Fasting alters the gut microbiome reducing blood pressure and body weight in metabolic syndrome patients

Cardiometabolic disease (CMD) is a significant health concern, often exacerbated by the Western diet. While exercise and a healthy diet are recommended for reducing CMD risk, compliance can be challenging. Periodic fasting has shown promise in reducing disease burden in animal models, and this study explores its effects in humans with metabolic syndrome (MetS). The gut microbiota plays a crucial role in health and disease, and dysbiosis is linked to various metabolic disorders, including hypertension. This study investigates the effects of a 5-day fast followed by a modified DASH diet on the gut microbiome, immune system, and clinical parameters in patients with MetS, using a multi-omics approach combining gut microbiome analysis and deep immunophenotyping. The researchers hypothesize that this combined intervention will lead to significant improvements in blood pressure and other metabolic parameters.

The literature review highlighted the existing evidence regarding the impact of fasting and diet on cardiometabolic health. Studies in animal models demonstrated the potential benefits of intermittent fasting in reducing disease burden and improving metabolic parameters. Human studies on fasting have shown varied effects on the gut microbiome, with some indicating enrichment of short-chain fatty acid (SCFA) producers. The DASH diet has also been shown to effectively lower blood pressure. However, information on the combined impact of fasting and a modified DASH diet on the gut microbiome and immune system in MetS patients was lacking, motivating the current research.

This study was a substudy of NCT02099968, a randomized controlled trial involving 35 patients with MetS and systolic hypertension. Participants were randomly assigned to either a 5-day fast followed by a modified DASH diet or a modified DASH diet alone. Clinical parameters, including 24-hour ambulatory blood pressure monitoring (ABPM), body weight, BMI, and medication use, were assessed at baseline, one week, and three months post-intervention. Deep immunophenotyping of peripheral blood mononuclear cells was performed using flow cytometry, analyzing various immune cell populations. Gut microbiome composition and function were analyzed using 16S rRNA gene sequencing and shotgun metagenomics. Data analysis included PERMANOVA tests, Mann-Whitney U tests, correlation analysis, and machine learning (decision trees and logistic regression) to predict treatment response based on baseline immunome and microbiome data. Medication changes were accounted for as confounders during statistical analyses. A previously published dataset investigating fasting in healthy men was also reanalyzed for comparison.

The 5-day fast followed by a modified DASH diet significantly reduced 24-hour ambulatory systolic blood pressure (SBP) and mean arterial pressure (MAP) at three months, compared to the DASH diet alone. Fasting also led to a significant reduction in BMI and body weight, and a greater reduction in antihypertensive medication use. Fasting induced significant changes in the gut microbiome composition and function, with shifts in several bacterial taxa and gene modules related to SCFA production. These changes were mostly reversed upon refeeding, but the BP reduction persisted. Immunophenotyping revealed changes in several immune cell populations after fasting, which were also partially reversed with refeeding. Machine learning models using baseline immunome or microbiome data successfully predicted sustained SBP response to the fasting intervention with an accuracy of 71% for the immunome and 67% for the microbiome. Responders were depleted at baseline for certain SCFA-producing taxa which recovered during and after the intervention, compared to non-responders.

This study demonstrates that a 5-day fast followed by a modified DASH diet produces a synergistic effect on blood pressure reduction in hypertensive metabolic syndrome patients, exceeding the effect of the DASH diet alone. The significant changes in the gut microbiome and immune system suggest that these factors contribute to the observed clinical improvements. The successful prediction of treatment response using baseline omics data highlights the potential of personalized approaches based on an individual's initial microbiome and immune profile. The findings support the hypothesis that the increased SCFA availability due to a more diversified microbiome following the fast, or other downstream effects, plays a critical role in this improvement.

This study provides strong evidence supporting the combined use of a short-term fast and a modified DASH diet as an effective non-pharmacological intervention for managing hypertension in metabolic syndrome patients. The ability to predict treatment response based on baseline microbiome and immunome data opens doors for personalized interventions. Further research is needed to investigate the long-term effects, optimal fasting frequency, and the role of specific gut microbial metabolites and immune pathways in the observed benefits. Expanding the study to more diverse populations is also crucial for generalizability.

The relatively small sample size and the homogeneous Caucasian-European population limit the generalizability of the findings. The study design did not allow for blinding of participants, potentially introducing bias. The long-term effects of the intervention without the subsequent DASH diet were not investigated. The precise mechanisms by which the microbiome and immune changes mediate the observed BP reduction require further investigation. The observed differences between responders and non-responders could also stem from varying degrees of MetS severity at baseline.