The anti-inflammatory effect of bacterial short chain fatty acids is partially mediated by endocannabinoids

The endocannabinoid (EC) system has pleiotropic functions in the body. It plays a key role in energy homeostasis and the development of metabolic disorders being a mediator in the relationship between the gut microbiota and host metabolism. In the current study we explore the functional interactions between the endocannabinoid system and the gut microbiome in modulating inflammatory markers. Using data from a 6week exercise intervention (treatment n =38 control n =40) and a cross sectional validation cohort (n=35), we measured the associations of 2-arachidonoylglycerol (2-AG), anandamide (AEA), N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA) with gut microbiome composition, gut derived metabolites (SCFAs) and inflammatory markers both cross-sectionally and longitudinally. At baseline AEA and OEA were positively associated with alpha diversity (β(SE)=.32 (.06), P =.002;.44 (.04), P <.001) and with SCFA producing bacteria such as Bifidobacterium (2-AG β(SE)=.21 (.10), P <.01; PEA β(SE)=.23 (.08), P <.01), Coprococcus 3 and Faecalibacterium (PEA β(SE)=.29 (.11), P =.01;.25 (.09), P <.01) and negatively associated with Collinsella (AEA β(SE)=−.31 (.12), P =.004). Additionally, we found AEA to be positively associated with SCFA Butyrate (β(SE)=.34 (.15), P =.01). AEA, OEA and PEA all increased significantly with the exercise intervention but remained constant in the control group. Changes in AEA correlated with SCFA butyrate and increases in AEA and PEA correlated with decreases in TNF-ɑ and IL-6 statistically mediating one third of the effect of SCFAs on these cytokines. Our data show that the anti-inflammatory effects of SCFAs are partly mediated by the EC system suggesting that there may be other pathways involved in the modulation of the immune system via the gut microbiome

Serum Levels of Proinflammatory Lipid Mediators and Specialized Proresolving Molecules Are Increased in Patients With Severe Acute Respiratory Syndrome Coronavirus 2 and Correlate With Markers of the Adaptive Immune Response

BACKGROUND: Specialized proresolution molecules (SPMs) halt the transition to chronic pathogenic inflammation. We aimed to quantify serum levels of pro- and anti-inflammatory bioactive lipids in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients, and to identify potential relationships with innate responses and clinical outcome. METHODS: Serum from 50 hospital admitted inpatients (22 female, 28 male) with confirmed symptomatic SARS-CoV-2 infection and 94 age- and sex-matched controls collected prior to the pandemic (SARS-CoV-2 negative), were processed for quantification of bioactive lipids and anti-nucleocapsid and anti-spike quantitative binding assays. RESULTS: SARS-CoV-2 serum had significantly higher concentrations of omega-6-derived proinflammatory lipids and omega-6- and omega-3-derived SPMs, compared to the age- and sex-matched SARS-CoV-2-negative group, which were not markedly altered by age or sex. There were significant positive correlations between SPMs, proinflammatory bioactive lipids, and anti-spike antibody binding. Levels of some SPMs were significantly higher in patients with an anti-spike antibody value >0.5. Levels of linoleic acid and 5,6-dihydroxy-8Z,11Z,14Z-eicosatrienoic acid were significantly lower in SARS-CoV-2 patients who died. CONCLUSIONS: SARS-CoV-2 infection was associated with increased levels of SPMs and other pro- and anti-inflammatory bioactive lipids, supporting the future investigation of the underlying enzymatic pathways, which may inform the development of novel treatments

Prevalence of ultrasound-detected knee synovial abnormalities in a middle-aged and older general population—the Xiangya Osteoarthritis Study

Background: There is paucity of data on the prevalence of ultrasound-detected synovial abnormalities in the general population, and the relationship between synovial changes and knee pain remains unclear. We examined the prevalence of synovial abnormalities on ultrasound and the relationship of these features with knee pain and radiographic osteoarthritis (ROA) in a community sample. Methods: Participants aged 50 years or over were from the Xiangya Osteoarthritis Study, a community-based cohort study. Participants were questioned about chronic knee pain and underwent (1) ultrasonography of both knees to determine presence of synovial hypertrophy (≥ 4 mm), effusion (≥ 4 mm), and Power Doppler signal [PDS; yes/no]; and (2) standard radiographs of both knees (tibiofemoral and patellofemoral views) to determine ROA. Results: There were 3755 participants (mean age 64.4 years; women 57.4%). The prevalence of synovial hypertrophy, effusion, and PDS were 18.1% (men 20.2%; women 16.5%), 46.6% (men 49.9%; women 44.2%), and 4.9% (men 4.9%; women 5.0%), respectively, and increased with age (P for trend < 0.05). Synovial abnormalities were associated with knee pain, with adjusted odds ratios (aORs) of 2.39 (95% confidence interval [CI] 2.00–2.86) for synovial hypertrophy, 1.58 (95%CI 1.39–1.80) for effusion, and 4.36 (95%CI 3.09–6.17) for PDS. Similar associations with ROA were observed, the corresponding aORs being 4.03 (95%CI 3.38–4.82), 2.01 (95%CI 1.76–2.29), and 6.49 (95%CI 4.51–9.35), respectively. The associations between synovial hypertrophy and effusion with knee pain were more pronounced among knees with ROA than those without ROA, and the corresponding P for interaction were 0.004 and 0.067, respectively. Conclusions: Knee synovial hypertrophy and effusion are more common and increase with age, affecting men more than women. All three ultrasound-detected synovial abnormalities associate both with knee pain and ROA, and knee synovial hypertrophy or effusion and ROA may interact to increase the risk of knee pain

Clinical and Preclinical Evidence for Roles of Soluble Epoxide Hydrolase in Osteoarthritis Knee Pain

Objective: Chronic pain due to osteoarthritis (OA) is a major clinical problem, and existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous antiinflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (EH) to dihydroxyeicosatrienoic acids (DHETs). We undertook this study to assess whether soluble EH–driven metabolism of EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment. Methods: Potential associations of chronic knee pain with single-nucleotide polymorphisms (SNPs) in the gene-encoding soluble EH and with circulating levels of EETs and DHETs were investigated in human subjects. A surgically induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of soluble EH by N-[1-(1-oxopropy)-4-piperidinyl]-N′-(trifluoromethoxy)phenyl]-urea (TPPU) on weight-bearing asymmetry, hind paw withdrawal thresholds, joint histology, and circulating concentrations of EETs and DHETs. Results: In human subjects with chronic knee pain, 3 pain measures were associated with SNPs of the soluble EH gene EPHX2, and in 2 separate cohorts of subjects, circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviors and decreased circulating levels of 8,9-DHET and 14,15-DHET. EET levels were unchanged by TPPU administration. Conclusion: Our novel findings support a role of soluble EH in OA pain and suggest that inhibition of soluble EH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain

Effectiveness of internet-based exercises aimed at treating knee osteoarthritis (iBEAT-OA): a randomized clinical trial

Importance Osteoarthritis is a prevalent, debilitating and costly chronic disease for which recommended first-line treatment is underused. Objective To compare the effect of digital treatment for knee osteoarthritis via app versus routine self-management in a randomized, parallel-group clinical trial. Design A 6-week randomised controlled trial (iBEAT-OA) started in winter 2018. Setting Primary care. Participants 551 participants, 45 years or older, with a diagnosis of knee osteoarthritis from an existing primary care database or from social media advertisements, were invited. Intervention The intervention (n=48) and control group (n=57) conformed to first-line knee osteoarthritis treatment. For intervention group, treatment was delivered via a smartphone application. The control group received routine self-management care. Main outcome and measures Primary outcome at 6 weeks was change from baseline in self-reported pain during the last seven days, reported on a Numerical Rating Scale (NRS, 0-10, 0 no pain, 10 worst pain), compared between the two groups. Secondary outcomes included two physical functioning scores, hamstring and quadriceps muscle strength, Sleep assessment, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Pittsburgh Sleep Quality Index (PSQI), General health questionnaire (MSK-HQ), Inflammatory markers on ultrasound (synovial fluid, synovial hypertrophy and hypervascularity) and quantitative sensory testing (QST). Results 48 participants in the intervention group (mean age 65.2, 70.8% female, 30.4 BMI) and 57 participants in the control group (age 68, 64.9% female, 31.9 BMI) completed this study with no notable demographic difference between groups. The intervention group showed a greater NRS pain score decrease at follow-up than the control group (between-group difference -1.5 [95%CI, -0.8 to -2.2; P<0.001]. Similarly, the 30-second sit to stand test (30CST) and Timed Up and Go test (TUAG) improved more in the intervention group, 3.4 (95%CI, -2.2 to -4.5) and -1.8 (95%CI, -0.5 to -3.0), as did the WOMAC subscales for pain, stiffness and physical function (-1.1 [95%CI, -0.2 to -2.0], -1.0 [95%CI, -0.5 to -1.5], and -3.4 [95%CI, -0.7 to -6.2]). The magnitude of within-group changes in pain and function outcomes in the intervention group corresponded to medium to very strong effects. There was no between-group difference seen in actigraphy sleep data, PSQI, MSK-HQ, QST and sonographic features of knee OA. Conclusions and relevance Digitally delivered evidence-based first-line OA treatment is superior to routine self-managed care as usual and can be given without harming people with osteoarthritis. Effect sizes observed in the intervention group correspond to clinically important improvements

Effectiveness of internet-based exercises aimed at treating knee osteoarthritis (iBEAT-OA): a randomized clinical trial

Importance Osteoarthritis is a prevalent, debilitating and costly chronic disease for which recommended first-line treatment is underused. Objective To compare the effect of digital treatment for knee osteoarthritis via app versus routine self-management in a randomized, parallel-group clinical trial. Design A 6-week randomised controlled trial (iBEAT-OA) started in winter 2018. Setting Primary care. Participants 551 participants, 45 years or older, with a diagnosis of knee osteoarthritis from an existing primary care database or from social media advertisements, were invited. Intervention The intervention (n=48) and control group (n=57) conformed to first-line knee osteoarthritis treatment. For intervention group, treatment was delivered via a smartphone application. The control group received routine self-management care. Main outcome and measures Primary outcome at 6 weeks was change from baseline in self-reported pain during the last seven days, reported on a Numerical Rating Scale (NRS, 0-10, 0 no pain, 10 worst pain), compared between the two groups. Secondary outcomes included two physical functioning scores, hamstring and quadriceps muscle strength, Sleep assessment, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Pittsburgh Sleep Quality Index (PSQI), General health questionnaire (MSK-HQ), Inflammatory markers on ultrasound (synovial fluid, synovial hypertrophy and hypervascularity) and quantitative sensory testing (QST). Results 48 participants in the intervention group (mean age 65.2, 70.8% female, 30.4 BMI) and 57 participants in the control group (age 68, 64.9% female, 31.9 BMI) completed this study with no notable demographic difference between groups. The intervention group showed a greater NRS pain score decrease at follow-up than the control group (between-group difference -1.5 [95%CI, -0.8 to -2.2; P<0.001]. Similarly, the 30-second sit to stand test (30CST) and Timed Up and Go test (TUAG) improved more in the intervention group, 3.4 (95%CI, -2.2 to -4.5) and -1.8 (95%CI, -0.5 to -3.0), as did the WOMAC subscales for pain, stiffness and physical function (-1.1 [95%CI, -0.2 to -2.0], -1.0 [95%CI, -0.5 to -1.5], and -3.4 [95%CI, -0.7 to -6.2]). The magnitude of within-group changes in pain and function outcomes in the intervention group corresponded to medium to very strong effects. There was no between-group difference seen in actigraphy sleep data, PSQI, MSK-HQ, QST and sonographic features of knee OA. Conclusions and relevance Digitally delivered evidence-based first-line OA treatment is superior to routine self-managed care as usual and can be given without harming people with osteoarthritis. Effect sizes observed in the intervention group correspond to clinically important improvements

Effectiveness of Internet-Based Exercises Aimed at Treating Knee Osteoarthritis : The iBEAT-OA Randomized Clinical Trial

Importance: Osteoarthritis is a prevalent, debilitating, and costly chronic disease for which recommended first-line treatment is underused.Objective: To compare the effect of an internet-based treatment for knee osteoarthritis vs routine self-management (ie, usual care).Design, Setting, and Participants: This randomized clinical trial was conducted from October 2018 to March 2020. Participants included individuals aged 45 years or older with a diagnosis of knee osteoarthritis recruited from an existing primary care database or from social media advertisements were invited. Data were analyzed April to July 2020.Interventions: The intervention and control group conformed to first-line knee osteoarthritis treatment. For the intervention group, treatment was delivered via a smartphone application. The control group received routine self-management care.Main Outcomes and Measures: The primary outcome was change from baseline to 6 weeks in self-reported pain during the last 7 days, reported on a numerical rating scale (NRS; range, 0-10, with 0 indicating no pain and 10, worst pain imaginable), compared between groups. Secondary outcomes included 2 physical functioning scores, hamstring and quadriceps muscle strength, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and quantitative sensory testing.Results: Among a total of 551 participants screened for eligibility, 146 were randomized and 105 were analyzed (mean [SD] age, 66.7 [9.2] years, 71 [67.1%] women), including 48 participants in the intervention group and 57 participants in the control group. There were no significant differences in baseline characteristics between the groups. At the 6-week follow-up, the intervention group showed a greater NRS pain score reduction than the control group (between-group difference, -1.5 [95% CI, -2.2 to -0.8]; P < .001). Similarly, the intervention group had better improvements in the 30-second sit-to-stand test (between-group difference, 3.4 [95% CI, 2.2 to 4.5]; P < .001) and Timed Up-and-Go test (between-group difference, -1.8 [95% CI, -3.0 to -0.5] seconds; P = .007), as well as the WOMAC subscales for pain (between-group difference, -1.1 [95% CI, -2.0 to -0.2]; P = .02), stiffness (between-group difference, -1.0 [95% CI, -1.5 to -0.5]; P < .001), and physical function (between-group difference, -3.4 [95% CI, -6.2 to -0.7]; P = .02). The magnitude of within-group changes in pain (d = 0.83) and function outcomes (30 second sit-to-stand test d = 1.24; Timed Up-and-Go test d = 0.76) in the intervention group corresponded to medium to very strong effects. No adverse events were reported.Conclusions and Relevance: These findings suggest that this internet-delivered, evidence-based, first-line osteoarthritis treatment was superior to routine self-managed usual care and could be provided without harm to people with osteoarthritis. Effect sizes observed in the intervention group corresponded to clinically important improvements.Trial Registration: ClinicalTrials.gov Identifier: NCT03545048

Is physiotherapy an underused approach to prevent surgery in selective musculoskeletal disorders?

Objectives: the purpose of the literature review was to appraise the evidence that an early physiotherapy intervention helps to prevent the surgery in selective musculoskeletal disorders. A search of Google Scholar, Web of Science, Scopus, and PubMed was carried out utilizing the terms (“physiotherapy”, “surgery” OR “exercise, surgery” OR “rehabilitation”, “surgery”). Methods: The article titles and abstracts were screened for eligibility and included in the review. The recent literature evidently emphasized that physiotherapy has opted in selective musculoskeletal problems to avoid and delay surgeries. Results: regardless of recommended conservative treatment option and effectiveness of physiotherapy, a massive gap can be observed between its evidence and practice. Conversely, overuse of diagnostic imaging, surgeries, and medications is present in clinical practice. In most of the clinical problems the long-term outcomes were reported the same with surgical and physiotherapy intervention. Likewise, patients can also get the advantage of better clinical outcome and cost-effectiveness with physiotherapy as compared to surgical intervention. Conclusion: the cost-effectiveness is an important factor in low-income countries where economic aspects of health care are highly considered. These advantages of physiotherapy should be considered by the clinicians, policymakers, patients, and included in the clinical guidelines.</p

Serum Metabolome Analysis identified amino-acid metabolism associated with pain in people with symptomatic knee Osteoarthritis - a cross-sectional study.

Osteoarthritis (OA) is the most common arthritis affecting synovial joints such as knees and hips of millions of people globally. Usage-related joint pain and reduced function are the most common symptoms experienced by people with OA. To improve pain management, there is a need to identify validated biomarkers predicting therapeutic responses in targeted clinical trials. Our study aimed to identify the metabolic biomarkers for pain and pressure pain detection thresholds (PPTs) in participants with knee pain and symptomatic OA using metabolic phenotyping. Metabolite and cytokine measurements were done on serum samples using LC-MS/MS (liquid gas chromatography integrated magnetic resonance mass spectrometry) and Human Proinflammatory panel 1 kit respectively. Regression analysis was done in a test (n = 75) and replication study (n = 79) to investigate the metabolites associated with current knee pain scores and pressure pain detection thresholds (PPTs). Meta-analysis and correlation were done estimating precision of associated metabolites and identifying relationship between significant metabolites and cytokines respectively. Acyl ornithine, carnosine, cortisol, cortisone, cystine, DOPA, glycolithocholic acid sulphate (GLCAS), phenylethylamine (PEA) and succinic acid were found to be significantly (FDR < 0.1) associated with pain scores in meta-analysis of both studies. IL-10, IL-13, IL-1β, IL2, IL8 and TNF-α were also found to be associated with the significant metabolites. Significant associations of these metabolites and inflammatory markers with knee pain suggests that targeting relevant pathways of amino acid and cholesterol metabolism may modulate cytokines and these could be targeted as novel therapeutics development to improve knee pain and OA management. PERSPECTIVE: Foreseeing the global burden of knee pain in Osteoarthritis (OA) and adverse effects of current pharmacological therapies, this study is envisaged to investigate serum metabolites and molecular pathways involved in knee pain. The replicated metabolites in this study suggests targeting amino-acid pathways for better management of OA knee pain. [Abstract copyright: Copyright © 2023. Published by Elsevier Inc.

Reproducible microbiome composition signatures of anxiety and depressive symptoms

The gut microbiome is a significant contributor to mental health, with growing evidence linking its composition to anxiety and depressive disorders. Gut microbiome composition is associated with signs of anxiety and depression both in clinically diagnosed mood disorders and subclinically in the general population and may be influenced by dietary fibre intake and the presence of chronic pain. We provide an update of current evidence on the role of gut microbiome composition in depressive and anxiety disorders or symptoms by reviewing available studies. Analysing data from three independent cohorts (osteoarthritis 1 (OA1); n=46, osteoarthritis 2 (OA2); n=58, and healthy controls (CON); n=67), we identified microbial composition signatures of anxiety and depressive symptoms at genus level and cross-validated our findings performing meta-analyses of our results with results from previously published studies. The genera Bifidobacterium (fixed-effect beta (95% CI) = -0.22 (-0.34, -0.10), p = 3.90e-04) and Lachnospiraceae NK4A136 group (fixed-effect beta (95% CI) = -0.09 (-0.13, -0.05), p = 2.53e-06) were found to be the best predictors of anxiety and depressive symptoms, respectively, across our three cohorts and published literature taking into account demographic and lifestyle covariates, such as fibre intake. The association with anxiety was robust in accounting for heterogeneity between cohorts and supports previous observations of the potential prophylactic effect of Bifidobacterium against anxiety symptoms