Effects of probiotics on hypertension.

Emerging data have suggested that probiotics had good potential in regulating intestinal flora and preventing hypertension. Some studies in human and animal models have demonstrated probiotic intervention could attenuate hypertension, regulate intestinal flora to increase the abundance of beneficial bacteria, and regulate intestinal microbial metabolites such as trimethylamine oxide, short-chain fatty acids, and polyphenols. However, there is still some debate as to whether probiotics exert effective benefits. These recently published reviews did not systematically expound on the heterogeneity between the effect and mechanism of probiotics with different types, doses, and carriers to exert antihypertensive effects, as well as the possible application of probiotics in the prevention and treatment of hypertension in food and clinic. Here we try to systematically review the association between hypertension and intestinal microflora, the effect of probiotics and their metabolites on hypertension, and the recent research progress on the specific mechanism of probiotics on hypertension. In addition, we also summarized the potential application of probiotics in antihypertension. Future challenges include elucidating the functions of metabolites produced by microorganisms and their downstream pathway or molecules, identifying specific strains, not just microbial communities, and developing therapeutic interventions that target hypertension by modulation of gut microbes and metabolites.

Exploration of the molecular mechanisms underlying the antibiotic resistance of Helicobacter pylori: A whole-genome sequencing-based study in Southern China.

BACKGROUND: Although antimicrobial resistance (AMR) in Helicobacter pylori is a global threat to human health and the underlying molecular mechanisms have been explored previously, only a few of them are fully elucidated. MATERIALS AND METHODS: In the present study, we isolated 54 Helicobacter pylori strains from Southern China and assessed their susceptibility to five antibiotics using the agar dilution assay. Whole-genome sequencing was performed to screen the AMR genotypes of the Helicobacter pylori isolates. RESULTS: Our study revealed a high prevalence of resistance to clarithromycin (CLR), levofloxacin (LVX), and metronidazole (MTZ) in the Chinese isolates, 55.56% of which showed multidrug-resistant phenotypes. We screened for the 94 types of previously reported AMR mutations in 12 genes, but only a few of them were related to the AMR phenotype. Furthermore, we discovered four new mutations in the 23S rRNA gene and one mutation in infB related to CLR resistance. Another three mutations in gyrA and one in gyrB were closely correlated with the AMR pattern against LVX. We also demonstrated that the mutations R16C/H in rdxA, V56I in rpsU, and D54A in sodB might contribute to resistance to MTZ, which were previously reported in laboratory experiments but not found in clinical strains. We examined the concordance between the genotype and phenotype of AMR and identified several potential molecular biomarkers for predicting CLR and LVX resistance. CONCLUSIONS: Our study explored the molecular mechanisms underlying the antibiotic resistance of Helicobacter pylori isolates from Southern China. We propose further epidemiologic investigations in China.

Clonal expansion and horizontal transmission of epidemic F2:A1:B1 plasmids involved in co-spread of rmtB with qepA and blaCTX-M-27 in extensively drug-resistant Salmonella enterica serovar Indiana isolates.

Objectives: To investigate the prevalence and transmission of 16S rRNA methylase genes among Salmonella isolates from food animals in China. Methods: A total of 310 Salmonella isolates collected from food animals in seven provinces of China during 2016-17 were screened for 16S RMTase genes. The clonal relationship of the 16S RMTase-producing isolates and their plasmid contents were also characterized. Results: rmtB and armA were respectively identified in 12 and 1 Salmonella enterica serovar Indiana (Salmonella Indiana) isolates from farmed ducks. These 13 isolates concurrently expressed high-level resistance to amikacin, cefotaxime and ciprofloxacin. They were assigned to seven distinct PFGE patterns and the high similarity among 10 of the 12 rmtB-carrying isolates suggests clonal expansion. The rmtB gene was co-transferred with blaCTX-M-27-qepA and qepA in eight and two of the isolates, respectively, and was located on F2:A1:B1 plasmids with sizes of 135 and 100 kb, respectively. These 10 rmtB-bearing plasmids showed four restriction patterns with a high similarity. Four representative rmtB-bearing plasmids were fully sequenced and they exhibited remarkable similarity and possessed typical FII backbones. The primary differences were located in the region between blaTEM-1 and ycgA. Furthermore, a novel MDR region (13.5 kb) was identified that contained qepA, rmtB and blaCTX-M-27. Conclusions: This is the first report, to our knowledge, of the prevalence and complete sequences of plasmids simultaneously containing rmtB, qepA and blaCTX-M-27. These findings underscore a major public health threat posed by epidemic F2:A1:B1 plasmids bearing qepA-rmtB-blaCTX-M-27 that are circulating in XDR Salmonella Indiana clonal isolates from waterfowl husbandry.

Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model.

Objectives: The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes. Methods: To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose-response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs). Results: Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs. Conclusions: The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.

High colonization rate of a novel carbapenem-resistant Klebsiella lineage among migratory birds at Qinghai Lake, China.

OBJECTIVES: The emergence of carbapenemase-positive Enterobacteriaceae poses a serious threat to public health worldwide. Here we conducted a molecular surveillance study on carbapenem-resistant Enterobacteriaceae (CRE) colonization among migratory birds at Qinghai Lake in China. METHODS: A total of 420 samples from migratory birds and their surrounding environment were collected at three sites along the Qinghai Lake bird island. Carbapenem-non-susceptible isolates were identified by 16S rDNA sequencing and MALDI-TOF MS. Carbapenemase producers were determined by Carba NP testing. Antimicrobial susceptibility testing, transfer ability and PFGE were also performed, and 46 isolates from different pulsotypes were analysed by WGS. RESULTS: Three hundred and fifty isolates were carbapenemase producers based on Carba NP testing, while 233 Klebsiella spp. and 2 Escherichia coli isolates were NDM-5-carriers. PFGE was performed and showed that the isolates were grouped into five pulsotypes; among these, type A was predominant (86.7%, n = 202) and belonged to a novel Klebsiella lineage, ST1697. WGS analysis indicated that ST1697 strains may be a hybrid of the recombination of Klebsiella quasipneumoniae subsp. similipneumoniae and Klebsiella pneumoniae genomes. CONCLUSIONS: This high frequency of carbapenemase producers in migratory birds is unexpected. These results provide new insight into the spread of antibiotic resistance, and highlight that continued vigilance for MDR carbapenemase-producing Enterobacteriaceae in migratory birds is urgently needed.

High Genetic Plasticity in Multidrug-Resistant Sequence Type 3-IncHI2 Plasmids Revealed by Sequence Comparison and Phylogenetic Analysis.

We report a novel fusion plasmid, pP2-3T, cointegrating sequence type 3 (ST3)-IncHI2 with an IncFII plasmid backbone mediating multidrug resistance (MDR) and virulence. Phylogenetic analysis and comparative genomics revealed that pP2-3T and other MDR ST3-IncHI2 plasmids clustered together, representing a unique IncHI2 lineage that exhibited high conservation in backbones of plasmids but possessed highly genetic plasticity in various regions by acquiring numerous antibiotic resistance genes and fusing with other plasmids. Surveillance studies should be performed to monitor multiresistance IncHI2 plasmids among Enterobacteriaceae.

Increased activity of colistin in combination with amikacin against Escherichia coli co-producing NDM-5 and MCR-1.

Objectives: Colistin and carbapenem are two lines of last-resort antibiotics against lethal infections caused by MDR Gram-negative pathogens. The emergence of carbapenemase-positive Escherichia coli with colistin resistance poses a serious threat to public health worldwide. Here we report, for the first time (to the best of our knowledge), a novel combination therapy used for the treatment of E. coli co-producing MCR-1 and NDM-5. Methods: The MICs of colistin were determined alone and with 1-4 mg/L amikacin. A 7-by-4 time-kill array of colistin (0, 0.5, 1, 2, 4, 8 and 16 mg/L) and amikacin (0, 1, 2 and 4 mg/L) over 48 h was designed to characterize the in vitro activity of these agents alone and in combination against each E. coli isolate at an inoculum of 10 6 and 10 8 cfu/mL. The sigmoid E max model was utilized for better delineation of the concentration-effect relationship of each combination. In vivo effectiveness was investigated using a mouse model (combination therapy with intraperitoneal colistin plus amikacin compared with monotherapy). Results: For colistin-resistant isolates, the addition of amikacin demonstrated augmented susceptibility, reducing colistin MICs below the current susceptibility breakpoint. A concentration-dependent decrease in the EC 50 values of colistin was observed for all study isolates in the presence of increasing amikacin concentrations. Further in vivo treatment experiments demonstrated that this combination could achieve 1.5-2.8 log 10 killing after 24 h of therapy, while monotherapy was unable to achieve such a killing effect. Conclusions: The combination of colistin and amikacin may be a promising therapeutic option for the treatment of lethal infections caused by NDM-5-bearing MCR-1-positive superbugs.

Complete Nucleotide Sequence of an IncI2 Plasmid Coharboring blaCTX-M-55 and mcr-1.

We report the complete nucleotide sequence of a plasmid, pA31-12, carrying blaCTX-M-55 and mcr-1 from a chicken Escherichia coli isolate. pA31-12 has an IncI2 replicon that displays extensive sequence similarity with pHN1122-1-borne blaCTX-M-55 and pHNSHP45-borne mcr-1 Insertion sequences ISEcp1 and ISApl1 are responsible for the mobilization of blaCTX-M-55 and mcr-1, respectively. The colocalization of mcr-1 with an extended-spectrum ß-lactamase gene on a conjugative plasmid may accelerate the dissemination of both genes by coselection.

Emergence of NDM-5- and MCR-1-Producing Escherichia coli Clones ST648 and ST156 from a Single Muscovy Duck (Cairina moschata).

Two Escherichia coli clones (sequence type 648 [ST648] and ST156) that coproduce NDM-5 and MCR-1 were detected from a single fowl in China. The blaNDM-5 gene was found on the two indistinguishable IncX3 plasmids from the two different E. coli isolates, whereas the mcr-1 gene was located on IncHI2 and IncI2 plasmids, respectively, suggesting that blaNDM-5 and mcr-1 have spread in avian intestinal flora. Also, the two strains harbor blaTEM-1, blaCTX-M-55, fosA3, and aac(6')-Ib The multiresistant E. coli strains (especially the epidemic clone ST648) might raise a potential threat to human health via food chain transmission.

dupA + H. pylori reduces diversity of gastric microbiome and increases risk of erosive gastritis.

Helicobacter pylori is believed to induce gastropathy; however, the exact pathogenic molecules involved in this process have not been elucidated. Duodenal ulcer promoting gene A (DupA) is a virulence factor with a controversial role in gastric inflammation and carcinogenesis. To explore and confirm the function of DupA in gastropathy from the perspective of the microbiome, we investigated the microbial characteristics of 48 gastritis patients through 16S rRNA amplicon sequencing. In addition, we isolated 21 H. pylori strains from these patients and confirmed the expression of dupA using PCR and qRT-PCR. Bioinformatics analysis identified diversity loss and compositional changes as the key features of precancerous lesions in the stomach, and H. pylori was a characteristic microbe present in the stomach of the gastritis patients. Co-occurrence analysis revealed that H. pylori infection inhibits growth of other gastric inhabiting microbes, which weakened the degradation of xenobiotics. Further analysis showed that dupA+ H. pylori were absent in precancerous lesions and were more likely to appear in erosive gastritis, whereas dupA- H. pylori was highly abundant in precancerous lesions. The presence of dupA in H. pylori caused less disturbance to the gastric microbiome, maintaining the relatively richness of gastric microbiome. Overall, our findings suggest that high dupA expression in H. pylori is correlated with a high risk of erosive gastritis and a lower level of disturbance to the gastric microbiome, indicating that DupA should be considered a risk factor of erosive gastritis rather than gastric cancer.

Dynamic evolution of ceftazidime-avibactam resistance due to interchanges between blaKPC-2 and blaKPC-145 during treatment of Klebsiella pneumoniae infection.

Background: The emergence of ceftazidime-avibactam (CZA) resistance among carbapenem-resistant Klebsiella pneumoniae (CRKP) is of major concern due to limited therapeutic options. Methods: In this study, 10 CRKP strains were isolated from different samples of a patient with CRKP infection receiving CZA treatment. Whole-genome sequencing (WGS) and conjugation experiments were performed to determine the transferability of the carbapenem resistance gene. Results: This infection began with a KPC-2-producing K. pneumoniae (CZA MIC = 2 µg/mL, imipenem MIC ≥ 16 µg/mL). After 20 days of CZA treatment, the strains switched to the amino acid substitution of T263A caused by a novel KPC-producing gene, blaKPC-145, which restored carbapenem susceptibility but showed CZA resistance (CZA MIC ≥ 256 µg/mL, imipenem MIC = 1 µg/mL). The blaKPC-145 gene was located on a 148,185-bp untransformable IncFII-type plasmid. The subsequent use of carbapenem against KPC-145-producing K. pneumoniae infection led to a reversion of KPC-2 production (CZA MIC = 2 µg/mL, imipenem MIC ≥ 16 µg/mL). WGS analysis showed that all isolates belonged to ST11-KL47, and the number of SNPs was 14. This implied that these blaKPC-positive K. pneumoniae isolates might originate from a single clone and have been colonized for a long time during the 120-day treatment period. Conclusion: This is the first report of CZA resistance caused by blaKPC-145, which emerged during the treatment with CZA against blaKPC-2-positive K. pneumoniae-associated infection in China. These findings indicated that routine testing for antibiotic susceptibility and carbapenemase genotype is essential during CZA treatment.

Acquisition of a novel conjugative multidrug-resistant hypervirulent plasmid leads to hypervirulence in clinical carbapenem-resistant Klebsiella pneumoniae strains.

The co-occurrence of plasmid-mediated multidrug resistance and hypervirulence in epidemic carbapenem-resistant Klebsiella pneumoniae has emerged as a global public health issue. In this study, an ST23 carbapenem-resistant hypervirulent K. pneumoniae (CR-HvKP) strain VH1-2 was identified from cucumber in China and harbored a novel hybrid plasmid pVH1-2-VIR. The plasmid pVH1-2-VIR carrying both virulence and multidrug-resistance (MDR) genes was likely generated through the recombination of a virulence plasmid and an IncFIIK conjugative MDR plasmid in clinical ST23 18622 isolated from a sputum sample. The plasmid pVH1-2-VIR exhibited the capacity for transfer to the clinical ST11 carbapenem-resistant K. pneumoniae (CRKP) strain via conjugation assay. Acquisition of pVH1-2-VIR plasmid directly converted a CRKP into CR-HvKP strain characterized by hypermucoviscosity, heightened virulence for Galleria mellonella larvae, and increased colonization ability in the mouse intestine. The emergence of such a hybrid plasmid may expedite the spread of CR-HvKP strains, posing a significant risk to human health.

NDM-5-Producing Escherichia coli Co-Harboring mcr-1 Gene in Companion Animals in China.

Carbapenem and colistin are important antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. Here, we isolated the blaNDM-5-harboring Escherichia coli in companion animals in healthy or diseased companion animals from veterinary clinics in six cities in China from July to November 2016. A total of 129 rectal swabs of healthy or diseased dogs and cats were collected from veterinary clinics in six different cities in China, and the isolates were subjected to carbapenem and colistin susceptibility testing. Resistance genes were confirmed using PCR. Conjugation experiments were conducted to determine the transferability of antibiotic resistance genes (ARGs) in the strains. The isolated rate of blaNDM-5-harboring E. coli strains was 3.88% (five strains). These five strains were multidrug resistant to at least three antibiotics and corresponded to four sequence types including ST101. The blaNDM-5 gene was located on 46 kb IncX3 plasmids in these five strains, and the genetic contexts were shared and were nearly identical to the K. pneumoniae plasmid pNDM5-IncX3 from China. In addition, one strain (CQ6-1) co-harbored blaNDM-5-encoding-IncX3 plasmid along with a mcr-1-encoding-IncX4 plasmid, and their corresponding genetic environments were identical to the blaNDM-5-IncX3 and mcr-1-IncX4 hybrid plasmid reported previously from the same area and from the same clinic. The results indicated that the similar genetic contexts were shared between these isolates from companion animals, and the IncX3-type plasmids played a key role in the spread of blaNDM-5 among these bacteria.

Molecular Epidemiology of New Delhi Metallo-ß-Lactamase-Producing Escherichia coli in Food-Producing Animals in China.

We conducted a molecular surveillance study for carbapenem-resistant Enterobacteriaceae (CRE) colonization in food-producing animals in China that included primarily swine and poultry for three consecutive years. A total of 2,771 samples from food-producing animals and their surrounding environments were collected from different regions in China from 2015 to 2017. Enrichment cultures supplemented with meropenem were used to isolate carbapenem non-susceptible isolates and these were subsequently identified by MALDI-TOF MS. Resistance phenotypes and genotypes were confirmed using antimicrobial susceptibility testing and molecular biological techniques. Genomic characteristics of the carbapenemase-producing isolates were investigated using whole genome sequencing (WGS) and bioinformatic analysis. In total, 88 NDM-positive Enterobacteriaceae were identified from 2,771 samples and 96.6% were Escherichia coli. The New Delhi metallo-ß-lactamase (NDM)-positive E. coli displayed a diversity of sequence types (ST), and ST48 and ST165 were the most prevalent. Three variants of bla NDM (bla NDM-1, bla NDM-4, and bla NDM-5) were detected and WGS indicated that bla NDM-5 predominated and was carried primarily on IncX3 plasmids. All these isolates were also multiply-drug resistant. These results revealed that food-producing animals in China are an important reservoir for NDM-positive E. coli and pose a potential threat to public health.

Emergence of extensive multidrug-resistant Staphylococcus aureus carrying novel Sa-MRRlsa(E) in retail food.

OBJECTIVES: The aim of this study was to investigate the prevalence and genetic environment of the multidrug resistance gene lsa(E) in food-related Staphyloccocus aureus in China. METHODS: 1463 S. aureus from retail food products in 39 Chinese cities were investigated to determine the prevalence of lsa(E). Furthermore, antimicrobial susceptibility testing, whole-genome sequencing (WGS), and complete genetic analysis were performed in lsa(E)-positive isolates. RESULTS: Thirty-five isolates (2.4%) were positive for the lsa(E) gene, which had an extensive multidrug-resistance phenotype. ST9-t899 and ST1-t4792 were the common sequence types in positive strains. The lsa(E) genes were located in two different types of novel multidrug resistance region (MRRlsa[E]) on the chromosome. The Sa-MRRlsa(E)-I were inserted into the lctP gene. The Sa-MRRlsa(E)-II were inserted into the crtP gene, and were comprised of seven antibiotic resistance genes (ARGs) interspersed with varieties of insertion sequences (ISs), transposons, and DNA invertase genes, showing a novel arrangement harboring lsa(E). Part of transposon Tn1546 was inserted downstream of lnu(B) in the novel Sa-MRRlsa(E)-II. Both types of Sa-MRRlsa(E) could be excised from the chromosome, indicating that Sa-MRRlsa(E) may be transferable. CONCLUSION: Our study is the first systematical investigation of lsa(E)-positive S. aureus in retail foods in China. It indicated that the origin of most food-related lsa(E)-positive S. aureus in China might be associated with livestock or poultry breeding farms, and these strains may be transmitted between animals and food. S. aureus carrying novel Sa-MRRlsa(E), especially, serve as reservoirs of antibiotic resistance traits, and warrant further attention.

Bifidobacterium longum 070103 Fermented Milk Improve Glucose and Lipid Metabolism Disorders by Regulating Gut Microbiota in Mice.

BACKGROUND: Fermented milk is beneficial for metabolic disorders, while the underlying mechanisms of action remain unclear. This study explored the benefits and underlying mechanisms of Bifidobacterium longum 070103 fermented milk (BLFM) in thirteen-week high-fat and high-sugar (HFHS) fed mice using omics techniques. METHODS AND RESULTS: BLFM with activated glucokinase (GK) was screened by a double-enzyme coupling method. After supplementing BLFM with 10 mL/kg BW per day, fasting blood glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and leptin were significantly reduced compared with the HFHS group. Among them, the final body weight (BW), epididymal fat, perirenal fat, and brown fat in BLFM group had better change trends than Lacticaseibacillus rhamnosus GG fermented milk (LGGFM) group. The amplicon and metabolomic data analysis identified Bifibacterium as a key gut microbiota at regulating glycolipid metabolism. BLFM reverses HFHS-induced reduction in bifidobacteria abundance. Further studies showed that BLFM significantly reduces the content of 3-indoxyl sulofphate associated with intestinal barrier damage. In addition, mice treated with BLFM improved BW, glucose tolerance, insulin resistance, and hepatic steatosis. CONCLUSION: BLFM consumption attenuates obesity and related symptoms in HFHS-fed mice probably via the modulation of gut microbes and metabolites.

Exploration of the Molecular Mechanisms Underlying the Anti-Photoaging Effect of Limosilactobacillus fermentum XJC60.

Although lactic acid bacteria (LAB) were shown to be effective for preventing photoaging, the underlying molecular mechanisms have not been fully elucidated. Accordingly, we examined the anti-photoaging potential of 206 LAB isolates and discovered 32 strains with protective activities against UV-induced injury. All of these 32 LABs exhibited high levels of 2,2-diphenyl-picrylhydrazyl, as well as hydroxyl free radical scavenging ability (46.89-85.13% and 44.29-95.97%, respectively). Genome mining and metabonomic verification of the most effective strain, Limosilactobacillus fermentum XJC60, revealed that the anti-photoaging metabolite of LAB was nicotinamide (NAM; 18.50 mg/L in the cell-free serum of XJC60). Further analysis revealed that LAB-derived NAM could reduce reactive oxygen species levels by 70%, stabilize the mitochondrial membrane potential, and increase the NAD+/NADH ratio in UV-injured skin cells. Furthermore, LAB-derived NAM downregulated the transcript levels of matrix metalloproteinase (MMP)-1, MMP-3, interleukin (IL)-1ß, IL-6, and IL-8 in skin cells. In vivo, XJC60 relieved imflammation and protected skin collagen fiber integrity in UV-injured Guinea pigs. Overall, our findings elucidate that LAB-derived NAM might protect skin from photoaging by stabilizing mitochondrial function, establishing a therotical foundation for the use of probiotics in the maintenance of skin health.

Antihypertensive Activity of Milk Fermented by Lactiplantibacillus plantarum SR37-3 and SR61-2 in L-NAME-Induced Hypertensive Rats

Probiotic fermented milk can lower the incidence rate of hypertension and is beneficial to the regulation of the intestinal microecology. However, the underlying molecular mechanism remains elusive. Here, we evaluated the role of the gut microbiota and its metabolites in the antihypertensive effect of milk fermented by the Lactiplantibacillus plantarum strains SR37-3 (PFM-SR37-3) and SR61-2 (PFM-SR61-2) in Ng-nitro-L-arginine methyl ester induced hypertensive rats. The results showed that PFM-SR37-3 and PFM-SR61-2 intervention significantly lowered the blood pressure (BP) of NG-nitro-L-arginine methyl ester induced hypertensive rats and attenuated renal injury. In particular, long-term administration of PFM inhibited a progressive elevation in SBP (170.22 ± 8.40 and 133.28 ± 6.09 by model group and PFM-SR37-3 treated model group, respectively, at the end of the 4 weeks; p < 0.01 PFM-SR37-3 treated model group versus model group) and DBP (133.83 ± 5.91 and 103.00 ± 6.41 by model group and PFM-SR37-3 treated model group, respectively, at the end of the 4 weeks; p < 0.01 PFM-SR37-3 treated model group versus model group). PFM-SR37-3 and PFM-SR61-2 reshaped the gut microbiome and metabolome, and especially regulated the metabolic levels of L-phenylalanine, L-methionine and L-valine in the intestine and blood circulation. The analysis of the target organ's aortic transcriptome indicated that the protective effects of PFM-SR37-3 and PFM-SR61-2 were accompanied by the modulation of the BP circadian rhythm pathway, which was conducive to cardiovascular function. Vascular transcriptomic analysis showed that circadian rhythm and AMPK might be potential targets of hypertension. In addition, the ACE inhibition rates of Lactiplantibacillus plantarum SR37-3 and Lactiplantibacillus plantarum SR61-2 in vitro were 70.5% and 68.9%, respectively. Our research provides new insights into novel and safe options for hypertension treatment.