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

Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis

Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia

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

Immaterial boys? A large-scale exploration of gender-based differences in child sexual exploitation service users

Child sexual exploitation is increasingly recognised nationally and internationally as a pressing child protection, crime prevention and public health issue. In the UK, for example, a recent series of high-profile cases has fuelled pressure on policy-makers and practitioners to improve responses. Yet, prevailing discourse, research and interventions around child sexual exploitation have focused overwhelmingly on female victims. This study was designed to help redress fundamental knowledge gaps around boys affected by sexual exploitation. This was achieved through rigorous quantitative analysis of individual-level data for 9,042 users of child sexual exploitation services in the UK. One third of the sample was male and gender was associated with statistically significant differences on many variables. The results of this exploratory study highlight the need for further targeted research and more nuanced and inclusive counter-strategies

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

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut-brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.GB Rogers, DJ Keating, RL Young, M-L Wong, J Licinio, and S Wesseling

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