Effect of fruits granola (Frugra®) consumption on blood pressure reduction and intestinal microbiome in patients undergoing hemodialysis

Hemodialysis (HD) patients have markedly elevated cardiovascular disease (CVD) risk, with CVD-related mortality about tenfold higher than in healthy controls. Multiple CVD risk factors are diet- and lifestyle-related, including hypertension and dyslipidemia. Additionally, gut-derived uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate are elevated in chronic kidney disease and dialysis and are linked to CVD incidence and mortality. These toxins arise from bacterial metabolism of unabsorbed dietary proteins in the colon. HD patients face strict dietary restrictions, including sodium and fiber limitation; high sodium contributes to hypertension, while low fiber intake is associated with constipation and may adversely affect gut microbiota and uremic toxin generation. Prior reports suggest dietary fiber supplementation can improve lipid profiles, inflammation, and reduce IS and p-cresyl sulfate. A prior pilot study of fruits granola (FGR, rich in beta-glucan) in HD patients showed reduced blood pressure (BP), improved stool form, and lower serum IS, but did not analyze microbiota in detail. The present study investigates whether replacing breakfast with FGR for 8 weeks reduces BP and serum IS and favorably alters gut microbiota in HD patients.

Background literature highlights: (1) Progressive atherosclerosis in CKD with rising CVD mortality as renal function declines; (2) CVD death risk is ~10× higher in HD patients versus healthy controls; (3) Gut-derived uremic toxins (indoxyl sulfate, p-cresyl sulfate, trimethylamine-derived species) correlate with CVD and mortality and are produced by intestinal microbiota from unabsorbed dietary amino acids and related substrates; (4) Salt intake reduction in HD patients improves BP control and interdialytic weight gain, with recommended daily salt intake <6 g; (5) Constipation is common in HD patients, partly due to dietary potassium restrictions limiting fiber-rich foods; (6) Fermented fiber supplementation in HD has been associated with improved lipid profile, decreased systemic inflammation, and reduced IS and p-cresyl sulfate; (7) Prior work with FGR in healthy individuals increased defecation frequency and SCFA-related taxa, and a pilot study in HD patients suggested improved BP, stool form, and reduced IS with FGR.

Design and setting: Single-center interventional study at Izu Nagaoka Daiichi Clinic (Shizuoka, Japan) with a 4-week pre-observation period followed by an 8-week dietary intervention. Participants: 26 HD patients consented. Exclusion criteria included malignancy, active inflammation, steroid therapy, or reduced nutritional status (Geriatric Nutritional Risk Index [GNRI] < 90). Ethics approval: Juntendo University (approval number 17–247); conducted per Declaration of Helsinki. Trial registration: UMIN000031666. Written informed consent obtained. Intervention: Participants replaced their usual breakfast with 50 g of fruits granola (Frugra®, Calbee Inc.) plus 200 mL soy milk daily for 8 weeks to avoid phosphorus overload from dairy. Assessments and timing: Clinical labs, body composition, BP, and questionnaires were obtained at baseline (start), 1 month, and 2 months; some measures also at 1 month before start and 1 month after the study end as indicated. Fecal samples were collected at baseline (month 0) and after 2 months for microbiome analysis. Measurements: Predialysis BP measured noninvasively at the brachial artery on the non-fistula arm after 5 minutes rest. Blood sampled from arterial HD line before session; serum stored at −80°C. Serum indoxyl sulfate (IS) quantified by internal-surface reversed-phase HPLC (Fushimi Pharmaceutical). Inflammatory markers (IL-6, TNF-α, high-sensitivity CRP) and standard biochemistry measured by certified laboratories. Nutritional status assessed by GNRI = [1.489 × albumin (g/dL)] + [41.7 × (body weight/ideal body weight)]. Body composition (bone mineral content, total body volume, body fat percentage, total body water) via bioelectrical impedance (InBody 470). Bowel health assessed by questionnaire and Bristol Stool Form Scale (BSS). Estimated daily salt intake: Calculated using Watson’s formula incorporating sodium concentrations pre- and post-dialysis, body water estimates (sex-specific Vw formulas), body weight, height, and age. Microbiome: Stool DNA extracted; 16S rRNA gene sequencing (V1–V3) on Illumina MiSeq. Alpha diversity metrics (Shannon, Simpson, observed species) computed. Between-timepoint comparisons used centered log ratio-transformed data and ALDEx2. Statistics: Continuous data summarized as mean ± SD; categorical as frequencies and percentages. Within-group comparisons used paired t-test or Wilcoxon signed-rank with Benjamini–Hochberg correction (p<0.05 significant). BP analyzed by one-way repeated-measures ANOVA with Tukey post hoc; Friedman with Dunn’s post hoc applied as nonparametric alternative. Software: GraphPad Prism 8.4.3. Flow: Of 26 enrolled, 25 received intervention; 1 excluded for severe anemia; 1 hospitalized with COVID-19 during study; final analysis included 24 patients.

Safety and general parameters: No adverse effects among the 24 completers. No changes in electrolytes during the study. Despite iron content in FGR, hemoglobin and iron indices did not change. Lipid profile (LDL-C, HDL-C, triglycerides) and inflammatory markers (hs-CRP, IL-6) showed no significant changes. Body composition parameters were unchanged. Blood pressure and BNP: Systolic BP decreased from 158.0 ± 29.7 mmHg at start to 145.9 ± 26.0 mmHg after 2 months (p<0.05). Diastolic BP decreased from 78.4 ± 16.4 to 72.5 ± 14.0 mmHg after 2 months (p<0.05). At 1 month after the end of intervention, SBP and DBP tended to rise toward baseline (157.5 ± 28.3 and 77.8 ± 13.9 mmHg, respectively). BNP did not change significantly during the intervention. Estimated salt intake: Decreased from 16.7 ± 4.5 g/day at start to 13.0 ± 4.9 g/day after 2 months (p<0.05), suggesting reduced sodium intake associated with the intervention. Bowel health and uremic toxin: Stool characteristics improved per the Bristol Stool Form Scale. Serum indoxyl sulfate decreased from 36.2 ± 18.0 to 32.9 ± 16.0 µg/mL after 2 months (p<0.05). Gut microbiota: Alpha diversity increased: Simpson index and observed species significantly increased; Shannon index showed no difference. Functional group changes included increased lactic acid- and ethanol-producing bacteria and decreased indole-producing bacteria. At the genus level, Blautia and Neglecta significantly increased, while 11 other genera showed no significant change. Effect sizes for seven genera were <0.2. Medication adjustments: Antihypertensive medications were reduced or discontinued in four participants and increased in one during the study, consistent with a BP-lowering effect. Sample analyzed: N=24 patients (58.3% male; mean age 70.6 ± 10.8 years; dialysis duration 7.4 ± 6.7 years).

Replacing breakfast with a fiber-rich fruits granola (FGR) in HD patients was associated with clinically meaningful reductions in predialysis systolic and diastolic BP, a decrease in estimated daily salt intake, improvement in stool form, and a reduction in serum indoxyl sulfate. These outcomes address the study aim by linking a practical dietary modification to both hemodynamic and gut-derived uremic toxin risk factors for CVD in HD patients. The BP reductions and medication de-escalation in several participants support an antihypertensive benefit, plausibly mediated by reduced sodium intake and improved bowel habits. Microbiome findings—greater alpha diversity, increased Blautia and Neglecta, and shifts toward lactic acid- and ethanol-producing bacteria with fewer indole producers—suggest an improved intestinal environment that may contribute to lower IS levels. The absence of changes in BNP, lipids, inflammatory markers, and body composition indicates the intervention specifically influenced salt intake, BP, bowel function, and microbiota-related toxins over the 8-week period.

In HD patients, an 8-week substitution of breakfast with fruits granola (Frugra®) and soy milk was associated with reduced systolic and diastolic BP, decreased estimated daily salt intake, improved stool characteristics, lowered serum indoxyl sulfate, and favorable changes in gut microbiota diversity and composition, including increases in Blautia and Neglecta and reductions in indole-producing bacteria. The findings support FGR as a potentially useful approach for salt reduction, fiber supplementation, and gut environment improvement to mitigate CVD risk factors in HD patients.