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Disentangling the molecular mechanisms underlying statin-mediated gut dysbiosis
Statins are the drugs mainly use for reducing serum cholesterol level and risk of cardiac disease but its treatment is linked with some adverse effects such as, myopathy, type-2-dibetes mellitus, nausea, constipation, diarrhea, liver damage, and kidney damage. There are many research works which connect statins with muscular side effects, such as myalgia. (Joy and Hegele 2009, Magni, Macchi et al. 2015). The mechanism of causing all these adverse effects is not well known.
Statins inhibit HMG-CoA reductase an enzyme that catalysis a rate-limiting step in the synthesis of mevalonate pathway and subsequently the biosynthesis of cholesterol (Istvan 2002) . After reducing the concentration of cholesterol in hepatocytes statins starts the expression t of low-density lipoprotein (LDL) receptors, causing reduction in LDL-cholesterol (LDL-C) from blood. In addition to lowering LDL-C levels, statins have been reported to have anti-inflammatory and immunomodulatory activities, and there is mounting evidence that statins reduce growth and virulence of a number of bacterial pathogens (Rodriguez, Wojcik et al. 2012). Statins have been shown to have antibacterial effects (Jerwood and Cohen 2007) and have been proposed as potential alternatives to antibiotics (Motzkus-Feagans, Pakyz et al. 2012). Majority of bacteria lacks the HMG-R isoform therefore uses an alternative pathway for the synthesis of isoprenoids. The pleiotropic effects of statins upon host physiological processes and the reported antibacterial effects of these drugs led scientist to evaluate the potential impact of statin treatment upon the gastrointestinal microbiota and the expression of associated markers of microbe host interactions. Scientist administered a widely prescribed statin, Rosuvastatin (RSV) to mice at a physiologically relevant concentration and demonstrated significant changes to the community structure of the microbiota in both the caecum and the faeces of these animals relative to untreated controls. Examination of host inflammatory markers and systemic and faecal bile acids established that these parameters are also significantly altered by statin administration.(Nolan, Skuse et al. 2017)
Mevalonate pathway also support the synthesis of other biologically important molecules such as heme, vitamin K, coenzyme Q10 (CoQ10), steroid hormones or bile acids (BAs) (Holstein and Hohl 2004). HMG-reductase is also essential for the production of isoprene subunits such as isopentenyl diphosphate (IPP) and dimethyl allyl diphosphate (DMAPP), these subunits are part of large family of compounds known is isoprenoid. These organic molecules are key metabolites in mammals and bacteria (Heuston, Begley et al. 2012). These are two important end products of the mevalonate pathway that function as electron carrier and radical-scavenging antioxidants in the respiratory electron chain and oxidative phosphorylation pathways (Golomb BA and Evans MA 2008).Nevertheless, although complementing statin therapy with CoQ10 Supplements seem a logical option to prevent the incidence of myotoxicity, there is contradictory evidence as to whether statin-induced myopathy can be alleviated with CoQ10 supplementation (Caso, Kelly et al. 2007) (Young, Florkowski et al. 2007). Statins also increase the risk of type-2-diabetes mellitus (T2DM) (Mansi 2007)This is likely to be linked to interfering with insulin signaling and glucose homeostasis (Brault, Ray et al. 2014).
Role of statins in type 2 diabetes mellitus:
T2DM is a metabolic disorder associated with insulin resistance, with an initial increase in insulin secretion, however, over time beta cell death and insulin insufficiency. Although T2DM has multifactorial a etiology, recent association studies have highlighted the importance of perturbations in the gut microbiota as a T2DM-contributing factor (Qin, Li et al. 2012, Karlsson, Tremaroli et al. 2013, Forslund, Hildebrand et al. 2015). Thus, T2DM patients present a characteristic gut microbial profile depleted in butyric acid-producing bacteria that may contribute to developing this condition (Qin, Li et al. 2012) Butyric acid is a short chain fatty acid (SCFA) that is derived from the fermentation of non-digestible carbohydrates by saccharolytic gut microbes. This compound is one of the most important metabolites produced by intestinal bacteria based on its multiple beneficial effects on host health. These include the regulation of several processes affected by statin treatment, such as lipid and glucose metabolism and muscle homeostasis (Canfora, Jocken et al. 2015).
The aim of this study was to investigate the impact of statin treatment on the composition of the mouse gut microbiota and the development of T2DM. The data demonstrate that long-term exposure to statins perturbs the mouse gut microflora and upregulates transcription in the liver of fasting-related genes through a PXR-dependent mechanism. Importantly, this is the first study to demonstrate that statin therapy results in profound changes in the composition of the bacterial community in the gut.
A study was conducted by (Corsini, Bellosta et al. 1999)to find out effect of statins on host physiology, in this study two statins were used of different nature and properties foe 12 weeks i.e. atorvastatin (lipophilic, with longer half-life, absorb slowly in plasma and undergoes first-pass metabolism) and pravastatin (hydrophobic, short half-life, absorb quickly in plasma and undergoes late-pass metabolism then atorvastatin). A wild type female mice C57BL/6J was treated with both statins in this study, results shows increase in body weight but there was no difference in total plasma cholesterol level between statin-treated mice and control cohort. At week 11 insulin sensitivity was assayed by glucose tolerance test and by measuring fasting blood glucose level. It was been reported that both T2DM and non-diabetic patients have high fasting plasma glucose levels(Young, Florkowski et al. 2007) but it was not proof statistically.
Statins affect gut microbiota:
A 16s rRNA gene sequencing method was used which strong effect of statins on composition of gut microbiota. SILVA 16SrRNA gene database (SILVAngs 1.3) was used (Yilmaz, Parfrey et al. 2013). In the control cohort phyla Firmicutes (58.5 %) and phyla Bacteroidetes (39.6%)were dominant in the control cohort (ND-vehicle). Treatment with statins makes the community less diverse as compare to Shannon’s and Simpson’s indices. For finding out those relevant OTUs in the gut microbial composition which shows the observed changes after statin therapy, a pairwise comparison was done between statin-treated and control group by linear discriminant analysis effect size (LEfSe) algorithm (Segata, Izard et al. 2011). Different number of OTUs were obtain between these group, such as six OTUs between vehicle and pravastatin groups, thirteen OTUs between the vehicle and atorvastatin groups, while there was only two OTUs difference between both statin groups, showing that both statins have the same effects on composition and structure of gut microbiota. Statins therapy cause a big enrichment in the phylum Bacteroidetes while cause reduction in most of the gram-positive OTUs of phylum Firmicutes, belongs to Lachnospiraceae and Ruminococcaceae families, constituents of the Clostridium clusters XIVa and IV, respectively. Members of both groups are non-pathogenic commensals, spore forming and produce butyric acid by carbohydrate fermentation, butyric acid is important for the host health and homeostasis. This enrichment of Bacteriodetes over Fermicutes shows a shift from butyrate to acetate, lactate, and succinate production. These changes were also reported in diet-induced diabetes-sensitive mice (Canfora, Jocken et al. 2015).
Statin affect SCFA metabolism:
To find out the change in gut microbiota by statin therapy, result in changing the SCFA metabolism. A SCFA composition was determine in the faecal content of the caecum and the serum of the control and statin-treated ND cohorts. Statin treatment causes low production of butyric acid while no change in acetic, propionic and valeric acid was seen in both statin-treated and control groups. This changes in fermentation products shows that statin theory cause dysbiosis.
Statins affect the size and composition of BA pool in the gut:
The size and composition of BA pool have direct effects on gut microbiota; hence condition that interferes in bile acid excretion or absorption causes gut dysbiosis. (Duboc, Rajca et al. 2012, Mouzaki, Wang et al. 2016). To find out effect of statins on BA production , the expression of two main regulatory enzymes of BA synthesis Cyp7a1 and Cyp27a1 in the liver was examined by quantitative PCR q(PCR) (Chiang 2002).which show low expression of Cyp7a1 in both statin-treated groups but Cyp27a was highly expressed in the atorvastatin group only.
Statin cause dysbiosis and change in metabolism via a PXR-dependent mechanism:
As previously described Pxr-/- knockout mouse line was treated with statins (Scheer, Ross et al. 2008).To find out the dysbiosis and metabolic alteration cause by statins is PXR-dependent or not. In this experiment the same conditions and reagents were used as in the wild type mice study.in this case the statin therapy did not increase body weight and fasting blood glucose concentration .statin causing alteration in gut microbiota was weekend due to Pxr-/- knockout and there was a precise decrease in the Bacteroidetes a common increase in Firmicutes. To Find out the role of PXR in statin therapy of the gut microbiota of wild type and Pxr-/- mice, they carried out multivariate analysis on the Bray Curtis dissimilarity matrix of the combined dataset (PERMANOVA, model response as a function of treatment: Pseudo F= 4.027, P<0.01, R2=0.1598; genotype: Pseudo F= 7.76, P<0.001, R2=0.1540; interaction of treatment and genotype: Pseudo F= 6.279, P<0.001, R2=0.2493). A Pairwise comparisons show greater effect of statins on gut microbiota in wild type mice. There was reduction in the number of OTUs and consistency, when the microbial diversity was analyzed.
LEfSe analysis show changes in the presence of Lachnospiraceae NK4A136 group, in both statin-treated group. These changes in gram-positive bacteria did not affect the serum concentration of the endotoxin-related marker LBP. The metagenomics profile of gut microbiota also did not show differences between statin treated and non-treated groups as found in wild type mice.
There was no difference found in the production of SCFA by the gut microbiota due to statin therapy, but only in atorvastatin-treated group there was reduction of acetic acid levels.as release of hormones is stimulated by acetic acid to regulate appetite (Perry, Peng et al. 2016), this decrease in the production of acetic acid in atorvastatin-treated mice might show the low food intake profile of this group. If the level of acetic acid is not constantly reduce it may be due utilization of acetic acid by gut microbiota rather than production. Statin did not cause huge changes in the primary BA pool in the Pxr-/- mice as in wild type mice. There was no change observed in the Cyp7a1 or Cyp27a1 transcripts levels as well. BA profiling shown increase in the sulphate-conjugated BA 7-SCA in the pravastatin group , which suggest that pravastatin can control the activity of other pathways that control bile acid sulfation such as the constitutive androstane receptor (CAR) (Wagner, Halilbasic et al. 2005). Statin therapy did not affect the host gene expression and occurrence of Fgfr4 and Ppargc1a mRNA in pxr null mice. Due to the absence of PXR the statin-mediated transactivation of Slco1b2 and Ppar alpha was stopped while Slc2a2 mRNA transcript was improved. Statin therapy causes negative regulation of basal gene expression levels of Nr0b2 and Cyp3a11 in PXR null Hepatocytes. Which show possibility of statins attachment to different receptors in the absence of PXR, by suppressing expression of both Nr0b2 and Cyp3a11, Thus negative regulation of Nr0b2 is consistent with statins acting as ligands of Vitamin D Receptor (VDR) (Chow, Magomedova et al. 2014).As there is a hypothesis that statins, or some of their derived metabolites, could be VDR agonists (Grimes 2006).
Statins analogues of vitamin D:
Clinical properties introduce by statins are also shown by vitamin D and its look like statins activates vitamin D receptors (VDR) (Grimes 2006).because both shows many similarities in the effects towards disease like heat disease (Grimes, Hindle et al. 1996), multiple sclerosis (Munger, Zhang et al. 2004), (Stüve, Prod’homme et al. 2003).cancer(Demierre, Higgins et al. 2005, Yin, Raum et al. 2009), diabetes(Mathieu, Gysemans et al. 2005, Vogiatzi, Macklin et al. 2009),and rheumatoid arthritis ((McCarey, McInnes et al. 2004, Ponsonby, Lucas et al. 2005).
To find out if statins activate VDR in vitro , HEK cells were treated that have a stable expression of VDR and a transient transfection of vitamin D response element (VDRE)-luciferase reporter was introduced with simvastatin, pravastatin, or lovastatin and three other VDR agonist ( paricalcitol, calcitriol, and activated doxercalciferol) for 24 hours. No significant activity was found for statins while the other three agonist were effective to induce VDRE-dependent reporter gene expression. As these results shows that statins do not activate VDR directly but there is a possibility of statin modification into metabolites in vivo that’s can activate VDR. Because it is well known that vitamin D itself and some vitamin D analogs such as ergocalciferol, calcidiol, and doxercalciferol are all precursors, and require metabolic activation in vivo to become VDR agonists (Miwa and Akiba 2004, Salusky 2005)May be statins are also precursors of VDR agonists. Therefore in vivo study is needed to test the hypothesis that metabolites of statins can activate vitamin D receptor.
Vitamin D is produced in the skin by the action of UVB light, then in liver vitamin D is hydroxylated into 25-hydroxyvitamin D (25OHD), in many cells of the body 1-a hydroxylase (CYP27B1) is expressed, that catalysis hydroxylation of (25OHD)into active vitamin D (1,25 (OH)2 vitamin D)( (Pojednic and Ceglia 2014)). Active vitamin D binds to the vitamin D receptor (VDR) and is carried to the nucleus to forms a heterodimer with a cognate nuclear receptor partner. The heterodimer complex binds to vitamin D response elements (VDRE) in promoters of several genes, thereby regulating transcription (Saramäki, Diermeier et al. 2009).there are 3000 VDRE sequences been identified during the silico analyses of human genome, but in vivo importance of most of them is not known (Wang, Tavera-Mendoza et al. 2005). In blood (25ODH) form is more stable then (1,25 (OH)2 vitamin D) form, therefore (25ODH) is consider for measuring vitamin D level in patients serum(Holick 2007)( (Ross, Manson et al. 2011). (25ODH )vitamin D control the hemostasis of calcium and phosphate in bones, by increasing the absorption of calicium and phosphate from intestine, resorption of calicium and phosphate in bones, elevate the level of calcium and phosphate ions in blood (Marie-Louise Ovesj et al., 2015). Low concentration of vitamin D in blood circulation increases the risk of muscular pain (Wynn 2013).
Epidemiologic, genetic and metabolic data suggest that vitamin D has a vital role in obesity.(Ye, Reis et al. 2001, Schuch, Garcia et al. 2009).A transgenic mice study shows that over-expression of human VDR in fat cells/lipocytes cause a noticeable reduction in energy consumption and introduction of obesity (Wong, Kong et al. 2011).
In some studies the decrease level of (25OHD) is connected with statins induced myalgia (Torabinejad, Eby et al. 1985) The aim of this study was to test the hypothesis that 25OHD levels <50 nmol/L could predict the risk of statin-induced myopathy.
Low levels of 1,25OHD increase renal renin production, thus activating the renin-angiotensin-aldosterone system (RAAS), reduce renal expression of klotho, increase fibroblast growth factor-23 levels, and consequently suppress 1aOHase, further lowering 1,25OHD levels, all of which are associated with progression of renal damage (de Borst, Vervloet et al. 2011)Furthermore, FokI polymorphisms in the vitamin D receptor (VDR) gene differ between patients with diabetic nephropathy and healthy subjects (Vedralová, Kotrbova-Kozak et al. 2012). Taken together, this evidence suggests that 25OHD, 1,25OHD, and VDR may play a role in exacerbation of diabetic nephropathy, at least in part. However, there are no reports studying these three factors together. Therefore, we conducted a cross-sectional study of patients with type 2 diabetes for explaiation:
1) Which factor have strong association with eGFR levels and CKD stages, 25OHD or 1,25OHD.
2) If there is any interaction between 25OHD/1,25OHD and VDR polymorphisms, in association with CKD stages, after adjusting for other confounders.
VDR belongs to nuclear receptors super family, which regulate gene expression by ligand dependent manner (Baker, McDonnell et al. 1988, Mangelsdorf, Thummel et al. 1995). VDR facilitate the action of vitamin D for calcium and phosphate translocating tissue, mainly intestine. The VDR knockout mice experiment illustrate that deficiency of VDR results in low bone mass, hypercalcemia, hypophosphatemia, hyperparathyroidism, 10 fold elevated 1,25-(OH)2D3, and very decrease amount of 24,25(OH)2D3. VDR knock out mice born normal phenotypically, showing symptoms of rickets/osteomalacia and secondary parathyroidism essentially after weaning (Yoshizawa, Handa et al. 1997).
In a study of one year, patients having decrease level of 25OHD <50 nmol/L had high risk of statin induced myopathy, also showing specific genetic polymorphism in VDR had 4 times high risk of developing muscular symptoms. Some other studies also show muscular symptoms in patients having low vitamin D level. Patients having muscular symptoms were given vitamin D (50,000 units/week in 12 weeks), patients shows 92 % recovery rate. (Ahmed, Khan et al. 2009). Another study shows a strong relation between supplementation of deficient 25OHD levels and improved muscular symptoms.(Linde, Peng et al. 2010)
This study shows complex relationship between the vitamin D/VDR axis, metabolic diseases and inflammation. This was a genetic and immunologic analysis that VDR polymorphisms located in 39 haplotype block region of VDR gene correlate with obesity development. Furthermore, VDR haplotypes that are associated with statistically increased or reduced risks of obesity and with higher/lower BMI scores could be identified. Notably, genes that are part of the inflammosome complex, and cytokines that are the end product of the activation of such complex, were significantly up regulated in cells carrying the VDR haplotype that correlates with an increased risk of obesity and higher BMI scores; associated with such ‘‘at risk’’ VDR haplotype was also an increased plasma concentration
Of LPS and a reduced expression of VDR.
In particular haplotype segregation analyses revealed the presence of a significantly higher risk of obesity and increased BMI in individuals carrying the GTA (rs731236 (G), rs1544410 (T), rs7975232 (A) haplotype, whereas the complementary ACC (rs731236 (A), rs1544410(C), 7975232(C)) haplotype was associated to a reduced risk of obesity and lower BMI scores, possibly suggesting a protective role.
It has been convincingly shown that the vitamin D/VDR axis modulates the activity of the immune system, and that in turn the immune system plays a pivotal role in vitamin D metabolism (Al-Daghri, Guerini et al. 2014) (White 2012). Different reports suggest that chronic inflammation is a key marker of obesity, the origin of inflammation during obesity and the underlying molecular mechanisms that explain its occurrence are nevertheless not known. The importance of inflammation in obesity was analyzed in the animal model. Thus, recent data show that NLRP3-/- knockout mice do not increase weight when fed a high fat diet, and that elimination of NLRP3 expression prevents obesity-induced caspase-1 cleavage as well as IL1b and IL18 activation (Vandanmagsar, Youm et al. 2011). These results suggest a direct involvement of NLRP3-inflammosome in obesity, and are reinforced by results herein indicating that the VDR GTA ‘‘risk’’ haplotype correlates with a higher inflammatory response to LPS. mRNA expression for a number of genes, including those of the inflammosome component downstream signaling and effector molecules was indeed significantly augmented in GTA obese individuals.
The results herein reinforce the idea that the vitamin D/VDR axis plays a role in the pathogenesis of obesity that is dependent on the presence of particular SNP and is at least in part mediated by an ongoing degree of inflammation, possibly secondarily to microbial translocation. Understanding the mechanism underlying the inflammation that is associated with obesity could contribute to the identification of novel therapeutic strategies to prevent or treat this metabolic condition.
A study was conducted to see the effect of VDR on microbial community in gut. In this study fecal and cecal stool samples were used. Vdr knockout (Vdr-/- and wild-type (WT) mice were used.
In the Vdr-/- samples, Bacteroidia and Sphingo bacteria were enriched, and Bacilli was depleted in the fecal stool, whereas Bacteroidia was depleted in cecal stool. In WT mice, Clostridia were enriched, while Bacteroidia and Flavobacteria were depleted in the transition from cecal to fecal stool. Bacteroidia, Flavobacteria, Sphingo bacteria, and Cytophagia were depleted in Vdr-/- mice in the cecal-to-fecal transition. Vdr status and intestinal location thus altered the bacterial community in the gut. Clearly, Vdr deficiency was associated with dysbiotic changes in the gut. The Shannon diversity and Chao1 richness indexes suggested both intra group and inter group variability in microbial diversity. We also used PCoA to cluster the cecal and fecal microbiomes from Vdr-/- and WT mice. The Vdr-/- and WT samples clustered independently on the PCoA scale, as did the cecal and fecal samples. Therefore, Vdr status and intestinal location did cause variations in bacterial diversity.(Jin, Wu et al. 2015).
Phylogenetic Differences in the Gut Microbiome, by Vdr Status:
In the Vdr–/– mice, on the genus level, Lactobacillus was depleted in fecal stool, whereas Clostridium and Bacteroides were enriched. At higher taxonomic levels, Lactobacillales, which includes lactic acid bacteria other than Lactobacillus, was also depleted (from62.71% [4.63%] to33.23% [10.80%]; P o 0.01), indicating a dramatic decrease in the production of lactic acid. The Bacteroidia-to- Bacteroides lineage was consistently enriched. Greater than Clostridium, the lineage Clostridiaceae was also enriched (from2.48% [0.81%] to9.24% [4.58%]; P o 0.05). Bacterial taxa were enriched along the Sphingo bacteria-to-Sphingo bacteriaceae lineage, but no genera reached statistical significance. In cecal stool, Alistipes and Odoribacter were depleted, and Eggerthella was enriched in the Vdr–/– samples. The lineage from Bacteroidetes to Bacteroidales was depleted in Vdr–/– mice, as were the Rikenellaceae-to-Alistipes and Peptococcaceae-to- Odoribacter lineages. Notably, all the taxa upstream of Eggerthella remained unchanged. Compared with the changes in the fecal microbiota, the relative abundance of cecal genera affected by Vdr status was much less taken together, the dramatic reduction of lactic acid bacteria in the fecal microbiome in Vdr–/– mice is likely the most important alteration in fluencing in- testinal homeostasis. The fecal microbiome is more severely affected by Vdr status than is the cecal microbiome at the taxonomic level. Taxonomically the colon is the major site affected by Vdr status. The Vdr-associated defects in the intestinal microbiome may be related to the weakened capacity of the colon to increase lactic acid bacteria and to contain the growth of Clostridium and Bacteroides.(Jin, Wu et al. 2015).
The most important and complex habitat for microorganisms is the gut. Very important events occur in gut which regulates our metabolism, like fighting with infection, adaptation to immune system, signaling cell. We get these microbiomes from different things like baby from the mother, infant passes though the birth canal, its get coded with microbes from mom, these microbes seeding insides the baby , combine with microbes from breast feeding, and from the surrounding we have. For some reason if we lose the microbiome this will results in disease like colon cancer, colitis, diabetes, obesity etc. due to inhibition of important microbes. There are many reasons for losing the important microbes, like food we take, antibiotic we take, or due to some deficiency of vitamins.
The gut microbiome not only has been correlated with disorders such as inflammatory bowel diseases (IBD), obesity, and diabetes (Scaldaferri, Pizzoferrato et al. 2012) (Zak-Gołąb, Olszanecka-Glinianowicz et al. 2014) but has also been shown to have extended effects in other distant organs, Including autism spectrum disorder and Alzheimer disease conditions previously thought irrelevant to gastrointestinal bacteria thus foreshowing a new era of microbiome studies.
Type 2 diabetes has become the main health issue in populations all over the world, cause due to different environmental and genetic factors (Wellen and Hotamisligil 2005) (Risérus, Willett et al. 2009).research show influences of other genomes in the development of T2D such as gut microbiomes. (Musso, Gambino et al. 2011) .microbiomes can be linked with different diseases due to their taxonomy and functional composition. (Vijay-Kumar, Aitken et al. 2010). There are many studies which link obesity with increase and decrease in phylum Firmicutes and phylum Bacteroidetes respectively (Bäckhed, Ding et al. 2004, Ley, Bäckhed et al. 2005, Turnbaugh, Ley et al. 2006, Turnbaugh, Bäckhed et al. 2008, Turnbaugh, Hamady et al. 2009, Zhang, DiBaise et al. 2009).In T2D patient gut study showed reduction in the amount of phylum Firmicutes and the class Clostridia .significantly reduced (Larsen N et al., 2010).
A decrease in butyrate-producing bacteria was shown by Functional annotation analyses, which may be helpful for metabolism but increase many opportunistic infections. This increase in opportunistic infections was very diverse among the Chinese patients. This increase is reported for colorectal cancer patients (Wang, Cai et al. 2012) and ageing population (Biagi, Nylund et al. 2010). This reveals the protective function of butyrate-producing bacteria against many diseases. . These finding also expose that there is a chance of ‘functional dysbiosis’ in T2D patients and there is no direct link between a certain species with T2D pathophysiology. Also by the loss of butyrate-producing bacteria in other gut infections shows increase in opportunistic infection, may be dysbiosis make the body susceptible for other disease. (Qin, Li et al. 2012).
This information about Vdr deficiency and statin therapy shows that both have influence on gut microbiota. Both are associated with dysbiosis. In the Vdr–/– mice Lactobacillus was depleted in fecal stool, whereas Clostridium and Bacteroides were enriched, causing a big decrease in the production of lactic acid and this is the important change for the influencing intestinal homeostasis. These changes reduce the capability of the gut to increase lactic acid bacteria and to contain the growth of Clostridium and Bacteroides. Vdr deficiency have no effect n diversity of the community while
Treatment with statins makes the community less diverse as compare to Shannon’s and Simpson’s indices. Statins therapy cause a big enrichment in the phylum Bacteroidetes while cause reduction in most of the gram-positive OTUs of phylum Firmicutes, belongs to Lachnospiraceae and Ruminococcaceae families, constituents of the Clostridium clusters XIVa and IV, respectively. Butyric acid by carbohydrate fermentation, butyric acid is important for the host health and homeostasis. This enrichment of Bacteriodetes over Fermicutes shows a shift from butyrate to acetate, lactate, and succinate production. These changes were also reported in diet-induced diabetes-sensitive mice (Canfora, Jocken et al. 2015).
Statin affect SCFA metabolism, This change in fermentation products shows that statin theory cause dysbiosis. Statins affect the size and composition of BA pool in the gut as well.in this study we found the genetic evidence for the hepatic activation of PXR-dependent mechanism to see the secondary effects of statins. In all these research work mice is use, but still we need to find out that statin therapy also triggers the PXR_activation and gut dysbiosis in human.
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