Gut Microbiota-Associated Activation of TLR5 Induces Apolipoprotein A1 Production in the Liver.

RATIONALE: Dysbiosis of gut microbiota plays an important role in cardiovascular diseases but the molecular mechanisms are complex. An association between gut microbiome and the variance in HDL-C (high-density lipoprotein-cholesterol) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C (low-density lipoprotein-cholesterol) levels. We speculate that certain types of gut bacteria responding to dietary fat may help to regulate HDL-C level and potentially affect atherosclerotic development. OBJECTIVE: We aimed to investigate whether and how high-fat diet (HFD)-associated gut microbiota regulated HDL-C level. METHODS AND RESULTS: We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C level was adopted by mice receiving fecal microbiome transplantation from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5 (Toll-like receptor 5), a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and ApoA1 (apolipoprotein A1) levels. Overexpression of TLR5 in the liver of TLR5-knockout mice was able to partially restore the production of ApoA1 and HDL-C levels. Mechanistically, TLR5 activation by flagellin in primary hepatocytes stimulated ApoA1 production through the transcriptional activation responding to the binding of NF-κB (nuclear factor-κB) on Apoa1 promoter region. Furthermore, oral supplementation of flagellin was able to stimulate hepatic ApoA1 production and HDL-C level and decrease atherosclerotic lesion size in apolipoprotein E-deficient (Apoe-/-) mice without triggering hepatic and systemic inflammation. The stimulation of ApoA1 production was also seen in human ApoA1-transgenic mice treated with oral flagellin. CONCLUSIONS: Our finding suggests that commensal flagellated bacteria in gut can facilitate ApoA1 and HDL-C productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.

Association of genetic variants related to combined exposure to higher BMI and waist-to-hip ratio on lifelong cardiovascular risk in UK Biobank.

OBJECTIVE: This study examines the individual and combined association of BMI and waist-to-hip ratio (WHR) with CVD risk using genetic scores of the obesity measurements as proxies. DESIGN: A 2 × 2 factorial analysis approach was applied, with participants divided into four groups of lifetime exposure to low BMI and WHR, high BMI, high WHR, and high BMI and WHR based on weighted genetic risk scores. The difference in CVD risk across groups was evaluated using multivariable logistic regression. SETTING: Cohort study. PARTICIPANTS: A total of 408 003 participants were included from the prospective observational UK Biobank study. RESULTS: A total of 58 429 CVD events were recorded. Compared to the low BMI and WHR genetic scores group, higher BMI or higher WHR genetic scores were associated with an increase in CVD risk (high WHR: OR, 1·07; 95 % CI (1·04, 1·10)); high BMI: OR, 1·12; 95 % CI (1·09, 1·16). A weak additive effect on CVD risk was found between BMI and WHR (high BMI and WHR: OR, 1·16; 95 % CI (1·12, 1·19)). Subgroup analysis showed similar patterns between different sex, age (<65, ≥65 years old), smoking status, Townsend deprivation index, fasting glucose level and medication uses, but lower systolic blood pressure was associated with higher CVD risk in obese participants. CONCLUSIONS: High BMI and WHR were associated with increased CVD risk, and their effects are weakly additive. Even though there were overlapping of effect, both BMI and WHR are important in assessing the CVD risk in the general population.

Effects of continuity of care on health outcomes among patients with diabetes mellitus and/or hypertension: a systematic review.

BACKGROUND: The rising prevalence of non-communicable diseases (NCDs) such as diabetes mellitus (DM) and hypertension (HT) has placed a tremendous burden on healthcare systems around the world, resulting in a call for more effective service delivery models. Better continuity of care (CoC) has been associated with improved health outcomes. This review examines the association between CoC and health outcomes in patients with DM and/or HT. METHODS: This was a systematic review with searches carried out on 13 March 2021 through PubMed, Embase, MEDLINE and CINAHL plus, clinical trials registry and bibliography reviews. Eligibility criteria were: published in English; from 2000 onwards; included adult DM and/or HT patients; examined CoC as their main intervention/exposure; and utilised quantifiable outcome measures (categorised into health indicators and service utilisation). The study quality was evaluated with Critical Appraisal Skills Programme (CASP) appraisal checklists. RESULTS: Initial searching yielded 21,090 results with 42 studies meeting the inclusion criteria. High CoC was associated with reduced hospitalisation (16 out of 18 studies), emergency room attendances (eight out of eight), mortality rate (six out of seven), disease-related complications (seven out of seven), and healthcare expenses (four out of four) but not with blood pressure (two out of 13), lipid profile (one out of six), body mass index (zero out of three). Six out of 12 studies on diabetic outcomes reported significant improvement in haemoglobin A1c by higher CoC. Variations in the classification of continuity of care and outcome definition were identified, making meta-analyses inappropriate. CASP evaluation rated most studies fair in quality, but found insufficient adjustment on confounders, selection bias and short follow-up period were common limitations of current literatures. CONCLUSION: There is evidence of a strong association between higher continuity of care and reduced mortality rate, complication risks and health service utilisation among DM and/or HT patients but little to no improvement in various health indicators. Significant methodological heterogeneity in how CoC and patient outcomes are assessed limits the ability for meta-analysis of findings. Further studies comprising sufficient confounding adjustment and standardised definitions are needed to provide stronger evidence of the benefits of CoC on patients with DM and/or HT.

Diabetes with poor-control HbA1c is cardiovascular disease 'risk equivalent' for mortality: UK Biobank and Hong Kong population-based cohort study.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) has traditionally been considered a coronary heart disease 'risk equivalent' for future mortality, but significant heterogeneity exists across people with T2DM. This study aims to determine the risk of all-cause mortality of patients with cardiovascular disease (CVD) and T2DM in UK and Hong Kong, with stratifications for hemoglobin A1 (HbA1c) concentrations, compared with those without CVD and diabetes mellitus. RESEARCH DESIGN AND METHODS: This is a retrospective cohort study of 3 839 391 adults from Hong Kong and a prospective cohort study of 497 779 adults from the UK Biobank. Individuals were divided into seven disease groups: (1) no T2DM and CVD, (2) T2DM only with HbA1c <7%, (3) T2DM only with HbA1c 7%-7.9%, (4) T2DM only with HbA1c 8%-8.9%, (5) T2DM only with HbA1c ≥9%, (6) CVD only, and (7) T2DM and CVD. Differences in all-cause mortality between groups were examined using Cox regression. RESULTS: After around 10 years of median follow-up, 423 818 and 19 844 deaths were identified in the Hong Kong cohort and UK Biobank, respectively. Compared with individuals without T2DM and CVD, the adjusted HR for all-cause mortality in the other six disease groups for the Hong Kong cohort was 1.25 (95% CI 1.23 to 1.27) for T2DM only with HbA1c <7%, 1.21 (95% CI 1.19 to 1.23) for T2DM only with HbA1c 7%-7.9%, 1.36 (95% CI 1.33 to 1.39) for T2DM only with HbA1c 8%-8.9%, 1.82 (95% CI 1.78 to 1.85) for T2DM only with HbA1c ≥9%, 1.37 (95% CI 1.36 to 1.38) for CVD only, and 1.83 (95% CI 1.81 to 1.85) for T2DM and CVD, and for the UK Biobank the HR was 1.45 (95% CI 1.33 to 1.58), 1.50 (95% CI 1.32 to 1.70), 1.72 (95% CI 1.43 to 2.08), 2.51 (95% CI 2.05 to 3.08), 1.67 (95% CI 1.59 to 1.75) and 2.62 (95% CI 2.42 to 2.83), respectively. This indicates that patients with T2DM had an increased risk of mortality compared with those without T2DM and CVD, and in those with HbA1c ≥9% an even higher risk than people with CVD. CONCLUSIONS: Patients with T2DM with poor HbA1c control (8%-8.9% and ≥9%) were associated with similar and higher risk of mortality compared with patients with CVD, respectively. Optimal HbA1c, controlled for risk reduction and prevention of mortality and complications in diabetes management, remains important.

Association Between Team-Based Continuity of Care and Risk of Cardiovascular Diseases Among Patients With Diabetes: A Retrospective Cohort Study.

OBJECTIVE: Cardiovascular diseases (CVD) are a long-term sequela of diabetes. Better individual-based continuity of care has been reported to reduce the risk of chronic complications among patients with diabetes. Maintaining a one-to-one patient-physician relationship is often challenging, especially in public health care settings. This study aimed to evaluate the relationship between higher team-based continuity of care, defined as consultations provided by the same physician team, and CVD risks in patients with diabetes from public primary care clinics. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study in Hong Kong of 312,068 patients with type 2 diabetes and without any history of CVD at baseline (defined as the earliest attendance at a doctor's consultation in a public-sector clinic between 2008 and 2018). Team-based continuity of care was measured using the usual provider continuity index (UPCI), calculated by the proportion of consultations provided by the most visited physician team in the 2 years before baseline. Patients were divided into quartiles based on their UPCI, and the characteristics of the quartiles were balanced using propensity score fine stratification weights. Multivariable Cox regression was applied to assess the effect of team-based continuity of care on CVD incidence. Patient demographics, smoking status, physiological measurements, number of attendances, comorbidities, and medications were adjusted for in the propensity weightings and regression analyses. RESULTS: After an average follow-up of 6.5 years, the total number of new CVD events was 52,428. Compared with patients in the 1st quartile, patients in the 2nd, 3rd, and 4th quartiles of the UCPI had a CVD hazard ratio (95% CI) of 0.95 (0.92-0.97), 0.92 (0.89-0.94), and 0.87 (0.84-0.89), respectively, indicating that higher continuity of care was associated with lower CVD risks. The subtypes of CVD, including coronary heart disease and stroke, also showed a similar pattern. Subgroup analyses suggested that patients <65 years of age had greater benefits from higher team-based continuity of care. CONCLUSIONS: Team-based continuity of care was associated with lower CVD risk among individuals with type 2 diabetes, especially those who were younger. This suggests a potential flexible alternative implementation of continuity of care in public clinics.

TLR5 Supports Development of Placental Labyrinthine Zone in Mice.

Toll plays an important role in innate immunity and embryonic development in lower-ranked animals, but in mammals, the homolog toll-like receptors (TLR) are reported to facilitate postnatal development of immunity only. Here, we discovered a role of TLR5 in placental development. Tlr5 was highly transcribed during the placenta-forming and functional phases. TLR5 deletion led to a smaller placental labyrinthine zone and lower embryo weight, and the smaller size of embryo was overcorrected, resulting in a higher postnatal body weight. Examination of TLR5-deficient conceptus revealed a decrease in nuclear cAMP-response element-binding protein (CREB), mechanistic target of rapamycin (mTOR) and insulin growth factor-1 receptor (IGF1R) abundances in the placenta-forming phase. Non-flagellin-based TLR5 ligands were detected in serum of female mice and the overexpression of TLR5 alone was sufficient to induce CREB nuclear translocation and mTOR transcriptional activation in trophoblasts. Taken together, we uncovered the participation of TLR5 in the early placental formation in mice, unveiling a role of TLR in embryonic development in higher-ranked animals.