Gut microbiota depletion with antibiotics enhances fructose induced salt-sensitive hypertension in normal rats
Haque MZ, Rey F, and Ortiz PA. Gut microbiota depletion with antibiotics enhances fructose induced salt-sensitive hypertension in normal rats. FASEB J 2022; 36.
INTRODUCTION: We reported that 20% fructose in drinking water induced salt-sensitive hypertension in normal rats. High fructose (HF) or high salt (HS) intake reportedly alter the gut microbiota, which influences a variety of microbial-regulated bioactive metabolites that can affect blood pressure and renal function. The contribution of the gut microbiota to fructose induced salt-sensitive hypertension or renal function has not been studied.
AIM: We hypothesized that gut microbiota depletion with antibiotics (ABX) would change fructose induced salt-sensitive hypertension, renal excretory function and plasma levels of bacterial metabolites (lactate, β-hydroxy-butyrate).
METHODS: Sprague Dawley rats were treated with a cocktail of antibiotics (ABX group, in g/L 1.0 ampicillin, 1.0 neomycin sulphate, 1.0 metronidazole, and 0.5 vancomycin in drinking water) for 4 weeks followed by a 0.33 fractional maintenance dose for up to 12 weeks) or control diet (no-ABX). On week 5, all rats were given 20% fructose (HF) in drinking water and fed a diet with normal salt (NS, 0.4% Na) or high salt content (HS, 4% Na). Rats were divided as: Group 1 (HF + NS, no-ABX, n= 6), Group 2 (HF + NS + ABX, n=6), Group 3 (HF + HS, no-ABX, n= 8), Group 4 (HF + HS + ABX, n= 8). We trained rats and measured systolic blood pressure (SBP) for 12 weeks by tail-cuff and collected feces before and after ABX, to measure gut c-DNA content. On the 12th week, we collected 24- hour urine and plasma before the end of the protocol.
RESULTS: Antibiotics induced microbiome depletion (ABX) decreased fecal DNA content by 83%. Baseline SBP (in mmHg) or urine albumin excretion was not affected by ABX. Fructose with normal salt diet did not change SBP with (125±4) or without ABX (124±3). HS significantly increased SBP in rats fed fructose without ABX (from 123±3 to 141±4, p<.05) but the increase was greater in ABX rats (from 124±4 to 155±3, p<.05). Average increase on SBP was 26±2 in HF+HS with ABX, but only 15±2 without ABX (p<.001). In HF + HS groups, ABX decreased plasma lactate from 1657±259 to 905±144 µM (p<.01), and β-hydroxy-butyrate from 861±144 vs 220±53 µM (p<.001). Non-fasted plasma insulin was also decreased by ABX in HF+HS rats (0.77±0.13 to 0.36±0.06 ng/mL, p<.03). The increase in body weight was similar in HF+HS rats with or without ABX.
CONCLUSION: Chronic antibiotic treatment induced gut microbiota depletion and enhanced fructose induced salt-sensitive hypertension in normal rats, an effect that was associated with decreased plasma beta-hydroxy-butyrate, lactate and insulin. Additional studies should focus on direct renal effects of ABX on salt handling.