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.

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-cholesterol (HDL-C) level was suggested in a human study. Besides, dietary fat was shown to increase both HDL-C and LDL-C 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 level. Methods and Results: We found that HFD increased gut flagellated bacteria population in mice. The increase in HDL-C levels was adopted by mice receiving fecal microbiome transplantion from HFD-fed mouse donors. HFD led to increased hepatic but not circulating flagellin, and deletion of TLR5, a receptor sensing flagellin, suppressed HFD-stimulated HDL-C and apolipoprotein A1 (ApoA1) 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 NFkappaB 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 productions in liver through activation of TLR5 in hepatocytes. Hepatic TLR5 may be a potential drug target to increase ApoA1.

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.