Neuroinflammation has been suggested to be involved in the pathogenesis of postoperative cognitive dysfunction (POCD). Electroacupuncture (EA) is an irreplaceable method in traditional Chinese medicine that is used for treating neurodegenerative diseases in clinical and experimental studies. The aim of this study was to examine whether EA improves cognitive dysfunction caused by surgery and to investigate the pathological mechanism of TLR2 and TLR4 in the hippocampus of aged rats. A rat model of POCD was established and treated with EA or minocycline. Both EA- and minocycline-treated rats performed significantly better than untreated operated rats in spatial memory tasks of the Morris water maze (MWM) test, spending comparatively greater amounts of time in the target zone during the probe test. Additionally, decreased levels of proinflammatory cytokines (IL-1β, IL-6, TNF-α, and HMGB1) and decreased TLR2 and TLR4 protein expression in the hippocampus of EA- and minocycline-treated rats were detected. Our data suggested that EA treatment alleviated the cognition performance deficit and neuroinflammation in aged rats following surgery, which may be mediated by inhibiting the expression of hippocampal neuroinflammatory cytokines through the microglia/TLR2/4 pathway.

OBJECTIVE:To probe into effect of electroacupuncture on intestinal permeability in the patient with acute pancreatitis and the mechanism.

METHODS:Sixty-eight cases of acute pancreatitis were randomly divided into a treatment group and a control group. The control group and the treatment group were treated with anti-infection, inhibiting secretion of pancreas, improving microcirculation and protective agent of gastric mucosa, with electroacupuncture at Zusanli (ST 36), Shangjuxu (ST 37), Gongsun (SP 4), Taichong (LR 3) and Xuanzhong (GB 39) added, twice daily for 3 days, in the treatment group. Their clinical therapeutic effects and changes of endothelin (ET), nitric oxide (NO), tumor necrosis factor (TNF-alpha) and lactulose/mannose ratio (L/M) before and after treatment were compared.

RESULTS:The total effective rate of 86.7% in the treatment group was better than 76.3% in the control group (P<0.05). After treatment, ET, NO, TNF-alpha contents and L/M all were higher than those before treatment, with those in the treatment group being significantly lower than those in the control group (P<0.05).

CONCLUSION:Electroacupuncture can significantly decrease permeability of intestinal mucosa in the patient with acute pancreatitis, reduce accumulation of endogenous inflammatory mediators (ET, TNF-alpha) and vascular active substance (NO) in intestinal mucosa, so as to alleviate necrosis of intestinal epithelial cells and protect the barrier of gastro-intestinal mucosa.

Integrative approaches such as electroacupuncture, devoid of drug effects are gaining prominence for treating pain. Understanding the mechanisms of electroacupuncture induced analgesia would benefit chronic pain conditions such as sickle cell disease (SCD), for which patients may require opioid analgesics throughout life. Mouse models are instructive in developing a mechanistic understanding of pain, but the anesthesia/restraint required to administer electroacupuncture may alter the underlying mechanisms. To overcome these limitations, we developed a method to perform electroacupuncture in conscious, freely moving, unrestrained mice. Using this technique we demonstrate a significant analgesic effect in transgenic mouse models of SCD and cancer as well as complete Freund's adjuvant-induced pain. We demonstrate a comprehensive antinociceptive effect on mechanical, cold and deep tissue hyperalagesia in both genders. Interestingly, individual mice showed a variable response to electroacupuncture, categorized into high-, moderate-, and non-responders. Mechanistically, electroacupuncture significantly ameliorated inflammatory and nociceptive mediators both peripherally and centrally in sickle mice correlative to the antinociceptive response. Application of sub-optimal doses of morphine in electroacupuncture-treated moderate-responders produced equivalent antinociception as obtained in high-responders. Electroacupuncture in conscious freely moving mice offers an effective approach to develop a mechanism-based understanding of analgesia devoid of the influence of anesthetics or restraints.

Sepsis is associated with high morbidity and mortality. This study was to investigate the protective effects of electroacupuncture (EA) pretreatment with different waveforms on septic brain injury in rats and its mechanism. Male Sprague-Dawley rats were pretreated by EA with different waveforms (continuous wave, dilatational wave, or intermittent wave) at Baihui (GV20) and Tsusanli (ST36) acupoints for 30min, and underwent cecal ligation and puncture (CLP) or sham operation. The results showed that EA pretreatment with different waveforms improved survival rate, attenuated encephaledema, brain injury, neuronal apoptosis and cognitive dysfunction, and preserved blood-brain barrier (BBB). EA pretreatment decreased the production of tumor necrosis factor(TNF)-α, interleukin(IL)-6, malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) and catalase (CAT) in serum and hippocampus at 48h after sham or CLP operation. Additionally, EA pretreatment downregulated the expressions of toll-like receptor-4 (TLR-4), nuclear factor-kappa B (NF-κB) and ionized calcium binding adaptor molecule 1(Iba 1). The effect of dilatational wave was the most significant, followed by intermittent wave, and continuous wave was relatively poor. In conclusion, our results demonstrate that EA pretreatment with three waveforms alleviates sepsis-inducedbrain injury by inhibition of microglial activation and attenuation of inflammation, oxidative stress and apoptosis. These findings suggest that EA pretreatment with dilatational wave at Baihui and Tsusanli acupoints might be a promising therapeutic strategy for relieving septic brain injury.

Elevation of the proinflammatory cytokine IL-6 has been implicated in depression; however, the mechanisms remain elusive. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression post-transcriptionally. The lethal-7 (let-7) miRNA family was suggested to be involved in the inflammation process and IL-6 was shown to be one of its targets. In the present study, we report elevation of Il6 in the prefrontal cortex (PFC) of a genetic rat model of depression, the Flinders Sensitive Line (FSL) compared to the control Flinders Resistant Line. This elevation was associated with an overexpression of LIN28B and downregulation of let-7 miRNAs, the former an RNA-binding protein that selectively represses let-7 synthesis. Also DROSHA, a key enzyme in miRNA biogenesis was downregulated in FSL. Running was previously shown to have an antidepressant-like effect in the FSL rat. We found that running reduced Il6 levels and selectively increased let-7i and miR-98 expression in the PFC of FSL, although there were no differences in LIN28B and DROSHA expression. Pri-let-7i was upregulated in the running FSL group, which associated with increased histone H4 acetylation. In conclusion, the disturbance of let-7 family biogenesis may underlie increased proinflammatory markers in the depressed FSL rats while physical activity could reduce their expression, possibly through regulating primary miRNA expression via epigenetic mechanisms.

Irritable bowel syndrome (IBS) global burden is underestimated despite its high prevalence. It's a gastrointestinal disease having obscure pathophysiology with multiple therapies yet unsatisfactory remedies. The Endocannabinoid system (ECS) of our body plays a key role in maintaining normal physiology of the gastrointestinal tract as well as involves abnormalities including functional diseases like IBS. This review highlights the importance of the Endocannabinoid system, its connections with the normal gastrointestinal functions and abnormalities like IBS. It also discusses the role of cannabis as medical therapy in IBS patients. A literature search for articles related to endocannabinoids in IBS and medical cannabis in PubMed and Google Scholar was conducted. The studies highlighted the significant participation of ECS in IBS. However, the breach in obtaining the promising therapeutic model for IBS needed further investigation in ECS and uncover other treatments for IBS. This review summarizes ECS, highlights the relationship of ECS with IBS and explores cannabis as a potential therapy to treat IBS.

Background:The physiological and biochemical demands of intense exercise elicit both muscle-based and systemic responses. The main adaptations to endurance exercise include the correction of electrolyte imbalance, a decrease in glycogen storage and the increase of oxidative stress, intestinal permeability, muscle damage, and systemic inflammatory response. Adaptations to exercise might be influenced by the gut microbiota, which plays an important role in the production, storage, and expenditure of energy obtained from the diet as well as in inflammation, redox reactions, and hydration status.

Methods:A systematic and comprehensive search of electronic databases, including MEDLINE, Scopus, ClinicalTrials.gov, ScienceDirect, Springer Link, and EMBASE was done. The search process was completed using the keywords:"endurance","exercise","immune response","microbiota","nutrition", and"probiotics".

Results:Reviewed literature supports the hypothesis that intestinal microbiota might be able to provide a measureable, effective marker of an athlete's immune function and that microbial composition analysis might also be sensitive enough to detect exercise-induced stress and metabolic disorders. The review also supports the hypothesis that modifying the microbiota through the use of probiotics could be an important therapeutic tool to improve athletes' overall general health, performance, and energy availability while controlling inflammation and redox levels.

Conclusion:The present review provides a comprehensive overview of how gut microbiota may have a key role in controlling the oxidative stress and inflammatory responses as well as improving metabolism and energy expenditure during intense exercise.

BACKGROUND:Poria cocos Wolf, a medicinal fungus, is widely used in traditional medicines in East Asian countries owing to its various therapeutic potentials. Although several studies have demonstrated the anti-inflammatory activity of this fungus, its underlying mechanisms have not yet been clearly defined.

METHODS:In the present study, we have demonstrated the anti-inflammatory effects of ethanol extract of P. cocos (EEPC) in lipopolysaccaride (LPS)-stimulated RAW 264.7 macrophages. As inflammatory parameters, the productions of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-1β and tumor necrosis factor (TNF)-α were evaluated. We also examined the EEPC's effect on the nuclear factor-kappaB (NF-κB) signaling pathway.

RESULTS:Our results indicated that EEPC exhibits a potent inhibitory effect on NO production and inhibits PGE2 release in LPS-induced macrophages without affecting cell viability. EEPC also significantly attenuated LPS-induced secretion of inflammatory cytokines IL-1β and TNF-α. Additionally, LPS-induced expression of inducible NO synthase (iNOS), cyclooxygenase (COX)-2, IL-1β, and TNF-α was decreased by pre-treatment with EEPC at the transcriptional level. Moreover, EEPC clearly inhibited LPS-induced nuclear translocation of NF-κB p65 subunits, which correlated with EEPC's inhibitory effects on inhibitor kappaB (IκB) degradation. Moreover, EEPC clearly suppressed the LPS-induced DNA-binding activity of NF-κB, as well as the nuclear translocation of the NF-κB p65, which correlated with EEPC's inhibitory effects on inhibitor kappaB (IκB) degradation.

CONCLUSIONS:Taken together, our data indicates that EEPC targets the inflammatory response of macrophages via inhibition of iNOS, COX-2, IL-1β, and TNF-α through inactivation of the NF-κB signaling pathway, supporting the pharmacological basis of P. cocos as a traditional herbal medicine for treatment of inflammation and its associated disorders.

Cytokine proteins may have important roles during different human physiological and pathological processes. In the oral cavity, the bone loss and periodontal tissue pathology was related to inflammatory process activation. The aim of the present study was to assess the effects of etiological periodontal therapy with and without the use of Low Level Laser Therapy (LLLT) on clinical periodontal parameters and interleukin (IL)-1β level in gingival crevicular fluid (GCF) from chronic periodontitis (CP) patients. Thirty non-smoker CP patients were selected from the Foggia University Dental Clinic and other 2 private dental clinics. All patients were divided into two homogeneous randomized groups: 15 patients were treated with only scaling and root planing (group 1) and 15 patients with scaling and root planing etiological treatment and LLLT (group 2). In all sites, at baseline before treatment, the periodontal pocket depth (PPD) and bleeding on probing (BOP) were measured. In the PPD sites, the GCF samples were collected from 30 deep (≥5 mm) and shallow (≤3 mm) sites and IL-1β were evaluated at baseline, after 10 days and 1 month. In all the samples at baseline, the IL-1β concentration in GCF and BOP rate were significantly higher at deep PPD sites than at the shallow ones. After 10 days in all samples noPPD improvement was observed in the BOP rate but the IL-1 β level was statistically significantly improved (p<0.005) in group 2 compared to group 1. At 10 days and 1 month, in all deep PPD sites, PPD and BOP improvements were observed. At same time, IL-1β levels were lower and statistically significantly (p<0.005) improved in group 2 compared to group 1. The results confirmed that the periodontal etiology treatment of deep PPD sites with or with-out associated LLLT promotes periodontal health. Etiological treatment associated with LLLT, improves BOP and inflammation in periodontal disease. Moreover, the IL-1β concentration changes in GCF suggest these cytokines as a predictable marker of gingival inflammation in chronic periodontitis patients.

There is robust evidence that habitual physical activity is anti-inflammatory and protective against developing chronic inflammatory disease. Much less is known about the effects of habitual moderate exercise in the gut, the compartment that has the greatest immunological responsibility and interactions with the intestinal microbiota. The link between the two has become evident, as recent studies have linked intestinal dysbiosis, or the disproportionate balance of beneficial to pathogenic microbes, with increased inflammatory disease susceptibility. Limited animal and human research findings imply that exercise may have a beneficial role in preventing and ameliorating such diseases by having an effect on gut immune function and, recently, microbiome characteristics. Emerging data from our laboratory show that different forms of exercise training differentially impact the severity of intestinal inflammation during an inflammatory insult (for example, ulcerative colitis) and may be jointly related to gut immune cell homeostasis and microbiota-immune interactions. The evidence we review and present will provide data in support of rigorous investigations concerning the effects of habitual exercise on gut health and disease.

Chronic noncommunicable diseases (CNCDs), which include cardiovascular disease, some cancers, for example, colon cancer, breast cancer, and type 2 diabetes, are reaching epidemic proportions worldwide. It has now become clear that low-grade chronic inflammation is a key player in the pathogenesis of most CNCDs. Given that regular exercise offers protection against all causes of mortality, primarily by protection against atherosclerosis and insulin resistance, we suggest that exercise may exert some of its beneficial health effects by inducing anti-inflammatory actions. Recently, IL-6 was introduced as the first myokine, defined as a cytokine, which is produced and released by contracting skeletal muscle fibres, exerting its effects in other organs of the body. We suggest that skeletal muscle is an endocrine organ and that myokines may be involved in mediating the beneficial effects against CNCDs associated with low-grade inflammation.

Epidemiological studies indicate that patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing dementia/Alzheimer's disease (AD). This review, which is based on recent studies, presents a molecular framework that links the two diseases and explains how physical training could help counteract neurodegeneration in T2DM patients. Inflammatory, oxidative, and metabolic changes in T2DM patients cause cerebrovascular complications and can lead to blood-brain-barrier (BBB) breakdown. Peripherally increased pro-inflammatory molecules can then pass the BBB more easily and activate stress-activated pathways, thereby promoting key pathological features of dementia/AD such as brain insulin resistance, mitochondrial dysfunction, and accumulation of neurotoxic beta-amyloid (Aβ) oligomers, leading to synaptic loss, neuronal dysfunction, and cell death. Ceramides can also pass the BBB, induce pro-inflammatory reactions, and disturb brain insulin signaling. In a vicious circle, oxidative stress and the pro-inflammatory environment intensify, leading to further cognitive decline. Low testosterone levels might be a common risk factor in T2DM and AD. Regular physical exercise reinforces antioxidative capacity, reduces oxidative stress, and has anti-inflammatory effects. It improves endothelial function and might increase brain capillarization. Physical training can further counteract dyslipidemia and reduce increased ceramide levels. It might also improve Aβ clearance by up-regulating Aβ transporters and, in some cases, increase basal testosterone levels. In addition, regular physical activity can induce neurogenesis. Physical training should therefore be emphasized as a part of prevention programs developed for diabetic patients to minimize the risk of the onset of neurodegenerative diseases among this specific patient group.

Despite the wealth of epidemiological and experimental studies indicating the protective role of regular physical activity/exercise training against the sequels of aging and cardiovascular diseases, the molecular transducers of exercise/physical activity benefits are not fully identified but should be further investigated in more integrative and innovative approaches, as they bear the potential for transformative discoveries of novel therapeutic targets. As aging and cardiovascular diseases are associated with a chronic state of oxidative stress and inflammation mediated via complex and interconnected pathways, we will focus in this review on the antioxidant and anti-inflammatory actions of exercise, mainly exerted on adipose tissue, skeletal muscles, immune system, and cardiovascular system by modulating anti-inflammatory/proinflammatory cytokines profile, redox-sensitive transcription factors such as nuclear factor kappa B, activator protein-1, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha, antioxidant and prooxidant enzymes, and repair proteins such as heat shock proteins, proteasome complex, oxoguanine DNA glycosylase, uracil DNA glycosylase, and telomerase. It is important to note that the effects of exercise vary depending on the type, intensity, frequency, and duration of exercise as well as on the individual's characteristics; therefore, the development of personalized exercise programs is essential.

The mechanisms by which regular exercise prevents the development and progression of chronic inflammatory diseases are largely unknown. We find that exercise enhances resolution of acute inflammation by augmenting resolvin D1 (RvD1) levels and by promoting macrophage phagocytosis. When compared with sedentary controls, mice that performed a four-week treadmill exercise regimen displayed higher macrophage phagocytic activity, enhanced RvD1 levels, and earlier neutrophil clearance following an acute inflammatory challenge. In acute inflammatory cell extracts from exercised mice, we found elevated expression ofandand higher RvD1 levels. Because exercise stimulates release of epinephrine, which has immunomodulatory effects, we questioned whether epinephrine exerts proresolving actions on macrophages. Epinephrine-treated macrophages displayed higher RvD1 levels and 15-lipoxygenase-1 protein abundance, which were prevented by incubation with theα1 adrenergic receptor (α1-AR) antagonist prazosin. Likewise, stimulation of the α1-AR with phenylephrine enhanced macrophage phagocytosis and RvD1 production. During acute inflammation, prazosin abrogated exercise-enhanced neutrophil clearance, macrophage phagocytosis, and RvD1 biosynthesis. These results suggest that exercise-stimulated epinephrine enhances resolution of acute inflammation in an α1-AR-dependent manner. To our knowledge, our findings provide new mechanistic insights into the proresolving effects of exercise that could lead to the identification of novel pathways to stimulate resolution.

BACKGROUND:Exercise may help to mitigate symptoms of depression by reducing inflammation; however, little is known about the influence of exercise intensity on depressed mood.

METHODS:In the present study, sixty-one university students were assigned to six weeks of high-intensity interval training (HIT), moderate continuous training (MCT), or no exercise (CON) during their academic term. We measured changes in depression, anxiety and perceived stress along with pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and C-reactive protein (CRP).

RESULTS:Depression increased for CON, demonstrating how quickly mental health can decline for students during their academic term. In contrast, MCT decreased depression and pro-inflammatory cytokine TNF-α levels. Although HIT decreased depressive symptoms, it also increased perceived stress, TNF-α and IL-6 relative to MCT. This may be due to the higher level of physical stress evoked by the more strenuous exercise protocol.

CONCLUSIONS:Taken together, the results suggest that moderate-intensity exercise may be an optimal intensity of exercise for the promotion of mental health by decreasing TNF-α. This is critical for informing the use of exercise as medicine for mental health.

The failure of Kupffer cells (KCs) to remove endotoxin is an important factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In this study, the effects of exercise training on KC function were studied in terms of in vivo endotoxin clearance and inflammatory responses. Mice were allocated into rest and exercise groups. KC bead phagocytic capacity and plasma steroid hormone levels were determined following exercise training. Endotoxin and inflammatory cytokine levels in plasma were determined over time following endotoxin injection. KC bead phagocytic capacity was potentiated and clearance of exogenously-injected endotoxin was increased in the exercise group. Inflammatory cytokine (TNF-α and IL-6) levels were lower in the exercise group. We found that only DHEA was increased in the plasma of the exercise group. In an in vitro experiment, the addition of DHEA to RAW264.7 cells increased bead phagocytic capacity and attenuated endotoxin-induced inflammatory responses. These resultssuggest that exercise training modulates in vivo endotoxin clearance and inflammatory responses in association with increased DHEA production. These exercise-induced changes in KC capacity may contribute to a slowing of disease progression in NAFLD patients.

OBJECTIVE:This study examined the effects of exercise training (ExT) upon concentration of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) in the gastrocnemius of rats with heart failure (HF) induced by left coronary artery ligation.

METHODS:Adult male Wistar rats submitted to myocardial infarction (MI) or sham surgery were randomly allocated into one of four experimental groups: trained HF (Tr-HF), sedentary HF (Sed-HF), trained sham (Tr-Sham) and sedentary sham (Sed-Sham). ExT protocol was performed on treadmill for a period of 8 weeks (60m/days, 5×/week, 16m/min), which started 6 weeks after MI. Cardiac hemodynamic evaluations of left ventricular end-diastolic pressure (LVEDP) and morphometric cardiac were used to characterize HF. The hemodynamic variables were recorded and gastrocnemius muscle was collected. TNF-α, IL-6 and IL-10 proteinlevels were determined by multiplex bead array.

RESULTS:Sed-HF group presented increase of TNF-α level when compared with the Sed-Sham group (mean difference, MD 1.3; 95% confidence interval, CI -0.04 to 2.5). ExT reduced by 59% TNF-α level in Tr-HF group (MD -1.7; 95% CI -2.9 to -0.3) and increased IL-10 (MD 15; 95% CI 11-26) when compared with the Sed-HF group. Thus, the gastrocnemius muscle IL-10/TNF-α ratio was increased in Tr-HF rats (MD 15; 95% CI -8 to 47) when compared with the Sed-HF rats.

CONCLUSION:These results demonstrate that ExT not only attenuates TNF-α level but also improves the IL-10 cytokine level in skeletal muscle of HF rats.

:The aim of the study was to determine the effects of exercise training on improving the thoracic perivascular adipose tissue (tPVAT) phenotype (inflammation, oxidative stress, and proteasome function) in metabolic syndrome and its subsequent actions on aortic function.

METHODS:Lean and obese (model of metabolic syndrome) Zucker rats (n=8/group) underwent 8-weeks of control conditions or treadmill exercise (70% of max speed, 1 h/day, 5 days/week). At the end of the intervention, the tPVAT was removed and conditioned media was made. The cleaned aorta was attached to a force transducer to assess endothelium-dependent and independent dilation in the presence or absence of tPVAT-conditioned media. tPVAT gene expression, inflammatory /oxidative phenotype, and proteasome function were assessed.

RESULTS:The main findings were that Ex induced: (1) a beige-like, anti-inflammatory tPVAT phenotype; (2) a greater abundance ofNO in tPVAT; (3) a reduction in tPVAT oxidant production; and (4) an improved tPVAT proteasome function. Regarding aortic function, endothelium-dependent dilation was greater in exercised lean and obese groups vs. controls (p < 0.05). Lean control tPVAT improved aortic relaxation, whereas obese control tPVAT decreased aortic relaxation. In contrast, the obese Ex-tPVAT increased aortic dilation, whereas the lean Ex-tPVAT did not affect aortic dilation.

CONCLUSION:Overall, exercise had the most dramatic impact on the obese tPVAT reflecting a change towards an environment with less oxidant load, less inflammation and improved proteasome function. Such beneficial changes to the tPVAT micro-environment with exercise likely played a significant role in mediating the improvement in aortic function in metabolic syndrome following 8 weeks of exercise.

Exercise reduces the risk of inflammatory disease by modulating a variety of tissue and cell types, including those within the gastrointestinal tract. Recent data indicates that exercise can also alter the gut microbiota, but little is known as to whether these changes affect host function. Here, we use a germ-free (GF) animal model to test whether exercise-induced modifications in the gut microbiota can directly affect host responses to microbiota colonization and chemically-induced colitis. Donor mice (n = 19) received access to a running wheel (n = 10) or remained without access (n = 9) for a period of six weeks. After euthanasia, cecal contents were pooled by activity treatment and transplanted into two separate cohorts of GF mice. Two experiments were then conducted. First, mice were euthanized five weeks after the microbiota transplant and tissues were collected for analysis. A second cohort of GF mice were colonized by donor microbiotas for four weeks before dextran-sodium-sulfate was administered to induce acute colitis, after which mice were euthanized for tissue analysis. We observed that microbial transplants from donor (exercised or control) mice led to differences in microbiotaβ-diversity, metabolite profiles, colon inflammation, and body mass in recipient mice five weeks after colonization. We also demonstrate that colonization of mice with a gut microbiota from exercise-trained mice led to an attenuated response to chemical colitis, evidenced by reduced colon shortening, attenuated mucus depletion and augmented expression of cytokines involved in tissue regeneration. Exercise-induced modifications in the gut microbiota can mediate host-microbial interactions with potentially beneficial outcomes for the host.

BACKGROUND:Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity.

METHODS:We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation.

RESULTS:In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting.

CONCLUSIONS:Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease.

TRIAL REGISTRATION:ClinicalTrials.gov NCT02122575 and NCT00442195.

FUNDING:Division of Intramural Research, NHLBI of the NIH.