李晶
中国医学科学院阜外医院 小儿外科一病区
Gut microbiota dysbiosis promotes metabolic syndromes (e.g., hypertension); however, the patterns that drive hypertensive pathology and could be targeted for therapeutic intervention are unclear. We hypothesized that gut microbes might translocate to the kidney to trigger hypertension. We aimed to uncover their method of colonization, and thereby how to maintain blood pressure homeostasis. Using combined approaches based on fluorescence in situ hybridization (FISH) and immunofluorescence staining, electron microscopy analysis, bacterial cultures, species identification, and RNA-sequencing-based meta-transcriptomics, we first demonstrated the presence of bacteria within the kidney of spontaneously hypertensive rats (SHRs) and its normotensive counterpart, Wistar-Kyoto rats (WKYs), and patients with hypertension. Translocated renal bacteria were coated with secretory IgA (sIgA) or remained dormant in the L-form. Klebsiella pneumoniae (K.pn) was identified in the kidneys of germ-free (GF) mice following intestinal transplantation, which suggested an influx of gut bacteria into the kidneys. Renal bacterial taxa and their function are associated with hypertension. Hypertensive hosts showed increased richness in the pathobionts of their kidneys, which were partly derived from the gastrointestinal tract. We also demonstrated the indispensable role of bacterial IgA proteases in the translocation of live microbes. Furthermore, Tartary buckwheat dietary intervention reduced blood pressure and modulated the core renal flora-host ecosystem to near-normal states. Taken together, the unique patterns of viable and dormant bacteria in the kidney provide insight into the pathogenesis of non-communicable chronic diseases and cardiometabolic diseases (e.g., hypertension), and may lead to potential novel microbiota-targeted dietary therapies.
Gut microbes 2022
BACKGROUND:Previous studies have reported a strong association between gut microbiome and hypertension; yet, the exact bacterial species associated with the disease development and progression have not yet been detected. This study aimed to investigate whether opportunistic pathogen Klebsiella pneumoniae is a causal factor for hypertension pathogenesis, and explore the potential mechanisms.METHODS:The enrichment of Klebsiella pneumoniae in the gut of patients with hypertension was validated by meta-analysis based on 3 independent cohorts. Klebsiella pneumoniae was inoculated into germ-free mice, antibiotic pretreated and conventional mice.RESULTS:Klebsiella pneumoniae led to higher blood pressure, slight cardiac hypertrophy, and enhanced contractility of resistant arteries in recipient mice. Moreover, Klebsiella pneumoniae induced pathological damages, deficiency of tight junction proteins and transcriptional shifts. Metabolic alterations, especially the depletion of stearoylethanolamide, were observed upon Klebsiella pneumoniae administration. In addition, renal transcriptome dysfunction with significant upregulation of genes related to hypertension pathogenesis was observed in Klebsiella pneumoniae treated mice.CONCLUSIONS:These results provide evidence that the enrichment of Klebsiella pneumoniae acts as a direct contributor to blood pressure elevation and hypertension pathogenesis, and Klebsiella pneumoniae induced intestinal damages, fecal metabolic changes, and renal shifts may be integrated mediators.
Hypertension (Dallas, Tex. : 1979) 2022
BACKGROUND AND AIMS:Elevated resting heart rate (RHR) is associated with risk of type 2 diabetes mellitus (T2DM). However, the association of change in RHR (ΔRHR) and incident T2DM is not fully elucidated. We aimed to assess the dose-response association between 6-year ΔRHR and T2DM.METHODS AND RESULTS:A total of 12155 non-T2DM participants ≥18 years old were enrolled during 2007-2008 and followed up during 2013-2014. ΔRHR was calculated by subtracting the baseline RHR from the RHR value at 6-year follow-up. Age-, sex-, and RHR-specific relative risks (RRs) and 95% confidence intervals (CIs) for the effect of ΔRHR on incident T2DM were calculated by using modified Poisson regression models. As compared with ΔRHR of 0 beats/min, the adjusted risk of T2DM was significantly increased with RHR increment and reduced with RHR reduction. ΔRHR was positively associated with future risk of T2DM [RR per unit increase: 1.03 (1.03-1.04)]. As compared with stable change in RHR group (-5<ΔRHR<5 beats/min), for ΔRHR ≤ -10 beats/min, -10<ΔRHR ≤ -5 beats/min, 5≤ΔRHR<10 beats/min, and ΔRHR ≥10 beats/min groups, the pooled adjusted RR (95% CI) of T2DM was 0.69 (0.55-0.86), 0.90 (0.73-1.11), 1.31 (1.07-1.61), and 1.90 (1.59-2.26), respectively. This significant association still existed on subgroup analyses based on age, sex, and baseline RHR and sensitivity analyses.CONCLUSIONS:Dynamic RHR change was significantly associated with incident T2DM. Our study suggests that RHR may be a non-invasive clinical indicator for interventions aiming to reduce incident T2DM in the general population.
Nutrition, metabolism, and cardiovascular diseases : NMCD 2019
AIM:To evaluate the image quality and diagnostic agreement with a head-to-head comparison of late gadolinium enhancement (LGE) images acquired by the motion-corrected (MOCO) balanced steady-state free precession (bSSFP) phase sensitivity inversion recovery (PSIR) and conventional segmented fast low angle shot (FLASH) PSIR methods15,16 in a patient cohort with a wide spectrum of cardiovascular disease.MATERIALS AND METHODS:In 59 consecutive patients, signal-to-noise ratios (SNRs), contrast-to-noise ratios (CNRs) of the normal myocardium (NM), LGE, and blood pool (BP) were pair-wise compared between the two different sequences. A further semi-qualitative score system (graded 1 -4) was used to compare the overall image quality (OIQ). The diagnostic agreement of the two techniques were evaluated by both transmural severity and absolutely quantitative size of LGE.RESULTS:The SNRs of the NM, LGE, and BP of MOCO bSSFP were 4.8±3.4, 53.6±35.6 and 43.2±29.3, compared with 3.9±3.6 (p=0.126), 27.7±18.5 (p<0.001) and 24.3±13.4 (p<0.001) of FLASH LGE, respectively. The CNRs of LGE to NM, LGE to BP, and BP to NM were 48.3±33.1 versus 23.8±16.7 (p<0.001), 6.5±21.6 versus 3.8±10.8 (p<0.001), and 38.3±27.2 versus 20.3±10.7 (p=0.448), respectively. The OIQ of MOCO bSSFP was higher than that of segmented FLASH (median 4 versus median 3, p<0.001). For quantification of LGE size, there is good agreement and high correlation (r=0.992, p<0.001) between the two methods.CONCLUSIONS:MOCO bSSFP is a feasible, robust sequence for LGE imaging, especially for patients with arrhythmia and those incapable of breath-holding due to severe heart failure.
Clinical radiology 2018
Recent studies reported some long noncoding RNAs (lncRNAs)-mediated vascular smooth muscle cells (VSMCs) phenotypic switch, which was a common pathophysiological process of vascular diseases. However, whether human-specific expressed lncRNAs would modulate VSMCs phenotype and participate into the pathogenesis of essential hypertension remains unclear. By comparing the circulating lncRNAs expression profiles between hypertensive patients and healthy controls, we identified a lncRNA-AK098656, strongly upregulated in the plasma of hypertensive patients, and predominantly expressed in VSMCs. AK098656 promoted VSMCs synthetic phenotype evidenced by increasing VSMC proliferation and migration, elevating extracellular matrix proteins, whereas lowering contractile proteins. Furthermore, AK098656 was demonstrated to directly bind with the VSMCs-specific contractile protein, myosin heavy chain-11, and an essential component of extracellular matrix, fibronectin-1, and finally lowered these protein levels through protein degradation. AK098656 was also shown to bind with 26S proteasome non-ATPase regulatory subunit 11 and facilitated myosin heavy chain-11 to interact with this protein. In vivo, AK098656 transgenic rats showed spontaneous development of hypertension, with elevated VSMCs synthetic phenotype and narrowed resistant arteries. Transgenic rats also showed slight cardiac hypertrophy without other complications, which was similar with early pathophysiological changes of hypertension. All these data indicated AK098656 as a new human VSMC-dominant lncRNA, which could promote hypertension through accelerating contractile protein degradation, increasing VSMC synthetic phenotype, and finally narrowed resistance arteries.
Hypertension (Dallas, Tex. : 1979) 2018
BACKGROUND:Recently, the potential role of gut microbiome in metabolic diseases has been revealed, especially in cardiovascular diseases. Hypertension is one of the most prevalent cardiovascular diseases worldwide, yet whether gut microbiota dysbiosis participates in the development of hypertension remains largely unknown. To investigate this issue, we carried out comprehensive metagenomic and metabolomic analyses in a cohort of 41 healthy controls, 56 subjects with pre-hypertension, 99 individuals with primary hypertension, and performed fecal microbiota transplantation from patients to germ-free mice.RESULTS:Compared to the healthy controls, we found dramatically decreased microbial richness and diversity, Prevotella-dominated gut enterotype, distinct metagenomic composition with reduced bacteria associated with healthy status and overgrowth of bacteria such as Prevotella and Klebsiella, and disease-linked microbial function in both pre-hypertensive and hypertensive populations. Unexpectedly, the microbiome characteristic in pre-hypertension group was quite similar to that in hypertension. The metabolism changes of host with pre-hypertension or hypertension were identified to be closely linked to gut microbiome dysbiosis. And a disease classifier based on microbiota and metabolites was constructed to discriminate pre-hypertensive and hypertensive individuals from controls accurately. Furthermore, by fecal transplantation from hypertensive human donors to germ-free mice, elevated blood pressure was observed to be transferrable through microbiota, and the direct influence of gut microbiota on blood pressure of the host was demonstrated.CONCLUSIONS:Overall, our results describe a novel causal role of aberrant gut microbiota in contributing to the pathogenesis of hypertension. And the significance of early intervention for pre-hypertension was emphasized.
Microbiome 2017
