Stunted children display ectopic small intestinal colonization by oral bacteria, which cause lipid malabsorption in experimental models.

Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbiota in the context of stunting and EED and to test for a causal role of these bacterial isolates in the underlying pathophysiology. We performed a cross-sectional study in two African countries recruiting roughly 1,000 children aged 2 to 5 years and assessed the microbiota in the stomach, duodenum, and feces. Upper gastrointestinal samples were obtained from stunted children and stratified according to stunting severity. Fecal samples were collected. We then investigated the role of clinical isolates in EED pathophysiology using tissue culture and animal models. We find that small intestinal bacterial overgrowth (SIBO) is extremely common (>80%) in stunted children. SIBO is frequently characterized by an overgrowth of oral bacteria, leading to increased permeability and inflammation and to replacement of classical small intestinal strains. These duodenal bacterial isolates decrease lipid absorption in both cultured enterocytes and mice, providing a mechanism by which they may exacerbate EED and stunting. Further, we find a specific fecal signature associated with the EED markers fecal calprotectin and alpha-antitrypsin. Our study shows a causal implication of ectopic colonization of oral bacterial isolated from the small intestine in nutrient malabsorption and gut leakiness in vitro. These findings have important therapeutic implications for modulating the microbiota through microbiota-targeted interventions.

Contributions of elevated CRP, hyperglycaemia, and type 2 diabetes to cardiovascular risk in the general population: observational and Mendelian randomization studies.

OBJECTIVE: To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease (CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related. RESEARCH DESIGN AND METHODS: Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC. RESULTS: Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (ß-coefficient: 0.02 (0.02, 0.03), p = 3 × 10- 20); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13)). CONCLUSIONS: Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation.

Prospective associations of technostress at work, burnout symptoms, hair cortisol, and chronic low-grade inflammation.

BACKGROUND: Working conditions in the age of digitalization harbor risks for chronic stress and burnout. However, real-world investigations into biological effects of technostress, that is stress in the context of digital technology use, are sparse. This study prospectively assessed associations between technostress, general work stress, burnout symptoms, hair cortisol, and chronic low-grade inflammation. METHODS: Hospital employees (N = 238, 182 females, Mage = 28.5 years) participated in a prospective cohort study with two follow-ups six months apart (T2, T3). Participants answered standardized questionnaires on general job strain (job demand-control ratio), technostressors (work interruptions, multitasking, information overload), burnout symptoms (exhaustion, mental distance), and relevant confounders. Moreover, they provided capillary blood samples for C-reactive protein (CRP) and hair strands for hair cortisol concentration (HCC) analysis. Structural equation modelling was performed. RESULTS: The factorial structure of survey measures was confirmed. Burnout symptoms (MT2 = 2.17, MT3 = 2.33) and HCC (MT2 = 4.79, MT3 = 9.56; pg/mg) increased over time, CRP did not (MT2 = 1.15, MT3 = 1.21; mg/L). Adjusted path models showed that technostress was negatively associated with HCC (ß = -0.16, p =.003), but not with burnout and CRP. General work stress in contrast, was not significantly associated with burnout, HCC or CRP. Furthermore, there were reciprocal effects of CRP on HCC (ß = 0.28, p =.001) and of HCC on CRP (ß = -0.10, p ≤.001). Associations were robust in additional analyses including further confounders. CONCLUSION: This is the first study on prospective effects of technostress on employees' endocrine and inflammatory systems. Results suggest differential effects of technostress on the hypothalamic-pituitary-adrenocortical axis activity. Given its key role for long-term health, the findings have important implications for occupational health and safety in digitalized work environments.

Gene expression alterations of purinergic signaling components in obesity-associated intestinal low-grade inflammation in type 2 diabetes.

Intestinal low-grade inflammation induced by a high-fat diet has been found to detonate chronic systemic inflammation, which is a hallmark of obesity, and precede the apparition of insulin resistance, a key factor for developing type 2 diabetes (T2D). Aberrant purinergic signaling pathways have been implicated in the pathogenesis of inflammatory bowel disease and other gastrointestinal diseases. However, their role in the gut inflammation associated with obesity and T2D remains unexplored. C57BL/6 J mice were fed a cafeteria diet for 21 weeks and received one injection of streptozotocin in their sixth week into the diet. The gene expression profile of purinergic signaling components in colon tissue was assessed by RT-qPCR. Compared to control mice, the treated group had a significant reduction in colonic length and mucosal and muscular layer thickness accompanied by increased NF-κB and IL-1ß mRNA expression. Furthermore, colonic P2X2, P2X7, and A3R gene expression levels were lower, while the P2Y2, NT5E, and ADA expression levels increased. In conclusion, these data suggest that these purinergic signaling components possibly play a role in intestinal low-grade inflammation associated with obesity and T2D and thus could represent a novel therapeutic target for the treatment of the metabolic complications related to these diseases.

Association between walking pace and risks of major chronic diseases in individuals with hypertension based on a prospective study in UK Biobank: Involvement of inflammation.

OBJECTIVE: Walking pace is associated with risks of major chronic diseases including cancer, cardiovascular disease (CVD) and diabetes mellitus type 2 (T2DM) in the general population. However, whether increasing walking pace could reduce risks of major chronic diseases in individuals with hypertension remains to be explored, and the underlying mechanism potentially mediated by low-grade inflammation is also unclear. METHODS: A total of 160,470 participants with hypertension were included based on the UK Biobank. The relationships of the walking pace and low-grade inflammation with risks of major chronic diseases in individuals with hypertension were assessed by the Cox proportional hazards model. Mediation analyses were performed to investigate the contribution of low-grade inflammation to the association between walking pace and risks of major chronic diseases. RESULTS: Individuals with hypertension at the brisk walking pace had decreased risks of overall cancer and site-specific cancers (liver, lung, and endometrial cancers), all CVD events (angina, atrial fibrillation, heart failure, myocardial infarction, peripheral vascular disease and stroke), and T2DM (hazard ratios: 0.42-0.91). Increasing low-grade inflammation was associated with higher risks of aforementioned diseases except liver cancer and atrial fibrillation. Furthermore, low-grade inflammation partially mediated associations of the walking pace with risks of lung cancer, T2DM, and all CVD events (except atrial fibrillation), with mediation proportion of 2.0%-9.8%. CONCLUSIONS: Brisk walking pace was linked to reduced risks of major chronic diseases in individuals with hypertension, partially mediated by low-grade inflammation. Improving walking pace may be beneficial for health in individuals with hypertension.

The impact of fish oil and/or probiotics on serum fatty acids and the interaction with low-grade inflammation in pregnant women with overweight and obesity: secondary analysis of a randomised controlled trial.

N-3 long-chain PUFA (LC-PUFA) and probiotics are generally considered to induce health benefits. The objective was to investigate (1) the impact of fish oil and/or probiotics on serum fatty acids (sFA), (2) the interaction of sFA with low-grade inflammation and (3) the relation of sFA to the onset of gestational diabetes mellitus (GDM). Pregnant women with overweight/obesity were allocated into intervention groups with fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo in early pregnancy (fish oil: 1·9 g DHA and 0·22 g EPA, probiotics: Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 CFU, each daily). Blood samples were collected in early (n 431) and late pregnancy (n 361) for analysis of fatty acids in serum phosphatidylcholine (PC), cholesteryl esters (CE), TAG and NEFA with GC and high-sensitivity C-reactive protein and GlycA by immunoassay and NMR spectroscopy, respectively. GDM was diagnosed according to 2 h 75 g oral glucose tolerance test. EPA in PC, CE and TAG and DHA in PC, CE, TAG and NEFA were higher in fish oil and fish oil + probiotics groups compared with placebo. EPA in serum NEFA was lower in women receiving probiotics compared with women not receiving. Low-grade inflammation was inversely associated with n-3 LC-PUFA, which were related to an increased risk of GDM. Fish oil and fish oil + probiotics consumption increase serum n-3 LC-PUFA in pregnant women with overweight/obesity. Although these fatty acids were inversely related to inflammatory markers, n-3 LC-PUFA were linked with an increased risk for GDM.

The mediating role of chronic low-grade inflammation participation in the relationship between obesity and type 2 diabetes: findings from the NHANES.

BACKGROUND: Chronic low-grade inflammation may mediate the relationship between obesity and diabetes, yet clinical research in this area remains scarce. Thus, this study aimed to explore the mediating role of chronic low-grade inflammation in this relationship using the National Health and Nutrition Examination Survey (NHANES). METHODS: This study involved 2,482 participants enrolled in the NHANES between 2005 and 2016. Based on the complex sampling survey weights of NHANES, logistic regression models were fitted, adjusting for various covariates to investigate the relationship between BMI, INFLA score, and diabetes. Moreover, weighted quantile sum (WQS) regression models were fitted to analyze the proportional contribution of individual components within the INFLA score. Finally, mediation analysis was conducted to quantitatively assess the magnitude of the mediating effect of the INFLA score on the relationship between BMI and diabetes. RESULTS: After adjusting for all potential confounding factors, a significant positive correlation was noted between INFLA score and diabetes [OR (95% CI), 1.038(1.003-1.075), p = 0.035]. Additionally, a significant positive correlation was observed between the high INFLA group and diabetes compared to the low INFLA group [OR (95% CI), 1.599(1.031-2.481), p = 0.037]. WQS regression models revealed that the proportional contributions of C-reactive protein, white blood cell count, platelet count, and neutrophil-to-lymphocyte ratio (NLR) were 55.5%, 34.8%, 8.46%, and 1.19%, respectively. Finally, the results of the mediation analysis indicated that the indirect effect of the INFLA score accounted for 10.20%. CONCLUSIONS: Chronic low-grade inflammation was associated with diabetes and partially mediates the relationship between obesity and diabetes.

Lipoprotein(a) is linked to atherothrombosis and aortic valve stenosis independent of C-reactive protein.

AIMS: Recent evidence suggest that the lipoprotein(a)-associated risk of atherosclerotic cardiovascular disease (ASCVD) may be observed only in individuals with low-grade systemic inflammation. It was hypothesized that high lipoprotein(a) is a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis irrespective of C-reactive protein levels. METHODS AND RESULTS: A total of 68 090 individuals from the Copenhagen General Population Study, a prospective cohort study, were included. During a median follow-up of 8.1 years, 5104 individuals developed ASCVD, 2432 myocardial infarction, and 1220 aortic valve stenosis. The risk of ASCVD, myocardial infarction, and aortic valve stenosis increased with higher values of both lipoprotein(a) and C-reactive protein. For individuals with lipoprotein(a) in the 91st-100th percentiles (≥70 mg/dl, ≥147 nmol/l) vs. the 1st-33rd percentiles (≤6 mg/dl, ≤9 nmol/l), the multivariable-adjusted hazard ratio for ASCVD was 1.61 (95% confidence interval 1.43-1.81) for those with C-reactive protein <2 mg/l and 1.57 (1.36-1.82) for those with C-reactive protein ≥2 mg/l (P for interaction = 0.87). The corresponding values were 2.08 (1.76-2.45) and 1.65 (1.34-2.04) for myocardial infarction, and 2.01 (1.59-2.55) and 1.73 (1.31-2.27) for aortic valve stenosis, respectively (P for interaction = 0.15 and = 0.18). The highest absolute 10-year risks were found in men aged 70-79 years with lipoprotein(a) levels in the 91st-100th percentiles and C-reactive protein ≥2 mg/l, with 34% for ASCVD, 19% for myocardial infarction, and 13% for aortic valve stenosis. The corresponding values in women were 20%, 10%, and 8%, respectively. CONCLUSION: High lipoprotein(a) was a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis independent of C-reactive protein levels.

Capsaicin Reduces Obesity by Reducing Chronic Low-Grade Inflammation.

Chronic low-grade inflammation (CLGI) is associated with obesity and is one of its pathogenetic mechanisms. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, is the principal cause of CLGI. Studies have found that capsaicin significantly reduces the relative abundance of LPS-producing bacteria. In the present study, TRPV1-knockout (TRPV1-/-) C57BL/6J mice and the intestinal epithelial cell line Caco-2 (TRPV1-/-) were used as models to determine the effect of capsaicin on CLGI and elucidate the mechanism by which it mediates weight loss in vivo and in vitro. We found that the intragastric administration of capsaicin significantly blunted increases in body weight, food intake, blood lipid, and blood glucose in TRPV1-/- mice fed a high-fat diet, suggesting an anti-obesity effect of capsaicin. Capsaicin reduced LPS levels in the intestine by reducing the relative abundance of Proteobacteria such as Helicobacter, Desulfovibrio, and Sutterella. Toll-like receptor 4 (TLR4) levels decreased following decreases in LPS levels. Then, the local inflammation of the intestine was reduced by reducing the expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6 mediated by TLR4. Attenuating local intestinal inflammation led to the increased expression of tight junction proteins zonula occludens 1 (ZO-1) and occludin and the restoration of the intestinal barrier function. Capsaicin increased the expression of ZO-1 and occludin at the transcriptional and translational levels, thereby increasing trans-endothelial electrical resistance and restoring intestinal barrier function. The restoration of intestinal barrier function decreases intestinal permeability, which reduces the concentration of LPS entering the circulation, and reduced endotoxemia leads to decreased serum concentrations of inflammatory cytokines such as TNF-α and IL-6, thereby attenuating CLGI. This study sheds light on the anti-obesity effect of capsaicin and its mechanism by reducing CLGI, increasing our understanding of the anti-obesity effects of capsaicin. It has been confirmed that capsaicin can stimulate the expression of intestinal transmembrane protein ZO-1 and cytoplasmic protein occludin, increase the trans-epithelial electrical resistance value, and repair intestinal barrier function.

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement.

Long COVID (LC), also referred to as Post COVID-19 Condition, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and other terms, represents a complex multisystem disease persisting after the acute phase of COVID-19. Characterized by a myriad of symptoms across different organ systems, LC presents significant diagnostic and management challenges. Central to the disorder is the role of low-grade inflammation, a non-classical inflammatory response that contributes to the chronicity and diversity of symptoms observed. This review explores the pathophysiological underpinnings of LC, emphasizing the importance of low-grade inflammation as a core component. By delineating the pathogenetic relationships and clinical manifestations of LC, this article highlights the necessity for an integrated approach that employs both personalized medicine and standardized protocols aimed at mitigating long-term consequences. The insights gained not only enhance our understanding of LC but also inform the development of therapeutic strategies that could be applicable to other chronic conditions with similar pathophysiological features.

[Research progress on curcumin improving chronic low-grade inflammation and related diseases].

Chronic low-grade inflammation(CLGI), a relatively new concept without a clear definition, refers to a nonspecific, chronic, continuous, and low-grade inflammation state, and it is closely associated with various chronic diseases, including obesity, inflammatory bowel disease, neurodegenerative diseases, and tumors. Improvement of CLGI can slow down disease progression. Anti-inflammatory treatment is an important strategy for prevention and treatment of CLGI. However, there is currently no definitive drug treatment method. Curcumin is a polyphenolic compound extracted from the rhizome of zingiberaceae, with significant anti-inflammatory activity. Research has shown that curcumin can play an anti-inflammatory role by regulating NF-κB, JAK/STAT, PI3K/Akt, MAPK, NLRP3 inflammasome, Nrf2/ARE, and other inflammation-related pathways. This paper summarized the anti-inflammatory mechanisms, pharmacological effect, and clinical application of curcumin in improving CLGI and other diseases, so as to provide a reference for in-depth research and clinical application of curcumin in improving CLGI.

Influence of dietary and lifestyle factors on levels of inflammatory markers (IL-6, IFN-γ and TNF-α) in obese subjects.

Introduction: The low-grade inflammation occurring in obese individuals leads to many diseases, including cardiovascular disease (CVD). Dietary patterns, food groups or nutrients in a well-balanced diet may reduce the level of pro-inflammatory markers and the risk of obesity-related morbidities. Our study aims to describe three cytokines in obese patients in relation to dietary habits, lifestyle and body composition. Material and methods: Serum samples were collected from 84 obese adult volunteer subjects [body mass index (BMI) ≥ 30 kg/m2] to analyze the concentrations of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ). The subjects were tested by bioelectrical impedance analysis (BIA) and completed a three-day food diary and original questionnaire with the FFQ-6 food consumption frequency questionnaire. Results and conclusions: Higher serum levels of IL-6 and IFN-γ were found in patients with atherosclerosis, but the group was too small for a reliable correlation. Subcutaneous but not visceral adipose tissue correlated positively with IL-6 levels. Dietary factors such as amount of sugars, including galactose and sucrose, in the diet and the frequency of consumption of sweet flavored dairy products correlated positively with the levels of IL-6 and TNF-α, while the frequency of alcohol consumption negatively correlated with the level of IL-6. The greater the frequency of sports, the higher was the level of IL-6. In obese individuals, the level of pro-inflammatory cytokines could predispose to atherosclerosis and is associated with dietary factors and lifestyle.

The Interconnection between Hepatic Insulin Resistance and Metabolic Dysfunction-Associated Steatotic Liver Disease-The Transition from an Adipocentric to Liver-Centric Approach.

The central mechanism involved in the pathogenesis of MAFLD is insulin resistance with hyperinsulinemia, which stimulates triglyceride synthesis and accumulation in the liver. On the other side, triglyceride and free fatty acid accumulation in hepatocytes promotes insulin resistance via oxidative stress, endoplasmic reticulum stress, lipotoxicity, and the increased secretion of hepatokines. Cytokines and adipokines cause insulin resistance, thus promoting lipolysis in adipose tissue and ectopic fat deposition in the muscles and liver. Free fatty acids along with cytokines and adipokines contribute to insulin resistance in the liver via the activation of numerous signaling pathways. The secretion of hepatokines, hormone-like proteins, primarily by hepatocytes is disturbed and impairs signaling pathways, causing metabolic dysregulation in the liver. ER stress and unfolded protein response play significant roles in insulin resistance aggravation through the activation of apoptosis, inflammatory response, and insulin signaling impairment mediated via IRE1/PERK/ATF6 signaling pathways and the upregulation of SREBP 1c. Circadian rhythm derangement and biological clock desynchronization are related to metabolic disorders, insulin resistance, and NAFLD, suggesting clock genes as a potential target for new therapeutic strategies. This review aims to summarize the mechanisms of hepatic insulin resistance involved in NAFLD development and progression.

Phenotypic and functional characterisation of synovial fluid-derived neutrophils in knee osteoarthritis and knee infection.

OBJECTIVE: An increase in the number of neutrophils (NEUs) has long been associated with infections in the knee joints; however, their impact on knee osteoarthritis (KOA) pathophysiology remains largely unexplored. DESIGN: This study compared the phenotypic and functional characteristics of synovial fluid (SF)-derived NEUs in KOA and knee infection (INF). RESULTS: KOA NEUs were characterised by a lower expression of CD11b, CD54, and CD64 and higher expression of CD62L, TLR2, and TLR4 compared with INF NEUs. Except for CCL2, lower levels of inflammatory mediators and proteases were detected in KOA SF than in INF SF. Functionally, KOA NEUs displayed increased reactive oxygen species production and phagocytic activity compared with INF NEUs. Moreover, KOA and INF NEUs differed in cell sizes, histological characteristics of the surrounding synovial tissues, and their effects on the endothelial cells assessed by human umbilical vein endothelial cells. When KOA patients were subdivided based on the SF NEU abundance, patients with high NEUs (10%-60%) were characterised by i) elevated SF protein levels of TNF-α, IL-1RA, MMP-9, sTREM-1, VILIP-1 and ii) lower CD54, CD64, TLR2 and TLR4 expression compared to patients with low NEUs (<10%). Analysis of paired SF samples suggests that low or high NEU percentages, respectively, persist throughout the course of disease. CONCLUSIONS: Our findings suggest that NEU may play a significant role in KOA pathophysiology. Further studies should explore the mechanisms that contribute to the increased number of NEUs in SF and the clinical consequences of neutrophilic phenotype in KOA.

A six-month low-carbohydrate diet high in fat does not adversely affect endothelial function or markers of low-grade inflammation in patients with type 2 diabetes: an open-label randomized controlled trial.

BACKGROUND: While a low-carbohydrate diet (LCD) reduces HbA1c in patients with type 2 diabetes (T2D), the associated high intake of fat may adversely affect cardiovascular risk factors. To address this, we examined the effect of a non-calorie-restricted LCD high in fat on endothelial function and markers of low-grade inflammation in T2D over 6 months. METHODS: In an open-label randomized controlled trial, 71 patients with T2D were randomized 2:1 to either a LCD (< 20 E% carbohydrates, 50-60 E% fat) or a control diet (50-60 E% carbohydrates, 20-30 E% fat) for six months. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were assessed by ultrasound in the brachial artery together with plasma interleukin-6 (IL-6) and serum high-sensitivity C-reactive protein (hsCRP) in the participants at baseline (n = 70) and after six months (n = 64). RESULTS: The FMD and NID were unaltered in both groups after six months, and there were no between-group differences in change of either FMD (p = 0.34) or NID (p = 0.53) in response to the interventions. The circulating hsCRP and IL-6 levels decreased only in response to LCD (both p < 0.05). However, comparing changes over time with the control diet, the LCD did not reduce either IL-6 (p = 0.25) or hsCRP (p = 0.07) levels. The lack of changes in FMD and NID in response to LCD persisted after adjustment for cardiovascular risk factors. CONCLUSION: A LCD high in fat for six months does not adversely affect endothelial function or selected markers of low-grade inflammation, which suggests that this nutritional approach does not increase the risk of cardiovascular disease. Trial registration ClinicalTrials.gov (NCT03068078).

Low-grade inflammation is negatively associated with live birth in women undergoing IVF.

RESEARCH QUESTION: Is low-grade inflammation, detected by C-reactive protein (CRP), a marker of IVF outcome addressing both blastocyst quality and pregnancy outcome? DESIGN: This sub-study of a multicentre randomized controlled trial included 440 women undergoing IVF treatment with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Serum CRP was measured on cycle day 2-3 (baseline) and on the day of ovulation triggering. The association between CRP concentrations and reproductive outcomes (number of retrieved oocytes, number of good-quality blastocysts, pregnancy, pregnancy loss and live birth), were analysed, adjusting for relevant confounders. RESULTS: A negative association was found between higher baseline CRP concentrations and live birth rate (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.62-0.96, P = 0.02) and higher CRP concentrations at baseline were associated with pregnancy loss among women who conceived (OR 1.37, 95% CI 1.07-1.76, P = 0.01). When testing for a specific cut-off, CRP concentrations above 2.34 (the highest quartile) were more likely to be associated with pregnancy loss (P = 0.02) and a lower chance of live birth (P = 0.04) compared with the lowest quartile. No associations were found between CRP concentrations and pregnancy outcomes on the day of ovulation triggering, and there were no associations between CRP concentrations and the number of good-quality blastocysts. CONCLUSIONS: Higher CRP concentrations at cycle day 2-3, before starting ovarian stimulation, are negatively associated with chance of live birth, possibly because of an increased risk of pregnancy loss. No association was found between the number of good-quality blastocysts and CRP concentration. More studies are needed to investigate the impact of low-grade inflammation.

Could very low-calorie ketogenic diets turn off low grade inflammation in obesity? Emerging evidence.

Obesity is an emerging non-communicable disease associated with chronic low-grade inflammation and oxidative stress, compounded by the development of many obesity-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, and a range of cancers. Originally developed for the treatment of epilepsy in drug non-responder children, the ketogenic diet (KD) is being increasingly used in the treatment of many diseases, including obesity and obesity-related conditions. The KD is a dietary pattern characterized by high fat intake, moderate to low protein consumption, and very low carbohydrate intake (<50 g) that has proved to be an effective and weight-loss tool. In addition, it also appears to be a dietary intervention capable of improving the inflammatory state and oxidative stress in individuals with obesity by means of several mechanisms. The main activity of the KD has been linked to improving mitochondrial function and decreasing oxidative stress. ß-hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species, improving mitochondrial respiration. In addition, KDs exert anti-inflammatory activity through several mechanisms, e.g., by inhibiting activation of the nuclear factor kappa-light-chain-enhancer of activated B cells, and the inflammatory nucleotide-binding, leucine-rich-containing family, pyrin domain-containing-3, and inhibiting histone deacetylases. Given the rising interest in the topic, this review looks at the underlying anti-inflammatory and antioxidant mechanisms of KDs and their possible recruitment in the treatment of obesity and obesity-related disorders.

Glucagon induces the hepatic expression of inflammatory markers in vitro and in vivo.

Glucagon exerts multiple hepatic actions, including stimulation of glycogenolysis/gluconeogenesis. The liver plays a crucial role in chronic inflammation by synthesizing proinflammatory molecules, which are thought to contribute to insulin resistance and hyperglycaemia. Whether glucagon affects hepatic expression of proinflammatory cytokines and acute-phase reactants is unknown. Herein, we report a positive relationship between fasting glucagon levels and circulating interleukin (IL)-1ß (r = 0.252, p = .042), IL-6 (r = 0.230, p = .026), fibrinogen (r = 0.193, p = .031), complement component 3 (r = 0.227, p = .024) and high sensitivity C-reactive protein (r = 0.230, p = .012) in individuals without diabetes. In CD1 mice, 4-week continuous treatment with glucagon induced a significant increase in circulating IL-1ß (p = .02), and IL-6 (p = .001), which was countered by the contingent administration of the glucagon receptor antagonist, GRA-II. Consistent with these results, we detected a significant increase in the hepatic activation of inflammatory pathways, such as expression of NLRP3 (p < .02), and the phosphorylation of nuclear factor kappaB (NF-κB; p < .02) and STAT3 (p < .01). In HepG2 cells, we found that glucagon dose-dependently stimulated the expression of IL-1ß (p < .002), IL-6 (p < .002), fibrinogen (p < .01), complement component 3 (p < .01) and C-reactive protein (p < .01), stimulated the activation of NLRP3 inflammasome (p < .01) and caspase-1 (p < .05), induced the phosphorylation of TRAF2 (p < .01), NF-κB (p < .01) and STAT3 (p < .01). Preincubating cells with GRA-II inhibited the ability of glucagon to induce an inflammatory response. Using HepaRG cells, we confirmed the dose-dependent ability of glucagon to stimulate the expression of NLRP3, the phosphorylation of NF-κB and STAT3, in the absence of GRA-II. These results suggest that glucagon has proinflammatory effects that may participate in the pathogenesis of hyperglycaemia and unfavourable cardiometabolic risk profile.

Applicability of the low-grade inflammation score in predicting 90-day functional outcomes after acute ischemic stroke.

BACKGROUND AND PURPOSE: The low-grade inflammation (LGI) score, a novel indicator of chronic LGI, combines C-reactive protein (CRP), leukocyte counts, the neutrophil/lymphocyte ratio (NLR), and the platelet (PLT) count to predict outcomes of patients with various conditions, such as cardiovascular diseases, cancers, and neurodegenerative diseases. However, few studies have examined the role of the LGI score in predicting functional outcomes of patients with ischemic stroke. The present study aimed to evaluate the association between the LGI score and functional outcomes of patients with ischemic stroke. METHODS: A total of 1,215 patients were screened in the present study, and 876 patients were finally included in this retrospective observational study based on the inclusion and exclusion criteria. Blood tests were conducted within 24 h of admission. Severity of ischemic stroke was assessed using the NIHSS score with severe stroke denoted by NIHSS > 5. Early neurological deterioration (END) was defined as an increment in the total NIHSS score of ≥ 2 points within 7 days after admission. Patient outcomes were assessed on day 90 after stroke onset using the modified Rankin Scale (mRS). RESULTS: The LGI score was positively correlated with baseline and the day 7 NIHSS scores (R2 = 0.119, p < 0.001;R2 = 0.123, p < 0.001). Multivariate regression analysis showed that the LGI score was an independent predictor of stroke severity and END. In the crude model, the LGI score in the fourth quartile was associated with a higher risk of poor outcomes on day 90 compared with the LGI score in the first quartile (OR = 5.02, 95% CI: 3.09-8.14, p for trend < 0.001). After adjusting for potential confounders, the LGI score in the fourth quartile was independently associated with poor outcomes on day 90 (OR = 2.65, 95% CI: 1.47-4.76, p for trend = 0.001). Finally, the ROC curve analysis showed an AUC of 0.682 for poor outcomes on day 90 after stroke onset. CONCLUSION: The LGI score is strongly correlated with the severity of acute ischemic stroke and that the LGI score might be a good predictor for poor outcomes on day 90 in patients with acute ischemic stroke.

Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (i) reduce cardiovascular and renal events in patients with and without type 2 diabetes (T2D). However, the underlying mechanisms are debated. Low-grade inflammation (LGI) is a key driver of vascular complications, suggested to be attenuated by SGLT-2i in animal models. Based on a specific working hypothesis, here we investigated the net effect of SGLT-2i on LGI in patients with T2D and the possible underlying mechanism. We enrolled patients with T2D treated either with a stable therapy with SGLT-2i or with other glucose-lowering drugs (GLD) (n = 43 per group after matching for a range of pro-inflammatory variables), and tested hs-CRP and interleukin (IL)-6 as primary variables of interest. Patients treated with SGLT-2i had lower circulating levels of IL-6, a prototypical marker of LGI, but also of uric acid and fasting insulin, compared with patients treated with other GLD. Then, to explore whether uric acid and insulin might mediate the effect of SGLT-2i on IL-6, we tested physiologically pertinent doses of these two molecules (i.e. 0.5 mM uric acid and 1 nM insulin) in two in vitro models of LGI, i.e. monocytes (THP-1) treated with LPS and endothelial cells (HUVEC) exposed to hyperglycaemia. Results from in vitro models supported a pro-inflammatory role for uric acid and its combination with insulin in monocytes and for uric acid alone in hyperglycaemia-stimulated endothelial cells. On the contrary, we observed no drug-intrinsic, anti-inflammatory effect for dapagliflozin, empagliflozin, and canagliflozin in the same models. Overall, these results suggest that SGLT-2i possess a tangible activity against LGI, an effect possibly mediated by their ability to lower uric acid and insulin concentrations and that juxtaposes other proposed mechanisms in explaining the observed benefit of this class on cardiovascular and renal endpoints.