W.M. de Vos, Diversity of the human gastrointestinal tract microbiota revisited, Environ. Microbiol. 9 (9) (2007) 2125–2136. [27] M. Arumugam, J. Raes, E. Pelletier, D. Le Paslier, T. Yamada, D.R. Mende, G.R. Fernandes, J. Tap, T. Bruls, J.M. Batto, M. Bertalan, N. Borruel, F. Casellas, L. Fernandez, L. Gautier, T. Hansen, M. Hattori, T. Hayashi, M. Kleerebezem, K. Kurokawa, M. Leclerc, F. Levenez, C. Manichanh, H.B. Nielsen, T. Nielsen, N. Pons, J. Poulain, J. Qin, T. Sicheritz-Ponten, S. Tims, D. Torrents, E. Ugarte, E.G. Zoetendal, J. Wang, F. Guarner, O. Pedersen, W.M. de Vos, S. Brunak, J. Dore, M. Antolin, F. Artiguenave, H.M. Blottiere, M. Almeida, C. Brechot, C. Cara, C. Chervaux, A. Cultrone, C. Delorme, G. Denariaz, R. Dervyn, K.U. Foerstner, C. Friss, M. van de Guchte, E. Guedon, F. Haimet, W. Huber, J. van Hylckama-Vlieg, A. Jamet, C. Juste, G. Kaci, J. Knol, O. Lakhdari, S. Layec, K. Le Roux, E. Maguin, A. Merieux, R. Melo Minardi, C. M’Rini, J. Muller, R. Oozeer, J. Parkhill, P. Renault, M. Rescigno, N. Sanchez, S. Sunagawa, A. Torrejon, K. Turner, G. Vandemeulebrouck, E. Varela, Y. Winogradsky, G. Zeller, J. Weissenbach, S.D. Ehrlich, P. Bork, Enterotypes of the human gut microbiome, Nature 473 (7346) (2011) 174–180. [28] S. Sandrini, M. Aldriwesh, M. Alruways, P. Freestone, Microbial endocrinology: host-bacteria communication within the gut microbiome, J. Endocrinol. 225 (2) (2015) R21–34. [29] E. Bezirtzoglou, E. Stavropoulou, Immunology and probiotic impact of the newborn and young children intestinal microflora, Anaerobe 17 (6) (2011) 369–374. [30] G.A. Weiss, T. Hennet, Mechanisms and consequences of intestinal dysbiosis, Cell. Mol. Life Sci. CMLS 74 (16) (2017) 2959–2977. [31] H.J. Flint, K.P. Scott, S.H. Duncan, P. Louis, E. Forano, Microbial degradation of complex carbohydrates in the gut, Gut Microb. 3 (4) (2012) 289–306. [32] A. Everard, P.D. Cani, Gut microbiota and GLP-1, Rev. Endocr. Metabol. Disord. 15 (3) (2014) 189–196. [33] B.S. Ramakrishna, W.E. Roediger, Bacterial short chain fatty acids: their role in gastrointestinal disease, Dig. Dis. 8 (6) (1990) 337–345. [34] K. Windey, V. De Preter, K. Verbeke, Relevance of protein fermentation to gut health, Mol. Nutr. Food Res. 56 (1) (2012) 184–196. [35] A. Ghazalpour, I. Cespedes, B.J. Bennett, H. Allayee, Expanding role of gut microbiota in lipid metabolism, Curr. Opin. Lipidol. 27 (2) (2016) 141–147. [36] Y. Lin, R.J. Vonk, M.J. Slooff, F. Kuipers, M.J. Smit, Differences in propionate-induced inhibition of cholesterol and triacylglycerol synthesis between human and rat hepatocytes in primary culture, Br. J. Nutr. 74 (2) (1995) 197–207. [37] M. Begley, C. Hill, C.G. Gahan, Bile salt hydrolase activity in probiotics, Appl. Environ. Microbiol. 72 (3) (2006) 1729–1738. [38] M.L. Jones, C.J. Martoni, S. Prakash, Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial, Eur. J. Clin. Nutr. 66 (11) (2012) 1234–1241. [39] P.J. Parekh, E. Arusi, A.I. Vinik, D.A. Johnson, The role and influence of gut microbiota in pathogenesis and management of obesity and metabolic syndrome, Front. Endocrinol. 5 (2014) 47. [40] A. Woting, M. Blaut, The intestinal microbiota in metabolic disease, Nutrients 8 (4) (2016) 202.

[41] G. Velmurugan, T. Ramprasath, M. Gilles, K. Swaminathan, S. Ramasamy, Gut microbiota, endocrine-Disrupting chemicals, and the diabetes epidemic, trends in endocrinology and metabolism, TEM 28 (8) (2017) 612–625. [42] J. Qin, Y. Li, Z. Cai, S. Li, J. Zhu, F. Zhang, S. Liang, W. Zhang, Y. Guan, D. Shen, Y. Peng, D. Zhang, Z. Jie, W. Wu, Y. Qin, W. Xue, J. Li, L. Han, D. Lu, P. Wu, Y. Dai, X. Sun, Z. Li, A. Tang, S. Zhong, X. Li, W. Chen, R. Xu, M. Wang, Q. Feng, M. Gong, J. Yu, Y. Zhang, M. Zhang, T. Hansen, G. Sanchez, J. Raes, G. Falony, S. Okuda, M. Almeida, E. LeChatelier, P. Renault, N. Pons, J.M. Batto, Z. Zhang, H. Chen, R. Yang, W. Zheng, H. Yang, J. Wang, S.D. Ehrlich, R. Nielsen, O. Pedersen, K. Kristiansen, A metagenome-wide association study of gut microbiota in type 2 diabetes, Nature 490 (7418) (2012) 55–60. [43] N. Qin, F. Yang, A. Li, E. Prifti, Y. Chen, L. Shao, J. Guo, E. Le Chatelier, J. Yao, L. Wu, J. Zhou, S. Ni, L. Liu, N. Pons, J.M. Batto, S.P. Kennedy, P. Leonard, C. Yuan, W. Ding, X. Hu, B. Zheng, G. Qian, W. Xu, S.D. Ehrlich, S. Zheng, L. Li, Alterations of the human gut microbiome in liver cirrhosis, Nature 513 (7516) (2014) 59–64. [44] O.O. Erejuwa, S.A. Sulaiman, M.S. Ab Wahab, Modulation of gut microbiota in the management of metabolic disorders: the prospects and challenges, Int. J. Mol. Sci. 15 (3) (2014) 4158–4188. [45] K.R. Pandey, S.R. Naik, B.V. Vakil, Probiotics prebiotics and synbiotics- a review, J. Food Sci. Technol. 52 (12) (2015) 7577–7587. [46] D.M. Lilly, R.H. Stillwell, Probiotics growth-promoting factors produced by microorganisms, Science 147 (3659) (1965) 747–748. [47] S. Parvez, K.A. Malik, S. Ah Kang, H.Y. Kim, Probiotics and their fermented food products are beneficial for health, J. Appl. Microbiol. 100 (6) (2006) 1171–1185. [48] P. Konieczna, C.A. Akdis, E.M. Quigley, F. Shanahan, L. O’Mahony, Portrait of an immunoregulatory Bifidobacterium, Gut Microb. 3 (3) (2012) 261–266. [49] D. Groeger, L. O’Mahony, E.F. Murphy, J.F. Bourke, T.G. Dinan, B. Kiely, F. Shanahan, E.M. Quigley, Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut, Gut Microb. 4 (4) (2013) 325–339. [50] G.R. Gibson, M.B. Roberfroid, Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics, J. Nutr. 125 (6) (1995) 1401–1412. [51] B.B. Adhyaru, T.A. Jacobson, New cholesterol guidelines for the management of atherosclerotic cardiovascular disease risk: a comparison of the 2013 American College of Cardiology/American Heart Association cholesterol guidelines with the 2014 National Lipid Association recommendations for patient-centered management of dyslipidemia, Cardiol. Clin. 33 (2) (2015) 181–196. [52] T.J. Anderson, G.B. Mancini, J. Genest Jr., J. Gregoire, E.M. Lonn, R.A. Hegele, The new dyslipidemia guidelines: what is the debate? Can. J. Cardiol. 31 (5) (2015) 605–612. [53] B.A. Hannon, S.V. Thompson, R. An, M. Teran-Garcia, Clinical outcomes of dietary replacement of saturated fatty acids with unsaturated fat sources in adults with overweight and obesity: a systematic review and meta-analysis of randomized control trials, Ann. Nutr. Metabol. 71 (1–2) (2017) 107–117. [54] K.A. Kim, W. Gu, I.A. Lee, E.H. Joh, D.H. Kim, High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway, PLoS One 7 (10) (2012) e47713. [55] O. Chavez-Talavera, A. Tailleux, P. Lefebvre, B. Staels, Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease, Gastroenterology 1679–1694 (2017) e3. [56] M. Blaut, T. Clavel, Metabolic diversity of the intestinal microbiota: implications for health and disease, J. Nutr. 37 (3 Suppl. 2) (2007) 751S–755S. [57] B. Kim, K.Y. Park, Y. Ji, S. Park, W. Holzapfel, C.K. Hyun, Protective effects of Lactobacillus rhamnosus GG against dyslipidemia in high-fat diet-induced obese mice, Biochem. Biophys. Res. Commun. 473 (2) (2016) 530–536. [58] D. Chen, Z. Yang, X. Chen, Y. Huang, B. Yin, F. Guo, H. Zhao, T. Zhao, H. Qu, J. Huang, Y. Wu, R. Gu, The effect of Lactobacillus rhamnosus hsryfm 1301 on the intestinal microbiota of a hyperlipidemic rat model, BMC Comp. Altern. Med. 14 (2014) 386. [59] W.J. Ting, W.W. Kuo, C.H. Kuo, Y.L. Yeh, C.Y. Shen, Y.H. Chen, T.J. Ho, V.P. Viswanadha, C.Y. Huang, Supplementary heat-killed Lactobacillus reuteri GMNL-263 ameliorates hyperlipidaemic and cardiac apoptosis in high-fat diet-fed hamsters to maintain cardiovascular function, Br. J. Nutr. 114 (5) (2015) 706–712. [60] W.C. Huang, Y.M. Chen, N.W. Kan, C.S. Ho, L. Wei, C.H. Chan, H.Y. Huang, C.C. Huang, Hypolipidemic effects and safety of Lactobacillus reuteri 263 in a hamster model of hyperlipidemia, Nutrients 7 (5) (2015) 3767–3782. [61] S.E. Gilliland, C.R. Nelson, C. Maxwell, Assimilation of cholesterol by Lactobacillus acidophilus, Appl. Environ. Microbiol. 49 (2) (1985) 377–381. [62] F.A. Klaver, R. van der Meer, The assumed assimilation of cholesterol by Lactobacilli and Bifidobacterium bifidum is due to their bile salt-deconjugating activity, Appl. Environ. Microbiol. 59 (4) (1993) 1120–1124. [63] M. Song, S. Park, H. Lee, B. Min, S. Jung, E. Kim, S. Oh, Effect of Lactobacillus acidophilus NS1 on plasma cholesterol levels in diet-induced obese mice, J. Dairy Sci. 98 (3) (2015) 1492–1501. [64] L.X. Wang, K. Liu, D.W. Gao, J.K. Hao, Protective effects of two Lactobacillus plantarum strains in hyperlipidemic mice, World J. Gastroenterol. 19 (20) (2013) 3150–3156. [65] N. Xie, Y. Cui, Y.N. Yin, X. Zhao, J.W. Yang, Z.G. Wang, N. Fu, Y. Tang, X.H. Wang, X.W. Liu, C.L. Wang, F.G. Lu, Effects of two Lactobacillus strains on

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85] [86]

[87]

[88]

[89]

[90]

lipid metabolism and intestinal microflora in rats fed a high-cholesterol diet, BMC Comp. Altern. Med. 11 (2011) 53. S.J. Kim, S.H. Park, H.S. Sin, S.H. Jang, S.W. Lee, S.Y. Kim, B. Kwon, K.Y. Yu, D.K. Yang, Hypocholesterolemic effects of probiotic mixture on diet-induced hypercholesterolemic rats, Nutrients 9 (3) (2017). C.S. Stancu, G.M. Sanda, M. Deleanu, A.V. Sima, Probiotics determine hypolipidemic and antioxidant effects in hyperlipidemic hamsters, Mol. Nutr. Food Res. 58 (3) (2014) 559–568. P. Girard, Y. Pansart, M. Verleye, Anti-hypercholesterolemic effect of Saccharomyces boulardii in the hamster, Pharmacology 94 (5–6) (2014) 239–244. S.J. Lewis, S. Burmeister, A double-blind placebo-controlled study of the effects of Lactobacillus acidophilus on plasma lipids, Eur. J. Clin. Nutr. 59 (6) (2005) 776–780. L.A. Simons, S.G. Amansec, P. Conway, Effect of Lactobacillus fermentum on serum lipids in subjects with elevated serum cholesterol, Nutrition, metabolism, and cardiovascular diseases, NMCD 16 (8) (2006) 531–535. M.C. Fuentes, T. Lajo, J.M. Carrion, J. Cune, Cholesterol-lowering efficacy of Lactobacillus plantarum CECT 7527 7528 and 7529 in hypercholesterolaemic adults, Br. J. Nutr. 109 (10) (2013) 1866–1872. J.W. Anderson, S.E. Gilliland, Effect of fermented milk (yogurt) containing Lactobacillus acidophilus L1 on serum cholesterol in hypercholesterolemic humans, J. Am. Coll. Nutr. 18 (1) (1999) 43–50. A. Ataie-Jafari, B. Larijani, H. Alavi Majd, F. Tahbaz, Cholesterol-lowering effect of probiotic yogurt in comparison with ordinary yogurt in mildly to moderately hypercholesterolemic subjects, Ann. Nutr. Metabol. 54 (1) (2009) 22–27. H.Y. Ahn, M. Kim, Y.T. Ahn, J.H. Sim, I.D. Choi, S.H. Lee, J.H. Lee, The triglyceride-lowering effect of supplementation with dual probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032: Reduction of fasting plasma lysophosphatidylcholines in nondiabetic and hypertriglyceridemic subjects, Nutrition, metabolism, and cardiovascular diseases, NMCD 25 (8) (2015) 724–733. M. Shimizu, M. Hashiguchi, T. Shiga, H.O. Tamura, M. Mochizuki, Meta-analysis: effects of probiotic supplementation on lipid profiles in normal to mildly hypercholesterolemic individuals, PLoS One 10 (10) (2015) e0139795. Z. Guo, X.M. Liu, Q.X. Zhang, Z. Shen, F.W. Tian, H. Zhang, Z.H. Sun, H.P. Zhang, W. Chen, Influence of consumption of probiotics on the plasma lipid profile: a meta-analysis of randomised controlled trials, Nutr. metabol. Cardiovasc. Dis. NMCD 21 (11) (2011) 844–850. C.A. Carrera Boada, J.M. Martinez-Moreno, Pathophysiology of diabetes mellitus type 2: beyond the duo insulin resistance-secretion deficit, Nutr. Hosp. 28 (Suppl. 2) (2013) 78–87. F.B. Hu, J.E. Manson, M.J. Stampfer, G. Colditz, S. Liu, C.G. Solomon, W.C. Willett, Diet, lifestyle, and the risk of type 2 diabetes mellitus in women, N. Engl. J. Med. 345 (11) (2001) 790–797. B. de Almeida-Pititto, M.L. Dias, A.C. de Moraes, S.R. Ferreira, D.R. Franco, F.G. Eliaschewitz, Type 2 diabetes in Brazil: epidemiology and management, Diabetes, metabolic syndrome and obesity, Targets Ther. 8 (2015) 17–28. F. Navab-Moghadam, M. Sedighi, M.E. Khamseh, F. Alaei-Shahmiri, M. Talebi, S. Razavi, N. Amirmozafari, The Association of Type II Diabetes with Gut Microbiota Composition Microbial Pathogenesis, 2017. J. Gerritsen, H. Smidt, G.T. Rijkers, W.M. de Vos, Intestinal microbiota in human health and disease: the impact of probiotics, Genes Nutr. 6 (3) (2011) 209–240. H.J. Flint, K.P. Scott, P. Louis, S.H. Duncan, The role of the gut microbiota in nutrition and health: nature reviews, Gastroenterol. Hepatol. 9 (10) (2012) 577–589. P.D. Cani, M. Osto, L. Geurts, A. Everard, Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity, Gut Microb. 3 (4) (2012) 279–288. F.H. Karlsson, V. Tremaroli, I. Nookaew, G. Bergstrom, C.J. Behre, B. Fagerberg, J. Nielsen, F. Backhed, Gut metagenome in European women with normal impaired and diabetic glucose control, Nature 498 (7452) (2013) 99–103. K.E. Wellen, G.S. Hotamisligil, Inflammation stress, and diabetes, J. Clin. Invest. 115 (5) (2005) 1111–1119. P.D. Cani, R. Bibiloni, C. Knauf, A. Waget, A.M. Neyrinck, N.M. Delzenne, R. Burcelin, Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice, Diabetes 57 (6) (2008) 1470–1481. L.D. Ly, S. Xu, S.K. Choi, C.M. Ha, T. Thoudam, S.K. Cha, A. Wiederkehr, C.B. Wollheim, I.K. Lee, K.S. Park, Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes, Exp. Mol. Med. 49 (2) (2017) e291. G. Wang, X. Li, J. Zhao, H. Zhang, W. Chen, Lactobacillus casei CCFM419 attenuates type 2 diabetes via a gut microbiota dependent mechanism, Food Funct. 20 (8 (9)) (2017) 3155–3164. X. Wang, Q.F. Juan, Y.W. He, L. Zhuang, Y.Y. Fang, Y.H. Wang, Multiple effects of probiotics on different types of diabetes: a systematic review and meta-analysis of randomized placebo-controlled trials, J. Pediatr. Endocrinol. Metabol. JPEM 30 (6) (2017) 611–622. X. Li, N. Wang, B. Yin, D. Fang, T. Jiang, S. Fang, J. Zhao, H. Zhang, G. Wang, W. Chen, Effects of Lactobacillus plantarum CCFM0236 on hyperglycaemia and insulin resistance in high-fat and streptozotocin-induced type 2 diabetic mice, J. Appl. Microbiol. 121 (6) (2016) 1727–1736.

11

[91] F. Memarrast, S. Ghafouri-Fard, S. Kolivand, S. Jafary-Nodooshan, N. Neyazi, E. Sadroddiny, E. Motevaseli, Comparative evaluation of probiotics effects on plasma glucose, lipid, and insulin levels in streptozotocin-induced diabetic rats, Diabetes/Metabol. Res. Rev. 33 (7) (2017), http://dx.doi.org/10.1002/ dmrr.2912. [92] X. Li, Q. Xu, T. Jiang, S. Fang, G. Wang, J. Zhao, H. Zhang, W. Chen, A comparative study of the antidiabetic effects exerted by live and dead multi-strain probiotics in the type 2 diabetes model of mice, Food Funct. 7 (12) (2016) 4851–4860. [93] M. Derrien, E.E. Vaughan, C.M. Plugge, W.M. de Vos, Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium, Int. J. Syst. Evol. Microbiol. 54 (Pt. 5) (2004) 1469–1476. [94] A. Everard, C. Belzer, L. Geurts, J.P. Ouwerkerk, C. Druart, L.B. Bindels, Y. Guiot, M. Derrien, G.G. Muccioli, N.M. Delzenne, W.M. de Vos, P.D. Cani, Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity, Proc. Natl. Acad. Sci. U. S. A. 110 (22) (2013) 9066–9071. [95] H. Plovier, A. Everard, C. Druart, C. Depommier, M. Van Hul, L. Geurts, J. Chilloux, N. Ottman, T. Duparc, L. Lichtenstein, A. Myridakis, N.M. Delzenne, J. Klievink, A. Bhattacharjee, K.C. van der Ark, S. Aalvink, L.O. Martinez, M.E. Dumas, D. Maiter, A. Loumaye, M.P. Hermans, J.P. Thissen, C. Belzer, W.M. de Vos, P.D. Cani, A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice, Nat. Med. 23 (1) (2017) 107–113. [96] P.D. Cani, W.M. de Vos, Next-generation beneficial microbes: the case of akkermansia muciniphila, Front. Microbiol. 8 (2017) 1765. [97] S. Firouzi, H.A. Majid, A. Ismail, N.A. Kamaruddin, M.Y. Barakatun-Nisak, Effect of multi-strain probiotics (multi-strain microbial cell preparation) on glycemic control and other diabetes-related outcomes in people with type 2 diabetes: a randomized controlled trial, Eur. J. Nutr. 56 (4) (2017) 1535–1550. [98] V. Akbari, F. Hendijani, Effects of probiotic supplementation in patients with type 2 diabetes: systematic review and meta-analysis, Nutr. Rev. 74 (12) (2016) 774–784. [99] M. Miraghajani, N. Zaghian, M. Mirlohi, A. Feizi, R. Ghiasvand, The impact of probiotic soy milk consumption on oxidative stress among type 2 diabetic kidney disease patients: a randomized controlled clinical trial, J. Renal Nutr. 27 (5) (2017) 317–324. [100] Z. Asemi, Z. Zare, H. Shakeri, S.S. Sabihi, A. Esmaillzadeh, Effect of multispecies probiotic supplements on metabolic profiles, hs-CRP, and oxidative stress in patients with type 2 diabetes, Ann. Nutr. Metabol. 63 (1–2) (2013) 1–9. [101] S. Feizollahzadeh, R. Ghiasvand, A. Rezaei, H. Khanahmad, A. Sadeghi, M. Hariri, Effect of probiotic soy milk on serum levels of adiponectin inflammatory mediators, lipid profile, and fasting blood glucose among patients with type II diabetes mellitus, Probiot. Antimicrob. Protiens 9 (1) (2017) 41–47. [102] L.B. Tonucci, K.M. Olbrich Dos Santos, L. Licursi de Oliveira, S.M. Rocha Ribeiro, H.S. Duarte Martino, Clinical application of probiotics in type 2 diabetes mellitus: a randomized double-blind, placebo-controlled study, Clin. Nutr. 36 (1) (2017) 85–92. [103] K.L. Ivey, J.M. Hodgson, D.A. Kerr, J.R. Lewis, P.L. Thompson, R.L. Prince, The effects of probiotic bacteria on glycaemic control in overweight men and women: a randomised controlled trial, Eur. J. Clin. Nutr. 68 (4) (2014) 447–452. [104] H.S. Ejtahed, J. Mohtadi-Nia, A. Homayouni-Rad, M. Niafar, M. Asghari-Jafarabadi, V. Mofid, A. Akbarian-Moghari, Effect of probiotic yogurt containing Lactobacillus acidophilus and Bifidobacterium lactis on lipid profile in individuals with type 2 diabetes mellitus, J. Dairy Sci. 94 (7) (2011) 3288–3294. [105] J.C. Longenecker, J. Coresh, N.R. Powe, A.S. Levey, N.E. Fink, A. Martin, M.J. Klag, Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study, J. Am. Soc. Nephrol. JASN 13 (7) (2002) 1918–1927. [106] F. Sommer, I. Nookaew, N. Sommer, P. Fogelstrand, F. Backhed, Site-specific programming of the host epithelial transcriptome by the gut microbiota, Genome Biol. 16 (2015) 62. [107] P.D. Cani, Gut microbiota – at the intersection of everything? Nature reviews, Gastroenterol. Hepatol. 14 (6) (2017) 321–322. [108] R.S. Goldszmid, G. Trinchieri, The price of immunity, Nat. Immunol. 13 (10) (2012) 932–938. [109] C. Greenhill, Obesity Gut microbiota, host genetics and diet interact to affect the risk of developing obesity and the metabolic syndrome, Nat. Rev. Endocrinol. 11 (11) (2015) 630. [110] M. Knip, H. Siljander, The role of the intestinal microbiota in type 1 diabetes mellitus, Nat. Rev. Endocrinol. 12 (3) (2016) 154–167. [111] N. Kamada, S.U. Seo, G.Y. Chen, G. Nunez, Role of the gut microbiota in immunity and inflammatory disease, Nat. Rev. Immunol. 13 (5) (2013) 321–335. [112] S. Roy, G. Trinchieri, Microbiota: a key orchestrator of cancer therapy, Nat. Rev. Cancer 17 (5) (2017) 271–285. [113] R. Poesen, B. Meijers, P. Evenepoel, The colon: an overlooked site for therapeutics in dialysis patients, Sem. Dial. 26 (3) (2013) 323–332. [114] W.R. Wikoff, A.T. Anfora, J. Liu, P.G. Schultz, S.A. Lesley, E.C. Peters, G. Siuzdak, Metabolomics analysis reveals large effects of gut microflora on

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020

G Model YPHRS-3806; No. of Pages 12 12

[115] [116]

[117]

[118]

[119]

[120]

[121]

[122] [123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132]

[133]

[134]

[135]

ARTICLE IN PRESS M.P. Cavalcanti Neto et al. / Pharmacological Research xxx (2018) xxx–xxx

mammalian blood metabolites, Proc. Natl. Acad. Sci. U. S. A. 106 (10) (2009) 3698–3703. P. Evenepoel, R. Poesen, B. Meijers, The gut-kidney axis, Pediatr. Nephrol. (2016). T. Khoury, K. Tzukert, R. Abel, A. Abu Rmeileh, R. Levi, Y. Ilan, The gut-kidney axis in chronic renal failure: a new potential target for therapy: hemodialysis international, Int. Symp. Home Hemodial. 21 (3) (2017) 323–334. F.C. Barreto, D.V. Barreto, S. Liabeuf, N. Meert, G. Glorieux, M. Temmar, G. Choukroun, R. Vanholder, Z.A. Massy, Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients, Clin. J. Am. Soc. Nephrol. CJASN 4 (10) (2009) 1551–1558. L. Dou, N. Jourde-Chiche, V. Faure, C. Cerini, Y. Berland, F. Dignat-George, P. Brunet, The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells, J. Thromb. Haemost. JTH 5 (6) (2007) 1302–1308. L. Dou, C. Cerini, P. Brunet, C. Guilianelli, V. Moal, G. Grau, R. De Smet, R. Vanholder, J. Sampol, Y. Berland, P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory cytokines, Kidney Int. 62 (6) (2002) 1999–2009. N.D. Vaziri, CKD impairs barrier function and alters microbial flora of the intestine: a major link to inflammation and uremic toxicity, Curr. Opin. Nephrol. Hypertens. 21 (6) (2012) 587–592. D. Mafra, J.C. Lobo, A.F. Barros, L. Koppe, N.D. Vaziri, D. Fouque, Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease, Future Microbiol. 9 (3) (2014) 399–410. L. Koppe, D. Mafra, D. Fouque, Probiotics and chronic kidney disease, Kidney Int. 88 (5) (2015) 958–966. S. Prakash, T.M. Chang, Microencapsulated genetically engineered live E. coli DH5 cells administered orally to maintain normal plasma urea level in uremic rats, Nat. Med. 2 (8) (1996) 883–887. N. Ranganathan, B. Patel, P. Ranganathan, J. Marczely, R. Dheer, T. Chordia, S.R. Dunn, E.A. Friedman, Probiotic amelioration of azotemia in 5/6th nephrectomized Sprague-Dawley rats, Sci. World J. 5 (2005) 652–660. A. Yoshifuji, S. Wakino, J. Irie, T. Tajima, K. Hasegawa, T. Kanda, H. Tokuyama, K. Hayashi, H. Itoh, Gut Lactobacillus protects against the progression of renal damage by modulating the gut environment in rats, Nephrol. Dial. Transpl. 31 (3) (2016) 401–412. B. Wu, H. Jiang, Q. He, M. Wang, J. Xue, H. Liu, K. Shi, M. Wei, S. Liang, L. Zhang, Liquid chromatography/mass spectrometry reveals the effect of lactobacillus treatment on the faecal metabolite profile of rats with chronic renal failure, Nephron 135 (2) (2017) 156–166. M.L. Simenhoff, S.R. Dunn, G.P. Zollner, M.E. Fitzpatrick, S.M. Emery, W.E. Sandine, J.W. Ayres, Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus, Miner. Electrol. Metabol. 22 (1–3) (1996) 92–96. N. Ranganathan, P. Ranganathan, E.A. Friedman, A. Joseph, B. Delano, D.S. Goldfarb, P. Tam, A.V. Rao, E. Anteyi, C.G. Musso, Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease, Adv. Ther. 27 (9) (2010) 634–647. B. Guida, R. Germano, R. Trio, D. Russo, B. Memoli, L. Grumetto, F. Barbato, M. Cataldi, Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: a randomized clinical trial, Nutr. Metabol. Cardiovasc. Dis. NMCD 24 (9) (2014) 1043–1049. M. Rossi, D.W. Johnson, M. Morrison, E.M. Pascoe, J.S. Coombes, J.M. Forbes, C.C. Szeto, B.C. McWhinney, J.P. Ungerer, K.L. Campbell, Synbiotics easing renal failure by improving gut microbiology (synergy): a randomized trial, Clin. J. Am. Soc. Nephrol. CJASN 11 (2) (2016) 223–231. H. Borgeraas, L.K. Johnson, J. Skattebu, J.K. Hertel, J. Hjelmesaeth, Effects of probiotics on body weight, body mass index, fat mass and fat percentage in subjects with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials, Obes. Rev. 19 (2) (2017) 219–232. S. Khalesi, J. Sun, N. Buys, R. Jayasinghe, Effect of probiotics on blood pressure: a systematic review and meta-analysis of randomized controlled trials, Hypertension 64 (4) (2014) 897–903. M. Rossi, K. Klein, D.W. Johnson, K.L. Campbell, Pre-, pro-, and synbiotics: do they have a role in reducing uremic toxins? A systematic review and meta-analysis, Int. J. Nephrol. 2012 (2012) 673631. Y. Suzuki, K. Ikeda, K. Sakuma, S. Kawai, K. Sawaki, T. Asahara, T. Takahashi, H. Tsuji, K. Nomoto, R. Nagpal, C. Wang, S. Nagata, Y. Yamashiro, Association between yogurt consumption and intestinal microbiota in healthy young adults differs by host gender, Front. Microbiol. 8 (2017) 847. S. Mueller, K. Saunier, C. Hanisch, E. Norin, L. Alm, T. Midtvedt, A. Cresci, S. Silvi, C. Orpianesi, M.C. Verdenelli, T. Clavel, C. Koebnick, H.J. Zunft, J. Dore, M. Blaut, Differences in fecal microbiota in different European study populations in relation to age gender, and country: a cross-sectional study, Appl. Environ. Microbiol. 72 (2) (2006) 1027–1033.

[136] S. Fijan, Microorganisms with claimed probiotic properties: an overview of recent literature, Int. J. Environ. Res. Public Health 11 (5) (2014) 4745–4767. [137] J. Adediran, M.P. Leatham-Jensen, M.E. Mokszycki, J. Frimodt-Moller, K.A. Krogfelt, K. Kazmierczak, L.J. Kenney, T. Conway, P.S. Cohen, An Escherichia coli Nissle 1917 missense mutant colonizes the streptomycin-treated mouse intestine better than the wild type but is not a better probiotic, Infect. Immun. 82 (2) (2014) 670–682. [138] T. Hosoi, R. Hirose, S. Saegusa, A. Ametani, K. Kiuchi, S. Kaminogawa, Cytokine responses of human intestinal epithelial-like Caco-2 cells to the nonpathogenic bacterium Bacillus subtilis (natto), Int. J. Food Microbiol. 82 (3) (2003) 255–264. [139] D. Kao, B. Roach, M. Silva, P. Beck, K. Rioux, G.G. Kaplan, H.J. Chang, S. Coward, K.J. Goodman, H. Xu, K. Madsen, A. Mason, G.K. Wong, J. Jovel, J. Patterson, T. Louie, Effect of oral capsule- vs colonoscopy-delivered fecal microbiota transplantation on recurrent clostridium difficile infection: a randomized clinical trial, JAMA 318 (20) (2017) 1985–1993. [140] E.O. Petrof, G.B. Gloor, S.J. Vanner, S.J. Weese, D. Carter, M.C. Daigneault, E.M. Brown, K. Schroeter, E. Allen-Vercoe, Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut, Microbiome 1 (1) (2013) 3. [141] T. Garcia-Lezana, I. Raurell, M. Bravo, M. Torres-Arauz, M.T. Salcedo, A. Santiago, A. Schoenenberger, C. Manichanh, J. Genesca, M. Martell, S. Augustin, Restoration of a healthy intestinal microbiota normalizes portal hypertension in a rat model of nonalcoholic steatohepatitis, Hepatology (2017), http://dx.doi.org/10.1002/hep.29646. [142] A. Vrieze, E. Van Nood, F. Holleman, J. Salojarvi, R.S. Kootte, J.F. Bartelsman, G.M. Dallinga-Thie, M.T. Ackermans, M.J. Serlie, R. Oozeer, M. Derrien, A. Druesne, J.E. Van Hylckama Vlieg, V.W. Bloks, A.K. Groen, H.G. Heilig, E.G. Zoetendal, E.S. Stroes, W.M. de Vos, J.B. Hoekstra, M. Nieuwdorp, Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome, Gastroenterology 913-6 (2012) e7. [143] ICMR-DBT guidelines for evaluation of probiotics in food, Indian J. Med. Res. 134 (2011) 22–25. [144] A.N. Wang, X.W. Yi, H.F. Yu, B. Dong, S.Y. Qiao, Free radical scavenging activity of Lactobacillus fermentum in vitro and its antioxidative effect on growing-finishing pigs, J. Appl. Microbiol. 107 (4) (2009) 1140–1148. [145] H. Weng, K. Endo, J. Li, N. Kito, N. Iwai, Induction of peroxisomes by butyrate-producing probiotics, PLoS One 10 (2) (2015) e0117851. [146] M. Coakley, R.P. Ross, M. Nordgren, G. Fitzgerald, R. Devery, C. Stanton, Conjugated linoleic acid biosynthesis by human-derived Bifidobacterium species, J. Appl. Microbiol. 94 (1) (2003) 138–145. [147] R. Kumar, R. Nagpal, R. Kumar, V. Hemalatha, A. Verma, C. Kumar, B. Chakraborty, F. Singh, S. Marotta, Cholesterol-lowering probiotics as potential biotherapeutics for metabolic diseases, Exp. Diabetes Res. 2012 (2012) 902917. [148] T.M.R. de Albuquerque, E.F. Garcia, A. de Oliveira Araujo, M. Magnani, M. Saarela, E.L. de Souza, In vitro characterization of lactobacillus strains isolated from fruit processing by-products as potential probiotics, Probiot. Antimicrob. Proteins (2017), http://dx.doi.org/10.1007/s12602-017-9318-2. [149] M. Schwarzer, K. Makki, G. Storelli, I. Machuca-Gayet, D. Srutkova, P. Hermanova, M.E. Martino, S. Balmand, T. Hudcovic, A. Heddi, J. Rieusset, H. Kozakova, H. Vidal, F. Leulier, Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition, Science 351 (6275) (2016) 854–857. [150] D.C. Cavallini, M.S. Manzoni, R. Bedani, M.N. Roselino, L.S. Celiberto, R.C. Vendramini, G. de Valdez, D.S. Abdalla, R.A. Pinto, D. Rosetto, S.R. Valentini, E.A. Rossi, Probiotic soy product supplemented with isoflavones improves the lipid profile of moderately hypercholesterolemic men: a randomized controlled trial, Nutrients 8 (1) (2016). [151] J.J. Ryan, D.A. Hanes, M.B. Schafer, J. Mikolai, H. Zwickey, Effect of the probiotic saccharomyces boulardii on cholesterol and lipoprotein particles in hypercholesterolemic adults: a single-arm, open-label pilot study, J. Altern. Complement. Med. 21 (5) (2015) 288–293. [152] A. Ostadrahimi, A. Taghizadeh, M. Mobasseri, N. Farrin, L. Payahoo, Z. Beyramalipoor Gheshlaghi, M. Vahedjabbari, Effect of probiotic fermented milk (kefir) on glycemic control and lipid profile in type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial, Iran. J. Public Health 44 (2) (2015) 228–237. [153] Z. Mazloom, A. Yousefinejad, M.H. Dabbaghmanesh, Effect of probiotics on lipid profile, glycemic control, insulin action, oxidative stress, and inflammatory markers in patients with type 2 diabetes: a clinical trial, Iran. J. Med. Sci. 38 (1) (2013) 38–43.

Please cite this article in press as: M.P. Cavalcanti Neto, et al., Gut microbiota and probiotics intervention: A potential therapeutic target for management of cardiometabolic disorders and chronic kidney disease? Pharmacol Res (2018), https://doi.org/10.1016/j.phrs.2018.01.020