Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism.

AIMS: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. METHODS AND RESULTS: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. CONCLUSION: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.

Significant increase in quantity and quality of knee arthroplasty related research in KSSTA over the past 15 years.

PURPOSE: This study aimed to evaluate both publication and authorship characteristics in Knee Surgery, Sports Traumatology, Arthroscopy journal (KSSTA) regarding knee arthroplasty over the past 15 years. METHODS: PubMed was searched for articles published in KSSTA between January 1, 2006, and December 31st, 2020, utilising the search term 'knee arthroplasty'. 1288 articles met the inclusion criteria. The articles were evaluated using the following criteria: type of article, type of study, main topic and special topic, use of patient-reported outcome scores, number of references and citations, level of evidence (LOE), number of authors, gender of the first author and continent of origin. Three time intervals were compared: 2006-2010, 2011-2015 and 2016-2020. RESULTS: Between 2016 and 2020, publications peaked at 670 articles (52%) compared with 465 (36%) published between 2011 and 2016 and 153 articles (12%) between 2006 and 2010. While percentage of reviews (2006-2010: 0% vs. 2011-2015: 5% vs. 2016-2020: 5%) and meta-analyses (1% vs. 6% vs. 5%) increased, fewer case reports were published (13% vs. 3% vs. 1%) (p < 0.001). Interest in navigation and computer-assisted surgery decreased, whereas interest in perioperative management, robotic and individualized surgery increased over time (p < 0.001). There was an increasing number of references [26 (2-73) vs. 30 (2-158) vs. 31 (1-143), p < 0.001] while number of citations decreased [30 (0-188) vs. 22 (0-264) vs. 6 (0-106), p < 0.001]. LOE showed no significant changes (p = 0.439). The number of authors increased between each time interval (p < 0.001), while the percentage of female authors was comparable between first and last interval (p = 0.252). Europe published significantly fewer articles over time (56% vs. 47% vs. 52%), whereas the number of articles from Asia increased (35% vs. 45% vs. 37%, p = 0.005). CONCLUSION: Increasing interest in the field of knee arthroplasty-related surgery arose within the last 15 years in KSSTA. The investigated topics showed a significant trend towards the latest techniques at each time interval. With rising number of authors, the part of female first authors also increased-but not significantly. Furthermore, publishing characteristics showed an increasing number of publications from Asia and a slightly decreasing number in Europe. LEVEL OF EVIDENCE: IV.

Constrained metal-on-metal hip arthroplasty: ever heard of a 50-year survival story?

BACKGROUND: The history of total hip arthroplasty dates back to the first half of the twentieth century. Data on hip endoprostheses implanted during the 1960s and 1970s suggest widely varying survival rates of the prosthesis. CASE: A case of a patient who underwent total hip arthroplasty in 1972 using a Sivash prosthesis, developed in 1956 in the former Soviet Union, is presented in this article. The prosthesis has remained unrevised in the patient's body for 50 years and he continues to be widely free of implant-related symptoms. Despite the constrained metal-on-metal design of the implant, which can lead to adverse reactions to metal debris, no elevated systemic metal ion levels were detected. CONCLUSION: The likelihood of encountering patients with prosthesis survival beyond 50 years is still rare. Nevertheless, changing demographics and the steadily improving designs and materials of hip endoprostheses may likely result in such cases.

Impact of the Gut Microbiota on Atorvastatin Mediated Effects on Blood Lipids.

BACKGROUND AND AIMS: The mechanisms of interindividual variation of lipid regulation by statins, such as the low-density lipoprotein cholesterol (LDL) lowering effects, are not fully understood yet. Here, we used a gut microbiota depleted mouse model to investigate the relation between the gut microbiota and the regulatory property of atorvastatin on blood lipids. METHODS: Mice (C57BL/6) with intact gut microbiota or antibiotic induced abiotic mice (ABS) were put on standard chow diet (SCD) or high fat diet (HFD) for six weeks. Atorvastatin (10 mg/kg body weight/day) or a control vehicle were applied per gavage for the last four weeks of dietary treatment. Blood lipids including total cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein and sphingolipids were measured to probe microbiota-dependent effects of atorvastatin. The expression of genes involved in hepatic and intestinal cholesterol metabolism was analyzed with qRT-PCR. The alteration of the microbiota profile was examined using 16S rRNA qPCR in mice with intact gut microbiota. RESULTS: HFD feeding significantly increased total blood cholesterol and LDL levels, as compared to SCD in both mice with intact and depleted gut microbiota. The cholesterol lowering effect of atorvastatin was significantly attenuated in mice with depleted gut microbiota. Moreover, we observed a global shift in the abundance of several sphingolipids upon atorvastatin treatment which was absent in gut microbiota depleted mice. The regulatory effect of atorvastatin on the expression of distinct hepatic and intestinal cholesterol-regulating genes, including Ldlr, Srebp2 and Npc1l1 was altered upon depletion of gut microbiota. In response to HFD feeding, the relative abundance of the bacterial phyla Bacteroidetes decreased, while the abundance of Firmicutes increased. The altered ratio between Firmicutes to Bacteroidetes was partly reversed in HFD fed mice treated with atorvastatin. CONCLUSIONS: Our findings support a regulatory impact of atorvastatin on the gut microbial profile and, in turn, demonstrate a crucial role of the gut microbiome for atorvastatin-related effects on blood lipids. These results provide novel insights into potential microbiota-dependent mechanisms of lipid regulation by statins, which may account for variable response to statin treatment.

Immune system-mediated atherosclerosis caused by deficiency of long non-coding RNA MALAT1 in ApoE-/-mice.

Aims: The immune system is considered a key driver of atherosclerosis, and beyond proteins and microRNAs (miRs), long non-coding RNAs (lncRNAs) are implicated in immune control. We previously described that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in cardiac innate immunity in a myocarditis model. Here, we investigated the impact of MALAT1 deficiency upon atherosclerosis development. Methods and results: Heterozygous MALAT1-deficient ApoE-/- mice displayed massive immune system dysregulation and atherosclerosis within 2 months even when kept on normal diet. Aortic plaque area (P < 0.05) and aortic root plaque size (P < 0.001) were increased in MALAT1-deficient vs. MALAT1-wildtype ApoE-/- mice. Serum levels of interferon-γ (IFN-γ), tumour necrosis factor (TNF), and interleukin 6 (IL6) were elevated (P < 0.001) in MALAT1-deficient animals. MALAT1-deficient bone marrow-derived macrophages showed enhanced expression of TNF (P = 0.001) and inducible NO synthase (NOS2) (P = 0.002), suppressed MMP9 (P < 0.001), and impaired phagocytic activity (P < 0.001) upon lipopolysaccharide stimulation. RNA-sequencing revealed grossly altered transcriptomes of MALAT1-deficient splenocytes already at baseline, with massive induction of IFN- γ, TNF, NOS2, and granzyme B; CC and CXC chemokines and CCR8; and innate immunity genes interferon-induced protein with tetratricopeptide repeats (IFIT)1/3, interferon-induced transmembrane protein (IFITM)1/3, ISG15. Multiple miRs were up to 45-fold upregulated. Further, selective ablation of the cytosolic part of the MALAT1 system only, the enzymatically MALAT1-derived mascRNA, resulted in massive induction of TNF (P = 0.004) and IL6 (P = 0.028) in macrophages. Northern analysis of post-myocardial infarction patient vs. control peripheral blood mononuclear cells showed reduced (P = 0.005) mascRNA in the patients. CHART-enriched RNA-sequencing reads at the genomic loci of MALAT1 and neighbouring nuclear enriched abundant transcript (NEAT1) documented direct interaction between these lncRNA transcripts. Conclusion: The data suggest a molecular circuit involving the MALAT1-mascRNA system, interactions between MALAT1 and NEAT1, and key immune effector molecules, cumulatively impacting upon the development of atherosclerosis. It appears reasonable to look for therapeutic targets in this circuit and to screen for anomalies in the NEAT1-MALAT1 region in humans, too, as possible novel disease risk factors.