Statin Therapy and Gut Microbiota

Abstract

Accumulating studies reveal that statins are associated with distinct gut microbiota profiles. Statin therapy helps maintain gut microbiota homeostasis, reducing the prevalence of gut microbiota dysbiosis and breaking antimicrobial resistance. The possible mechanisms may include improving bile acids metabolism, regulating intestinal innate immunity, and inhibiting cell membrane biosynthesis. Statin treatment might benefit patients with obesity, cardiovascular diseases, malignancies, and immune-related diseases by modulating the compositions and functions of gut microbiota. The altered gut microbiota functions by regulating the host metabolism with microbial-derived metabolites, such as primary and secondary bile acids (BAs) and short-chain fatty acids (SCFAs). Meanwhile, statins can be degraded or modified by the gut microbiota, which may affect the treatment effectiveness in clinic. The addition of probiotics could enhance the effects of statins on hypercholesterolemia and inflammation. Collectively, the interaction between statins and gut microbiota shows great promise for new therapeutic targets and personalized medicine in many diseases, which still need further investigation.

1. Introduction

Our intestinal tracts harbor countless microbes, considered as a new organ for their essential effects [1]. Gut microbiota regulates the occurrence and development of many kinds of diseases, including gastrointestinal disease, neuropsychiatric diseases (gut-brain axis), metabolic disorders, cardiovascular disease, infectious diseases, and malignant tumors. The related mechanisms include pathogen defense, maintaining mucosal homeostasis, interaction with immune system, and participation in human metabolic processes. Gut microbiome composition is influenced by age, diet, antibiotic drugs, and other environmental exposures [2]. Notably, gut microbiota can also interplay with nonantibiotic drugs, resulting in altered microbiota composition or changed drug effectiveness [3]. Microbiome-based therapeutics, such as fecal microbiota transplantation (FMT), have become promising for several diseases associated with changes in gut microbiota [4]. The concerns about the interaction between microbes and drugs may limit their practical use. Statins are the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-R), a rate-limiting enzyme in the cholesterol synthesis pathway. Statins show a potent effect of lowering plasma lipid levels and are considered as protector against atherosclerosis, inflammation, oxidation, and thrombogenesis [5]. Meanwhile, accumulating studies have also revealed that statins could regulate gut microbiota. Here, we aim to review the bidirectional interactions between statins and gut microbiota and the underlying clinical consequences.

2. The association between statin therapy and gut microbiota signature

Replace in a Dutch cohort of 1135 patients, statins were significantly associated with changes of β diversity [6]. Recently, Vieira-Silva et al. have divided gut microbial profiles into four enterotypes based on the abundance of signature species: Bacteroidetes 1 (Bact1), Bacteroidetes 2 (Bact2), Rumen cocci (Rum), and Prevotella (Prev). Bact2 enterotype is associated with inflammation, showing a high proportion of Bacteroides and a low proportion of Faecalibacterium. Patients with obesity who take statins show a lower prevalence of Bact2 than those who did not take statins (5.9 vs. 17.7%, P < 0.01), suggesting that statin therapy helped reduce gut microbiota dysbiosis [7]. Moreover, statins can alter the microbiome composition in patients with dementia, whose role in dementia remains to be elucidated [8].

Different statins show different influence on the microbiota. Atorvastatin promotes the relative abundance of anti-inflammatory microbiota, such as Faecalibacterium prausnitzii, and reduces the abundance of proinflammatory bacteria, such as Desulfovibrio sp., in patients with hypercholesterolemia [9]. In a rat obesity model induced by a high-fat diet (HFD), atorvastatin treatment restored the gut microbiota diversity with an increased abundance of Proteobacteria and a decreased proportion of Firmicutes [10]. And rosuvastatin mainly decreased the ratio of Firmicutes/Bacteroidetes [11, 12, 13]. Kim et al. found that rosuvastatin remarkably increases microbial diversity more than atorvastatin in HFD mice. FMT with fecal material collected from rosuvastatin-treated mice improves glucose tolerance and metabolic disorders and decreases inflammatory factor, IL-1β [11]. Martin et al. found that rosuvastatin had collective genetic changes of microbiota configuration for reduced transportation and metabolism of trimethylamine-N-oxide (TMAO) and increased betaine and gamma-butyl betaine [14].

Statins can show anti-bacterial effects to some extent. Statins help break antimicrobial resistance by acting synergistically with antibiotics to weaken virulence factors, boost the body’s immunity, or help wound healing [15, 16]. Simvastatin had the highest antibacterial activity against Gram-positive bacteria compared with atorvastatin, rosuvastatin, and fluvastatin. Atorvastatin is generally similar to or slightly better than simvastatin against Gram-negative bacteria, but both are more effective than rosuvastatin and fluvastatin [17]. The mechanism of antibacterial activity of statins is likely to interfere with the regulatory function of bacterial cells by binding to and destroying cell surface structures [18, 19]. Nolan et al. reported that rosuvastatin can inhibit HMG-R (+) bacteria pathogens such as Staphylococcus aureus and Listeria monocytogenes which was associated with a reduction in bacterial-induced mevalonate levels [20].

3. Mechanisms of statins in regulating gut microbiota composition

Since statins are potent cholesterol-lowering medicines, bacteria that depend on host cholesterol are inhibited directly [21]. Changes in bile acid metabolism are the main mechanism affecting gut microbiota caused by statins. Bile acids, the main components of bile, are produced in liver cells by the conversion of cholesterol. Animal experiments showed that a high-fat diet increased bile acid excretion, leading to an increase in Firmicutes/Bacteroidetes ratios and a decrease in microbial richness and biodiversity [22, 23]. The composition and diversity of microbiota caused by bile acid differences were also found in populations with different diets [24]. The major regulatory enzymes catalyzing bile acid synthesis are Cyp27a1 and Cyp7a1 [25]. lslam et al. found that statins can inhibit bile acid biosynthetic pathway by down-regulating Cyp27a1 gene and inhibit the conversion of 7 alpha hydroxycholesterol [12]. Caparros-Martin et al. demonstrated that statins induced metabolic alterations through pregnane X receptor (PXR) pathway, which was responsible for the deregulation of Cyp27a1 and Cyp7a1. PXR deletion significantly attenuated the statin-induced changes in gut microbiota composition [26]. Additionally, Cheng et al. found that statin therapy may activate NF-κB signaling pathway, induce intestinal inflammation and change mucosal barrier function, which alters the composition of gut microbiota [27]. Accumulating studies have revealed statins can inhibit certain pathogenic bacteria, which partly accounts for the regulatory effect of statins on gut microbiota composition. The mechanism of their antibacterial activity has been described previously.

4. Influence of gut microbiota on the therapeutic efficacy of statins

Statins have been shown to influence gut microbial profile; in turn, the cholesterol-lowering effect of statins can be regulated by gut microbiota. Compared to mice with intact gut microbiota, antibiotics-induced abiotic mice did not respond to atorvastatin treatment with the altered expression of cholesterol-lowering genes (Ldlr, Srebp2, and Npc1l1) [28]. Simvastatin showed a similar effect, which was associated with genes regulating bile acids synthesis [29]. Additionally, Gut microbiota can mediate the production and degradation of active β-hydroxy acid form of lovastatin [30]. Furthermore, patients with higher gut biodiversity predict well respond to statins, showing lower levels of total cholesterol and LDL cholesterol (LDL-C). A significant increase in Bacteroides, Holdemanella, Clostridium and a decrease in Lactobacillus, and Bifidobacterium, predict a poor response to statins therapy with more adverse effects [31, 32]. The effect of Faecalibacterium on statins is still controversial [33, 34].

Microbiota-derived productions can mediate statins efficiency through several pathways. Baseline concentrations of microbiota-produced lithocholic acid, taurolithocholic acid, and glycolithocholic acid were positively correlated with simvastatin-related LDL-C reduction levels [35]. Jones et al. performed a randomized controlled trial and found that patients treated with Lactobacillus reuteri, a bacteria containing bile salt hydrolases, have significantly reduced LDL-C levels [36]. Zhang et al. revealed that Bacteroidaceae, Prevotellaceae, and Porphyromonadaceae-mediated the effect of simvastatin through phenylalanine and tyrosine-associated amino acid metabolism pathways [37]. Statins influence the concentration of microbiota-derived metabolites, such as short-chain fatty acid (SCFAs), TMAO, and lipopolysaccharides (LPS), which in turn mediate lipid metabolism by targeting PPARγ, TLR4-Myd88, FXR, and PXR signaling pathways [38].

5. The interaction between statins and intestinal microbiota regulate several diseases

Statins modulate gut microbiota which influences intestinal barrier function. Zhang et al. found that atorvastatin increased the abundance of Firmicutes and Lactobacillus and decreased the abundance of Bacteroidetes, and improved the mucosal barrier function (increased protein levels of tight junction protein), then alleviates microbiota-mediated neuroinflammation in ischemic stroke mice [39]. Moreover, antibiotic prophylaxis are not suitable for cirrhosis, in case of antibiotic resistance. Statins have been found to inhibit bacterial pathogens, boost intestinal innate immunity, and maintain intestinal barrier function, which can be novel strategies to prevent infections in cirrhosis [40]. Similarly, simvastatin can maintain intestinal integrity and inhibit bacterial translocations from gut lumen to blood circulation, which can improve the prognosis of endotoxemia [41]. Increased production of methane was found in patients with irritable bowel syndrome with constipation due to their inhibitory activity on gut smooth muscle [42]. Lovastatin can reduce methane production by directly inhibiting cell membrane biosynthesis of methanogenic archaea without affecting bacteria numbers and inducing microbiota dysbiosis [43].

The interaction of statins with gut microbiota in malignant tumors has been extensively investigated. Helicobacter pylori infection is known as a crucial risk factor for gastric cancer (GC). H. pylori virulence factors promote inflammation and tumorigenesis, which requires the utilization of host cholesterol. Statins were found to inhibit H. pylori-associated GC by regulating H. pylori virulence factors and ROS production [21]. Zhang et al. demonstrated that nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) was associated with high cholesterol-mediated gut microbiota dysbiosis, that is, an increase in Desulfovibrio, Mucispirillum, Anaerotruncus, and Desulfovibrionaceae, and a decrease in Bifidobacterium and Bacteroides, while the administration of atorvastatin can prevent NAFLD-HCC significantly by restoring cholesterol-associated microbiota dysbiosis [44]. The anti-tumoural effect of checkpoint inhibitors may decrease when co-administration with proton pump inhibitors, glucocorticoids, antibiotics, and psychotropic drugs for their interaction with gut microbiota. However, baseline co-administration with statins was safe and did not affect patient prognosis [45].

Statin therapy may benefit patients with acute coronary syndrome (ACS) by regulating the composition and function of the gut microbiota. Statins regulate the gut microbiota of ACS patients in a healthier direction (characterized by an increased abundance of beneficial bacteria such as Anaerostipes hadrus and reduced abundance of potential pathogenic bacteria such as Paracetobacterium merdae) [46]. Additionally, Li et al. showed that statins can reduce the risk of major adverse cardiovascular events though reducing plasma TMAO levels derived from microbiota [47].

6. Conclusion

This review aims to summarize the bidirectional interaction between statin therapy and gut microbiota and to describe the underlying mechanisms. Statins regulate the composition of gut microbiota and change the microbiota-derived metabolites, which in turn influence the cholesterol-lowering effect of statins. However, inconsistent results have been reported regarding the altered gut microbiota profile in different studies, and most studies evaluating the effects of statins on gut microbiota to treat diseases are currently in the preclinical stage. Further experimental studies and clinical trials are required to investigate personalized treatment based on the interaction between statins and gut microbiota.

Acknowledgments

This project was supported by grant ZDXK202103 from Guangzhou Key Discipline of Medicine (Geriatric Medicine, 2021-2023), Guangdong Province, China.

Conflict of interest

The author declares that there are no conflicts of interest.