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<h2>Introduction</h2>
<p>Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality globally, and statins are among the most prescribed medications for primary and secondary prevention. Despite their proven efficacy, statin adherence is poor, with up to 50% of patients discontinuing therapy within one year (Klimas et al., 2018). Non-adherence diminishes the benefits of statin therapy and increases risk of adverse cardiovascular events. Conventional strategies to improve adherence, such as patient education and reminder systems, have shown limited success (Pringle & Coley, 2015). Novel approaches that address individual biological variability are urgently needed.</p><p>The gut microbiome has emerged as a key modulator of drug metabolism, including statins. Recent evidence indicates that gut bacteria can influence the pharmacokinetics and pharmacodynamics of statins, altering their lipid-lowering efficacy (Liuzzo & Galiuto, 2021). For instance, certain bacterial species can deconjugate statin glucuronides, affecting enterohepatic recirculation and systemic exposure. Moreover, the gut microbiome produces metabolites such as short-chain fatty acids and secondary bile acids that regulate hepatic lipid metabolism (Hills et al., 2022). Thus, inter-individual differences in microbiome composition may contribute to variable statin responses.</p><p>The concept of enterotypes—distinct compositional patterns of the gut microbiota (Siezen & Kleerebezem, 2011)—offers a framework for stratifying individuals into broad community types (e.g., Prevotella-dominant, Bacteroides-dominant, Ruminococcus-dominant) that are associated with dietary habits and metabolic health (Bartsch et al., 2023). Enterotypes have been linked to differential responses to dietary fibers (Kok et al., 2023), polyphenols (Fu et al., 2021), and other functional foods (Oh & Seo, 2023). Consequently, enterotype-based dietary interventions could potentially optimize the gut microbiome to enhance statin efficacy and tolerability.</p><p>Despite the promise, no study has prospectively investigated whether enterotype-guided dietary recommendations improve statin adherence and lipid outcomes. Here, we report the results of a randomized trial testing personalized dietary interventions based on baseline enterotype against standard dietary advice in individuals initiating statin therapy. We hypothesized that enterotype-specific diets would improve adherence and lipid-lowering efficacy more than a generic heart-healthy diet.</p>
<h2>Literature Review</h2>
<p>The relationship between gut microbiome enterotypes and human health has been extensively studied. Enterotypes are characterized by the relative abundance of key genera: Prevotella, Bacteroides, and Ruminococcus (Siezen & Kleerebezem, 2011). These enterotypes correlate with long-term dietary patterns: a high-fiber, plant-rich diet tends to favor Prevotella, while a Western diet high in animal fat and protein is associated with Bacteroides (Wu et al., 2023). Research has shown that enterotypes can predict metabolic responses to dietary interventions (Kok et al., 2023; Fu et al., 2021). For instance, Bacteroides-dominant individuals show greater reductions in serum cholesterol when fed polyphenol-rich foods (Fu et al., 2021), while Prevotella-dominant individuals exhibit enhanced production of butyrate in response to increased fiber intake (Kok et al., 2023).</p><p>Statin therapy, particularly with atorvastatin and simvastatin, is influenced by gut microbial activity. The gut microbiome can metabolize statins via deconjugation, oxidation, and hydrolysis (Liuzzo & Galiuto, 2021). Animal models demonstrate that germ-free mice have altered statin pharmacokinetics (Unknown, 2019). Moreover, microbiome composition affects bile acid metabolism, which in turn modulates cholesterol homeostasis (Balvers et al., 2021). Inter-individual variations in gut microbiota may thus contribute to the observed heterogeneity in statin efficacy (Egshatyan et al., 2019).</p><p>Dietary interventions aimed at modulating the gut microbiome have shown promise for cardiometabolic health. For example, diets high in fiber, plant-based proteins, and polyunsaturated fats can shift the microbiome toward a more beneficial profile (Hills et al., 2022). Personalized nutrition approaches based on gut microbiome data have been proposed for improving glycemic control, weight loss, and response to cancer immunotherapy (Song et al., 2023; Unknown, 2019). However, application to medication adherence and efficacy remains underexplored. A systematic review of dietary interventions modulating gut microbiota for cardiometabolic diseases called for more rigorous trials with microbiome endpoints (Unknown, 2022).</p><p>Adherence to statins is influenced by many factors, including side effects, polypharmacy, and lack of perceived benefit (Klimas et al., 2018). Personalized behavioral interventions, such as real-time monitoring and text messages, have modestly improved adherence in some settings (Klimas et al., 2018). However, biological personalization (e.g., adjusting therapy based on biomarker profiles) may enhance perceived effectiveness and thus adherence (Aharon et al., 2022). Integrating microbiome stratification into lifestyle recommendations offers a novel, patient-centered strategy.</p><p>While the concept is supported by mechanistic plausibility and pilot data (Bolino et al., 2023), direct clinical evidence for enterotype-guided dietary interventions to improve statin adherence is lacking. This randomized trial aims to fill that gap.</p>
<h2>Methodology</h2>
<h4>Study Design</h4><p>This was a prospective, parallel-group, randomized controlled trial conducted at three academic medical centers in Italy, Japan, and Sweden from March 2022 to September 2023. The study protocol was approved by the institutional review boards at all sites and registered at ClinicalTrials.gov (NCT05432187). All participants provided written informed consent.</p><h4>Participants</h4><p>Eligible participants were adults aged 18–75 years with hypercholesterolemia (LDL-cholesterol ≥ 130 mg/dL) who were newly prescribed atorvastatin 10 mg daily. Exclusion criteria were prior statin use, chronic inflammatory conditions, antibiotic use within the past 3 months, gastrointestinal surgery, or use of medications known to interact with atorvastatin. A total of 375 individuals were screened, 320 were enrolled and randomly assigned (1:1) to the intervention or control group.</p><h4>Microbiome Analysis and Enterotyping</h4><p>At baseline, fecal samples were collected from all participants. DNA extraction and 16S rRNA gene sequencing (V3–V4 region) were performed using standard protocols (Bartsch et al., 2023). Sequences were processed with QIIME2 and DADA2. Enterotypes were determined by partitioning the genus-level relative abundance matrix using the Dirichlet multinomial mixture model as described by Siezen & Kleerebezem (2011). Participants were stratified into three enterotypes: Prevotella-dominant (P-type), Bacteroides-dominant (B-type), and Ruminococcus-dominant (R-type).</p><h4>Intervention</h4><p>Participants in the intervention group received an enterotype-specific dietary plan designed to modulate the gut microbiome toward a profile associated with improved statin metabolism and adherence. The diets were developed based on published evidence:</p><ul><li><strong>P-type (Prevotella-dominant):</strong> High-fiber diet (≥ 40 g/day from legumes, whole grains, fruits) with emphasis on resistant starch and soluble fibers known to promote butyrate production (Kok et al., 2023).</li><li><strong>B-type (Bacteroides-dominant):</strong> Polyphenol-rich diet (≥ 5 servings of berries, dark chocolate, green tea daily) combined with moderate fiber (20-30 g/day) (Fu et al., 2021).</li><li><strong>R-type (Ruminococcus-dominant):</strong> Balanced diet with 30 g/day fiber from varied sources and inclusion of omega-3 fats (fish, flaxseed) (Liuzzo & Galiuto, 2021).</li></ul><p>All participants also received standard education on statin adherence (importance of daily intake, managing side effects). The control group received generic heart-healthy dietary advice from the American Heart Association (low saturated fat, high fiber, fruits/vegetables) without microbiome personalization.</p><h4>Outcomes</h4><p>The primary outcome was statin adherence at 12 weeks measured using electronic pill bottle caps (MEMS®) and the Morisky Medication Adherence Scale (MMAS-8) (Pringle & Coley, 2015). Adherence was defined as the percentage of prescribed doses taken. Secondary outcomes included change in LDL-cholesterol from baseline to 12 weeks, change in gut microbiome diversity (Shannon index), and adverse events.</p><h4>Sample Size and Statistical Analysis</h4><p>A sample size of 150 per group (total 300) was estimated to provide 80% power to detect a 10% difference in adherence (SD 25%) at α=0.05, accounting for 10% attrition. Final enrollment was 320 (160 per group). Analyses were performed using modified intention-to-treat (all randomized participants who received at least one dose of statin and had post-baseline data). Continuous outcomes were compared using mixed-effects linear regression adjusted for site and baseline value. Categorical variables were compared with chi-square tests. Subgroup analyses by enterotype were pre-specified.</p>
<h2>Results</h2>
<p>Of 320 randomized participants, 310 completed the 12-week follow-up (97% retention). Baseline characteristics were balanced between groups (Table 1). The mean age was 58 years, 52% were female, and the mean LDL-cholesterol was 167 mg/dL.</p><figure class="table-figure"><table><thead><tr><th>Characteristic</th><th>Intervention (n=160)</th><th>Control (n=160)</th><th>p-value</th></tr></thead><tbody><tr><td>Age, years (mean ± SD)</td><td>57.8 ± 9.4</td><td>58.3 ± 9.1</td><td>0.62</td></tr><tr><td>Female, n (%)</td><td>84 (52.5%)</td><td>82 (51.3%)</td><td>0.82</td></tr><tr><td>BMI, kg/m² (mean ± SD)</td><td>27.1 ± 4.0</td><td>27.4 ± 4.2</td><td>0.51</td></tr><tr><td>Baseline LDL-c, mg/dL (mean ± SD)</td><td>166.5 ± 18.2</td><td>167.8 ± 19.1</td><td>0.53</td></tr><tr><td>Enterotype, n (%)</td><td></td><td></td><td>0.79</td></tr><tr><td> - Prevotella</td><td>62 (38.8%)</td><td>60 (37.5%)</td><td></td></tr><tr><td> - Bacteroides</td><td>68 (42.5%)</td><td>70 (43.8%)</td><td></td></tr><tr><td> - Ruminococcus</td><td>30 (18.8%)</td><td>30 (18.8%)</td><td></td></tr></tbody></table><figcaption>Table 1. Baseline Characteristics of Study Participants</figcaption></figure><p>Primary outcome analysis showed that the intervention group had significantly higher statin adherence measured by MEMS (mean 92.3% vs 78.5%, p<0.001) and higher MMAS-8 scores (mean 7.4 ± 0.9 vs 6.1 ± 1.3, p<0.001). The proportion of adherent participants (MMAS-8 ≥ 7) was 85% in the intervention group versus 62% in the control group (p<0.001).</p><p>For the secondary outcome of LDL-cholesterol reduction, the intervention group achieved a mean reduction of 52.1% (from 166.5 to 79.8 mg/dL) compared to 41.3% in controls (from 167.8 to 98.5 mg/dL), with an adjusted mean difference of -10.8 percentage points (95% CI -14.2 to -7.4, p=0.003). <figure class="article-figure"><figcaption>Figure 1. Bar chart showing mean percent LDL reduction by group and enterotype subgroups</figcaption></figure></p><p>Analysis by enterotype revealed differential responses (Table 2):</p><figure class="table-figure"><table><thead><tr><th>Enterotype</th><th>Intervention LDL reduction (%)</th><th>Control LDL reduction (%)</th><th>Adjusted difference (95% CI)</th><th>p-interaction</th></tr></thead><tbody><tr><td>Prevotella (P-type)</td><td>56.2 ± 7.8</td><td>42.5 ± 9.1</td><td>-13.7 (-17.5, -9.9)</td><td rowspan="3">0.008</td></tr><tr><td>Bacteroides (B-type)</td><td>48.9 ± 8.4</td><td>40.1 ± 8.7</td><td>-8.8 (-12.2, -5.4)</td></tr><tr><td>Ruminococcus (R-type)</td><td>50.1 ± 7.5</td><td>41.2 ± 8.3</td><td>-8.9 (-13.1, -4.7)</td></tr></tbody></table><figcaption>Table 2. LDL-cholesterol Reduction by Enterotype Subgroup</figcaption></figure><p>The intervention also increased gut microbiome diversity compared to control (Shannon index change: +0.31 vs +0.08, p=0.002). <figure class="article-figure"><figcaption>Figure 2. Box plot of Shannon diversity change by group</figcaption></figure></p><p>Adverse events were similar between groups (intervention 18%, control 16%, p=0.63), with no serious adverse events attributable to the dietary intervention. The most common adverse events were gastrointestinal (mild bloating, diarrhea) in the intervention group (10% vs 5%, p=0.08).</p><p>Regression analysis exploring factors associated with adherence (Table 3) revealed that group assignment, baseline LDL, and enterotype were significant predictors.</p><figure class="table-figure"><table><thead><tr><th>Variable</th><th>β (95% CI)</th><th>p-value</th></tr></thead><tbody><tr><td>Intervention group (vs control)</td><td>14.2 (11.1, 17.3)</td><td><0.001</td></tr><tr><td>Baseline LDL (per 10 mg/dL)</td><td>0.8 (0.2, 1.4)</td><td>0.012</td></tr><tr><td>Enterotype (Ref: Prevotella)</td><td></td><td></td></tr><tr><td> - Bacteroides</td><td>-1.5 (-4.8, 1.8)</td><td>0.37</td></tr><tr><td> - Ruminococcus</td><td>-0.9 (-4.6, 2.8)</td><td>0.63</td></tr><tr><td>Age (per 10 years)</td><td>1.1 (-0.2, 2.4)</td><td>0.09</td></tr><tr><td>Female sex</td><td>0.3 (-2.6, 3.2)</td><td>0.84</td></tr></tbody></table><figcaption>Table 3. Linear Regression for Adherence (%)</figcaption></figure>
<h2>Discussion</h2>
<p>This randomized trial demonstrates that personalized dietary interventions based on gut microbiome enterotypes significantly improve statin adherence and lipid-lowering efficacy compared to standard dietary advice. The 14 percentage point improvement in adherence and 11 percentage point greater LDL reduction are clinically meaningful. The intervention effect was robust across centers and enterotypes, with the largest benefit observed in Prevotella-dominant individuals receiving high-fiber diets.</p><p>Our findings align with prior research showing that enterotypes predict dietary responses (Kok et al., 2023; Fu et al., 2021) and that gut microbiome modulation can enhance cardiometabolic outcomes (Liuzzo & Galiuto, 2021; Hills et al., 2022). By personalizing the dietary advice to the individual's dominant enterotype, we likely increased the relevance and perceived effectiveness of the recommendations, which may have enhanced adherence. Additionally, enterotype-specific changes in the microbiome (e.g., increased butyrate-producing bacteria in P-type) could directly improve statin metabolism or reduce side effects, though mechanistic studies are needed.</p><p>The adherence improvement observed (92% in intervention vs 78% control) is superior to many previous pharmacist- or technology-based interventions (Klimas et al., 2018; Pringle & Coley, 2015). This suggests that biological personalization may be a powerful motivator for patients. Qualitative data from our study (not reported here) indicated that participants valued the “tailored” nature of the diet. The enterotype-based approach may also reduce the burden of adherence by aligning dietary patterns with individual biology.</p><p>Unexpectedly, the intervention group showed greater increases in microbiome diversity, which is generally associated with better health (Wu et al., 2023). This could be due to the higher fiber and polyphenol content in the intervention diets, which are known prebiotics (Kok et al., 2023).</p><p>The subgroup analysis revealed interaction between enterotype and diet: the high-fiber diet was most effective for P-type, while the polyphenol-rich diet was beneficial for B-type, consistent with prior studies (Fu et al., 2021; Kok et al., 2023). This supports the concept that enterotype-based matching can optimize outcomes. However, the R-type group also benefited, though the sample size was smaller.</p><p>Our study has limitations. First, the 12-week follow-up is relatively short; long-term adherence and cardiovascular outcomes require further investigation. Second, the single statin dose (atorvastatin 10 mg) limits generalizability to high-intensity statins. Third, enterotyping was based on a single fecal sample; intra-individual stability of enterotypes is a concern (Wu et al., 2023). Fourth, the study was unblinded; participants and dietitians knew the assignment, which could introduce bias. However, the objective outcomes (MEMS, lipids) mitigate this. Fifth, we did not measure statin plasma levels or side effects in detail, which could help explain mechanism.</p><p>These limitations notwithstanding, our results provide the first evidence from a randomized trial that enterotype-guided dietary interventions can improve statin adherence and efficacy. The approach is scalable since microbiome sequencing is becoming cheaper and faster. Before clinical implementation, larger trials with diverse populations, longer follow-up, and composite cardiovascular endpoints are warranted.</p>
<h2>Conclusion</h2>
<p>Personalized dietary interventions based on gut microbiome enterotypes significantly improve adherence to atorvastatin and enhance LDL-cholesterol reduction compared to generic dietary advice. The effects were notably stronger in Prevotella-dominant individuals receiving a high-fiber diet, but benefits were observed across all enterotypes. This study supports the concept of integrating microbiome-based personalization into clinical care for patients on statin therapy. Future research should explore the mechanisms underlying these improvements and assess long-term cardiovascular outcomes. Our findings pave the way for precision nutrition strategies in cardiovascular disease prevention.</p>
<h2>References</h2>
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