Mechanism Of Dietary Lactulose In Negating The Effects Of A High-salt Diet On Hypertension

The intestinal microbiota is inextricably linked to the host and is considered a“microbial organ”.The gut microbiota's structure is generally determined by host genetic and environmental factors,particularly the diet.The rational diets can stimulate probiotics growth to produce active substances in the gut,while the unhealthy diets can induce the gut microbiota'structure imbalance to cause diseases.To date,Western diets,processed foods,and fast foods have high salt contents.High-salt diets are widely considered to cause health problems such as gut microecological imbalances,constipation,and salt-sensitive hypertension.Regulating the gut microbiota is a potential therapeutic means for salt-sensitive hypertension.Lactulose is a safe and beneficial molecule that can be added to food as a prebiotic to improve the gut microbiota and as a mild deobstruent to treat constipation.In this study,lactulose was supplemented in the high-salt diet(HSD)and normal diet(ND)to investigate the effects of dietary lactulose on fecal microbiota and metabolite profiles in HSD-and ND-fed mice.Meanwhile,the mechanisms of lactulose-host-microbe interactions and lactulose in negating salt-sensitive hypertension were discussed.1.Mice were fed with ND,HSD,and HSD plus lactulose diet(HSLD)groups for a 4-week intervention period.The systolic blood pressure(SBP)of mice,the gut microbiota composition,fecal metabolic profiles,serum biochemical parameters,left ventricular function,intestinal permeability,hypertension-related inflammatory factors,intestinal characteristics were determined to investigate the mechanism of lactulose in negating the effects of a high-salt diet on hypertension.(1)After 4 weeks,Results showed that the SBP and angiotensin I in the HSLD group were significantly lower than that in the ND and HSD groups,whereas the left ventricular function did not significantly differ among the three groups.HSD significantly increased the abundances of Alistipes and Ruminococcaceae?UCG?009 and reduced the abundance of Lactobacillus in mice's feces.Supplementing lactulose increased the abundances of Bifidobacterium,Alloprevotella,and Subdoligranulum.(2)The abundance of tryptophan in HSLD-fed mice was significantly lower than that in HSD-fed mice but was not significantly different from that in ND-fed mice.The abundances of indoles(indoles-3-acetic acid and indolelactate)in HSLD-fed mice were significantly higher than that in HSD-fed mice,but there was no significant difference compared with ND-fed mice.The fecal metabolism profiling indicated these metabolites were all related to ATP-binding cassette transporters and amino acid metabolism pathway that probably had positively effects to lactulose in alleviating salt-sensitive hypertension.(3)Lactulose supplementation significantly reduced the IL-17a and IL-22 m RNA levels in the small intestine and significantly reduce the levels of IL-17a and IL-22 in serum.Pathological section test showed inflammatory cell infiltration in the small intestine and colon of mice fed with the HSD,whereas inflammatory cells were no detected in HSLD-fed mice.(4)Additionally,the serum levels of glucose and total cholesterol,intestinal permeability,and the p H of the colon contents in the HSLD-fed mice were significantly lower than those of the HSD-fed mice.These results were showed that the lactulose improved glycolipid metabolism and maintained the health of the intestinal microenvironment.The villus height(V),crypt depth(C),and V/C ratio were significantly higher in the HSLD group than those in ND and HSD groups,which was indicated lactulose could increase the absorption function of small intestine.After 4 weeks,HSD-fed mice manifested constipation symptoms,whereas HSLD-fed mice increased the fecal water and sodium,reduced the serum Na~+concentration,had no constipation.In conclusion,lactulose changed the gut microbiota structures of HSD-fed mice,improved their metabolism,reduced relevant inflammatory cytokine levels,alleviated constipation,increased fecal sodium,and alleviated salt-sensitive hypertension.2.In the current study,the effects of a lactulose-rich diet(LAC group)versus a normal diet(ND group)in mice were compared by analyzing the gut microbiota,fecal metabolic profiles,serum biochemical parameters,intestinal permeability,and intestinal characteristics.(1)After 4 weeks,lactulose supplementation significantly increased the abundances of Bifidobacterium and Alloprevotella but decreased the abundances of Alistipes and Lactobacillus in mouse feces.(2)Twenty metabolites showed significantly increased abundances in the LAC group feces,including fructose 2,6-biphosphate degradation product,myo-inositol,and short-chain fatty acids(SCFAs,e.g.,maleic acid and succinic acid).The abundances of 23 metabolites decreased significantly in the LAC group feces,including isomaltose,xylose,linoleic acid,and behenic acid.These results indicated that lactulose supplementation in the mouse diets changed the fecal metabolic phenotype.(3)The serum concentrations of glucose and total cholesterol and the p H of colon contents were significantly decreased in lactulose-fed mice,while small intestine's absorption function was significantly increased compared with those of the controls.(4)However,intestinal permeability was significantly increased in lactulose-fed mice,and edema was noted in the submucosal layer of the colon and the lamina propria of the small intestine in lactulose-fed mice.And the mechanisms responsible for the negative effects of dietary lactulose on the gut microenvironment require further study.Overall,Lactulose negates salt-sensitive hypertension,while the enriching normal foods with lactulose should be approached with caution.