Introduction
At present, cardiovascular disease (CVD) remains the primary contributor to the marked upswing in global mortality [
1]. According to the latest statistical data from NHANES, the current overall prevalence of CVD is 49.2%, with the number of affected individuals reaching staggering 126.9 million [
2]. Dyslipidemia is an important driver of CVD progression. Elevated plasma concentrations of LDL cholesterol (LDL-C) and triglycerides (TG) and low concentration of HDL cholesterol (HDL-C) are leading contributors to an increased risk for CVD [
3‐
5]
. What's more crucial is that lipoproteins, as particles with complex compositions, include apolipoproteins as indispensable and vital components [
6]. Apolipoproteins can be widely involved in a variety of pathophysiological processes such as atherosclerosis formation [
7‐
10]. Therefore, lowering plasma lipoprotein levels will undoubtedly reduce the incidence of CVD [
11]. At this stage, although statin therapy has achieved remarkable and brilliant success [
12], researchers are still searching for new therapeutic approaches to combat CVD, in which the close relationship between intestinal flora and lipid levels has attracted increasing attention.
The intestinal flora consists of approximately 4 × 10
13 commensal bacteria, also known as the “human second genome” [
13]. Interventions on intestinal flora have become an important breakthrough in improving health [
14,
15]. Fecal transplantation in rodents suggests that the intestinal flora holds promise for treating chronic diseases [
16,
17]. Likewise, the important role of intestinal flora in CVD is becoming apparent. Takuo’s study demonstrates a correlation between coronary heart disease incidences and intestinal flora changes [
18]. Xuzhi Wan et al.find that changing the abundance of certain intestinal flora affects blood lipid levels to some extent [
19].
Prevotella and
Bacteroides in men and
Akkermansia and
Escherichia/Shigella in women may be associated with blood lipid levels in an observational study in Japan [
20]. However, most of these studies are observational, and the results may be confounded by reverse causality or confounding factors such as diet and antibiotics, making the conclusions less reliable.
Mendelian Randomization (MR) analysis is an important method to explore the causal relationship between exposure and outcome by using genetic variants as instrumental variables (IVs) [
21]. Its obvious advantage is that it can avoid the interference of confounding factors in traditional observational studies [
22,
23]. This is particularly fundamental in inferring causality. MR analysis can more reliably infer the causal relationship between intestinal flora and blood lipids. On this basis, we performed a two-sample MR analysis to investigate the causal relationship between intestinal flora and blood lipids. This may provide new treatments such as probiotic therapy, dietary modification, and fecal microbiota transplantation (FMT) for CVD in the future.
Discussion
In the past decade, our comprehension of the intestinal flora has undergone a nearly exponential expansion [
40]. The increasing recognition of the importance of the intestinal flora is helped by the advent of innovative methodologies and technologies, including germ-free animals [
41], fecal microbiota transplantation [
42], and omics [
43]. Genetic studies have estimated that human genetics can explain 1.9%-8.1% of the variation in the gut microbiome [
44,
45]. Some of these variants might be associated with certain traits, such as inflammatory bowel disease [
46] and tumors [
47]. Dyslipidemia is a significant risk factor for CVD. Recent investigations suggest a potential influence of the intestinal flora on circulating lipid levels. On this basis, we employed the large, publicly available GWAS database and applied MR analysis to explore the causal relationship between intestinal flora and lipids [
24,
25]. In the present study, we identified a total of 19 lipid-related intestinal flora. Among them, a significant negative causal relationship exists between Desulfovibrionaceae and ApoB. Besides, no reverse causality was found by the reverse MR analysis.
Desulfovibrionaceae is an important anaerobic bacterium in the digestive tract. It has the capability to bind with human colonic mucin and is enriched on the mucosal surface of the colon [
48,
49]. Researchers have noted a negative correlation between
Desulfovibrio and obesity indicators such as BMI [
50] and waist [
51]. An important characteristic of
Desulfovibrio is its ability to perform dissimilatory sulfate reduction by utilizing sulfate as an electron acceptor for respiration, thereby producing hydrogen sulfide (H
2S) [
52]. As an important gas transmitter, H
2S is involved in numerous biological processes, including posttranslational modifications of proteins by S-sulfhydration in the cardiovascular system [
53] and lipid metabolism [
54]. Some studies indicate that the reduction of H
2S is associated with an accelerated occurrence of atherosclerosis [
55,
56]. After feeding Cystathionine γ-lyase-deficient mice to a high-fat diet for 12 weeks, Mani observed significant disturbances in lipid metabolism and early atheromatous changes in the aorta. Treatment of these animals with the rapid H
2S donor sodium hydrosulfide reduced the development of atherosclerosis [
55].
This may suggest that future interventions on H2S could potentially serve as a viable direction for maintaining lipid metabolism homeostasis and slowing the development of atherosclerosis. However, at the current stage, how to manipulate H2S levels in a physiologically appropriate manner is a major concern. Desulfovibrionaceae as an important endogenous source of H2S, or targeting of Desulfovibrionaceae will help future studies in this regard.
Interestingly, metagenomics revealed that
Desulfovibrio can produce acetic acid [
57,
58], which, as an important member of short-chain fatty acids (SCFAS), is undoubtedly essential for lipid metabolism homeostasis [
59]. Acetic acid can activate the AMP-activated protein kinase signaling pathway to regulate hepatic lipid metabolism [
60]. Moreover, the polymorphism of gut microbial communities, particularly those associated with lipid metabolic homeostasis, such as
Coprococcus,
Ruminococcus,
Akkermansia,
Roseburia, and
Faecalibacterium, closely correlates with the relative abundance of Desulfovibrionaceae. The protective effects of
Coprococcus [
61],
Ruminococcus [
62],
Akkermansia [
63],
Roseburia [
64], and
Faecalibacterium[
65] are associated with the production of SCFAS. This phenomenon could have a synergistic effect with acetic acid produced by Desulfovibrionaceae, contributing to the maintenance of lipid metabolism homeostasis and the protection of host health. It is imperative to acknowledge that, while these mechanisms provide initial insights into the association between Desulfovibrionaceae and blood lipids, further investigation is still needed for a comprehensive understanding of the specific underlying mechanisms.
Additionally, ApoB functions as the primary transporter of LDL-C, and these two components are intricately connected within the organism. Elevated levels of LDL-C unquestionably expedite the progression of atherosclerosis, and our study indicates that certain intestinal flora may synergistically affect both.
Oscillospira, an intestinal anaerobe, can utilize host glycans and produce butyrate [
66]. Butyrate plays a crucial role in maintaining metabolic homeostasis [
67]. In animal models of metabolic diseases, supplementation with butyrate reportedly confers numerous benefits, including reduced serum triglycerides, total cholesterol and glucose, and reduced weight gain in response to a high fat diet (HFD) [
68‐
70] This protective effect may be attributed to epigenetic effects through inhibition of histone deacetylases (HDACs). HDACs are a group of epigenetic modifying enzymes that remove acetyl groups from histone tails, thereby modifying chromatin structure and the accessibility of genes for transcription [
71]. HDACs regulate a variety of metabolic pathways and deregulation of HDACs has been associated with CVD [
72]. Apart from this. Butyrate can bind and activate the G protein-coupled (GPR) free fatty acid receptors (FFAR) [
73], influencing the release of gut hormones. These gut hormones may play an important role in appetite suppression and lipid metabolism [
74]. In our study,
Parasutterella also could affect both Apo B and LDL-C. In a study on obesity, researchers found that
Parasutterella could impact human fatty acid synthesis [
75]. This may exert a direct impact on ApoB production and LDL-C metabolism.
Parasutterella colonies were also found to be significantly enriched in mice susceptible to obesity [
76]. Future interventions targeting
Parasutterella may be a feasible way to combat obesity and maintain lipid homeostasis. Apart from this, our analysis complements the findings of Lee. Lee et al. found that
Terrisporobacter could affect TG and HDL-C [
77], We will further delineate the causal relationship between
Terrisporobacter and ApoB and LDL-C. We are confident that our study can establish a more solid research foundation for future investigations.
In addition to the "bad cholesterol" mentioned above, HDL-C is widely recognized as the "good cholesterol" in our circulation. The latest research indicates that with each unit increase in HDL-C level, there is a corresponding 2–3% reduction in the risk of CVD [
78]. In the present MR analysis, we find a positive causal relationship between some intestinal flora and HDL-C, such as
Erysipelotrichia.
Erysipelotrichia is an important bacterium for maintaining intestinal health.
Erysipelotrichia microflora transplantation has demonstrated great potential advantages in promoting intestinal regeneration after radiation [
79,
80]. The crucial ability to maintain intestinal health is poised to become a significant consideration in the treatment of chronic diseases such as atherosclerosis in the future. Our results also suggest that
Ruminococcaceae affects lipid metabolism. Priscilla et al. had observed a significant increase in the abundance of
Ruminococcaceae in the control group compared to patients with atherosclerotic dyslipidemia [
81]. According to our analysis, this increase in abundance may regulate apolipoprotein and cholesterol, consequently exerting a protective effect on the host. To our surprise, we find for the first time a potential link between
Dorea and TG.
Dorea [
82] is a member of the family Lachnospiraceae which is reported to be strongly associated with lower TG levels in European and Chinese populations [
83,
84]. Our study suggests that we cannot exclude the influence of
Dorea on TG in this context, and we believe that our results can provide new evidence and confidence for the increasing of intestinal Dorea number in patients with dyslipidemia in the future.
In our study, although we did not observe a significant potential impact of blood lipids on the gut microbiota, it is important to note that certain genetic variations, such as the APOB rs693, may serve as an independent risk for dyslipidemia [
85]. In this subset of patients, the importance of lipids on intestinal flora needs to be further elucidated to formulate individualized treatment plans.
We also need to acknowledge certain limitations in our study. Firstly, this study mainly included individuals of European ancestry, and additional validation is required when extending the results to other populations. Secondly, exposure factors such as diet and environment also have an impact on the composition and abundance of intestinal flora, we will treat it as the focus of our upcoming study. Lastly, despite the theoretical causal impact of certain bacterial groups, the specific mechanisms remain unclear. To elucidate the role of intestinal flora and its contribution to lipid homeostasis, both single flora transplantation and a substantial number of animal experiments are warranted. Our research team is currently engaged in related investigations to identify potential strategic targets for lipid level control.
In conclusion, our study examined the causal relationship between 211 intestinal flora and blood lipids. We screened 19 intestinal flora that might have an association with dyslipidemia in humans. Among them, Desulfovibrionaceae showed a stable and significant negative association with ApoB levels. These findings will provide a meaningful reference to discover dyslipidemia for intervention to address CVD in the clinic.
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