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

Hemodialysis (HD) patients face a significantly increased risk of cardiovascular diseases (CVDs), with mortality rates approximately ten times higher than in healthy individuals. Several dietary and lifestyle factors contribute to this risk, including hypertension, obesity, diabetes, and elevated levels of uremic toxins like indoxyl sulfate (IS). IS, produced by gut microbiota metabolism, is associated with CVD incidence and mortality. Strict dietary restrictions for HD patients, including limitations on sodium and fiber intake, can exacerbate existing health problems such as hypertension and constipation. This study investigated the potential benefits of fruits granola (FGR), a fiber-rich food, in mitigating CVD risk factors in HD patients. Previous pilot studies indicated FGR's safety and potential to reduce BP and IS levels, and improve stool consistency. This larger study aimed to analyze the effect of FGR consumption on the gut microbiome and its correlation with CVD risk factors.

Extensive research links CVDs to various factors in HD patients, highlighting the crucial role of diet and lifestyle. Hypertension, often linked to high sodium intake and fluid retention, is a major concern. Dietary fiber supplementation shows promise in improving lipid profiles, reducing inflammation, and lowering uremic toxin levels, potentially reducing CVD risk. However, HD patients often face dietary restrictions, limiting fiber-rich food consumption, thus leading to constipation and elevated uremic toxin levels. Previous studies on FGR demonstrated its potential in improving intestinal health and lowering IS levels; this study expands upon this by investigating the effects on gut microbiota composition.

This study enrolled 26 HD patients from the Izu Nagaoka Daiichi Clinic, excluding those with malignancies, active inflammation, steroid therapy, or poor nutritional status (GNRI <90). Participants consumed 50g of FGR with 200ml of soy milk daily for 8 weeks, replacing their usual breakfast. Clinical and biochemical parameters (BP, IS, inflammatory markers, body composition) were measured at baseline, 4 weeks, and 8 weeks. Stool samples were collected at baseline and 8 weeks for gut microbiota analysis via 16S rRNA gene sequencing. Estimated daily salt intake was calculated using Watson's formula. Statistical analysis included paired t-tests, Wilcoxon signed-rank tests, one-way repeated measures ANOVA, Friedman tests, and appropriate post-hoc tests. Alpha diversity was assessed using the Simpson index and observed species richness.

After 8 weeks of FGR consumption, significant reductions were observed in systolic BP (from 158.0 ± 29.7 mmHg to 145.9 ± 26.0 mmHg), diastolic BP (from 78.4 ± 16.4 mmHg to 72.5 ± 14.0 mmHg), estimated daily salt intake (from 16.7 ± 4.5 g/day to 13.0 ± 4.9 g/day), and serum IS levels (from 36.2 ± 18.0 µg/mL to 32.9 ± 16.0 µg/mL). Stool characteristics, as assessed by the Bristol Stool Form Scale, improved significantly. Gut microbiota analysis revealed a significant increase in alpha diversity (Simpson index and observed species). The abundance of lactic acid- and ethanol-producing bacteria increased significantly, while indole-producing bacteria decreased significantly. At the genus level, *Blautia* and *Neglecta* showed significant increases in abundance. No adverse effects or significant changes in electrolyte levels, hemoglobin levels, or lipid profiles were observed.

The significant reductions in BP, salt intake, and IS levels, coupled with improvements in stool consistency and gut microbiota composition, strongly suggest that FGR consumption is beneficial for HD patients. The increased abundance of beneficial bacteria like *Blautia* and *Neglecta*, known to produce short-chain fatty acids, may contribute to improved gut health and reduced inflammation. The decrease in indole-producing bacteria likely contributed to lower IS levels. The observed BP reduction could be attributed to both reduced salt intake and improved gut microbiota. These findings align with previous research highlighting the importance of dietary fiber and gut microbiota in CVD risk reduction.

This study provides strong evidence supporting the inclusion of FGR in the diet of HD patients to mitigate CVD risk factors. FGR effectively reduces BP, IS levels, and improves gut microbiota composition. Further research should investigate the long-term effects of FGR consumption, explore optimal dosages, and examine its effects on other CVD risk markers in larger, more diverse populations.

This study's relatively small sample size and short duration limit the generalizability of the findings. The study design did not include a control group, preventing a direct comparison of FGR effects to standard dietary management. The potential impact of other dietary factors or individual variations was not fully controlled.