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Sickness behavior in humans is characterized by low mood and fatigue, which have been suggested to reflect changes in motivation involving reorganization of priorities. However, it is unclear which specific processes underlying motivation are altered. We tested whether bacterial endotoxin E. coli lipopolysaccharide (LPS) affected two dissociable constructs of motivational behavior, ie, effort and reward sensitivity. After familiarization with 5 effort levels, participants made a series of accept/reject decisions on whether the stake offered (1, 4, 8, 12, or 15 apples) was 'worth the effort' (10%, 27.5%, 45%, 62.5%, and 80% of maximal voluntary contraction in a hand-held dynamometer). Effort and reward levels were parametrically modulated to dissociate their influence on choice. Overall, 29 healthy young males were administered LPS (2 ng/kg; n=14) or placebo (0.9% saline; n=15). The effort-stake task, and self-reported depression and fatigue were assessed prior to LPS/placebo injection, 2 and 5 h post injection. Cytokines and sickness symptoms were assessed hourly till 8 h after LPS injection. LPS transiently increased interleukin-6 and tumor necrosis factor-α, sickness symptoms, body temperature and self-reported fatigue, and depression post injection relative to baseline and placebo. These changes were accompanied by LPS-induced decreases in acceptance rates of high-effort options, without significantly affecting reward sensitivity 2 h post injection, which were partially recovered 5 h post injection. We suggest that LPS-induced changes in motivation may be due to alterations to mesolimbic dopamine. Our behavioral paradigm could be used to further investigate effects of inflammation on motivational behavior in psychiatric and chronic illnesses.

Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well-controlled type 2 diabetes were randomised to a prebiotic (galacto-oligosaccharide mixture) or placebo (maltodextrin) supplement (5·5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r −0·90, P=0·042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes.

Diet-induced metabolic endotoxemia is an important factor in the development of many chronic diseases in animals and man. The gut epithelium is an efficient barrier that prevents the absorption of liposaccharide (LPS). Structural changes to the intestinal epithelium in response to dietary alterations allow LPS to enter the bloodstream, resulting in an increase in the plasma levels of LPS (termed metabolic endotoxemia). LPS activates Toll-like receptor-4 (TLR4) leading to the production of numerous pro-inflammatory cytokines and, hence, low-grade systemic inflammation. Thus, metabolic endotoxemia can lead to several chronic inflammatory conditions. Obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) can also cause an increase in gut permeability and potential pharmacological and dietary interventions could be used to reduce the chronic low-grade inflammation associated with endotoxemia.

The development of nitric oxide-donating antiphlogistics is intended to improve the tolerability of the parent compounds. The aim of the present study was to explore the potency and tolerability of nitric oxide-donating acetaminophen (NCX 701) in healthy volunteers and to test the hypothesis that NCX 701 could have additional anti-inflammatory efficacy in an experimental model of low-grade human endotoxemia. In this prospective, double-blind, placebo-controlled trial with parallel group design 40 healthy male volunteers were randomized to single oral treatment with NCX 701 (1–2 g), acetaminophen (1 g paracetamol) or placebo before lipopolysaccharide (2ng/kg) infusion. NCX 701 dose-dependently increased plasma and urine nitric oxide concentrations. Pooled analysis of both NCX 701 doses showed a significant, but obviously clinically irrelevant lowering effect on systolic and diastolic blood pressure during the first 5 h. Overall, peak levels of tumor necrosis factor-alpha correlated well with interleukin-6, interleukin-8, monocyte chemoattractant protein-1 and von Willebrand Factor release across all cohorts. There was no major difference between NCX 701 and acetaminophen with respect to their effect on the lipopolysaccharide-induced secretion of inflammation and endothelium activation markers. Overall, a total of 61 adverse events were reported in all treatment arms, mainly related to lipopolysaccharide. Both acetaminophen and NCX 701 effectively reduced the proportion of subjects experiencing headache. Despite substantial nitric oxide release by NCX 701, which reduced arterial blood pressure, nitric oxide did not result in relevant inhibition of lipopolysaccharide-induced inflammation. ISRCTN registry number: ISTCTN-13,358,268.

•Milk chocolate does not alter LPS and zonulin levels in patients with MASH.•Dark chocolate reduces low-grade endotoxemia in patients with MASH.•Dark chocolate reduces zonulin levels in patients with MASH. [Display omitted] Cocoa may have prebiotic effects and improve gut barrier function. However, it remains unclear whether dark chocolate can reduce lipopolysaccharide (LPS) levels in patients with metabolic dysfunction–associated steatohepatitis (MASH). This study aims to evaluate the effect of dark chocolate compared to milk chocolate on endotoxemia in patients with MASH. Nineteen patients with MASH were randomly assigned in a crossover design to consume either 40 g/d of dark chocolate (>85% cocoa) or 40 g/d of milk chocolate (<35% cocoa) for 2 weeks to evaluate circulating levels of LPS and zonulin. A significant difference between treatments was observed in LPS (P = 0.04) and zonulin (P = 0.02) levels based on the ANOVA conducted on the crossover study data. Pairwise comparisons revealed that, compared to baseline, after 14 days of dark chocolate consumption, LPS levels decreased from 22 ± 4 to 19 ± 4 pg/dL (–15%), and zonulin levels decreased from 3.2 ± 0.9 to 2.5 ± 0.8 pg/mL (–20%). Linear correlation analysis indicated that the change (Δ) in LPS values before and after chocolate intake correlated with the change (Δ) in zonulin levels (R = 0.340, P = 0.03). This study demonstrates that dark chocolate reduces circulating levels of LPS and zonulin in patients with MASH.

Metabolic endotoxemia is a condition in which blood lipopolysaccharide (LPS) levels are elevated, regardless of the presence of obvious infection. It has been suggested to lead to chronic inflammation-related diseases such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), pancreatitis, amyotrophic lateral sclerosis, and Alzheimer’s disease. In addition, it has attracted attention as a target for the prevention and treatment of these chronic diseases. As metabolic endotoxemia was first reported in mice that were fed a high-fat diet, research regarding its relationship with diets has been actively conducted in humans and animals. In this review, we summarize the relationship between fat intake and induction of metabolic endotoxemia, focusing on gut dysbiosis and the influx, kinetics, and metabolism of LPS. We also summarize the recent findings about dietary factors that attenuate metabolic endotoxemia, focusing on the regulation of gut microbiota. We hope that in the future, control of metabolic endotoxemia using dietary factors will help maintain human health.

Calgranulin genes (S100A8, S100A9 and S100A12) play key immune response roles in inflammatory disorders, including cardiovascular disease. Long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) may have systemic and adipose tissue-specific anti-inflammatory and cardio-protective action. Interactions between calgranulins and the unsaturated fatty acid arachidonic acid (AA) have been reported, yet little is known about the relationship between calgranulins and the LC n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We explored tissue-specific action of calgranulins in the setting of evoked endotoxemia and n-3 PUFA supplementation. Expression of calgranulins in adipose tissue in vivo was assessed by RNA sequencing (RNASeq) before and after n-3 PUFA supplementation and evoked endotoxemia in the fenofibrate and omega-3 fatty acid modulation of endotoxemia (FFAME) Study. Subjects received n-3 PUFA (n = 8; 3600mg/day EPA/DHA) or matched placebo (n = 6) for 6-8 weeks, before completing an endotoxin challenge (LPS 0.6 ng/kg). Calgranulin genes were up-regulated post-LPS, with greater increase in n-3 PUFA (S100A8 15-fold, p = 0.003; S100A9 7-fold, p = 0.003; S100A12 28-fold, p = 0.01) compared to placebo (S100A8 2-fold, p = 0.01; S100A9 1.4-fold, p = 0.4; S100A12 5-fold, p = 0.06). In an independent evoked endotoxemia study, calgranulin gene expression correlated with the systemic inflammatory response. Through in vivo and in vitro interrogation we highlight differential responses in adipocytes and mononuclear cells during inflammation, with n-3 PUFA leading to increased calgranulin expression in adipose, but decreased expression in circulating cells. In conclusion, we present a novel relationship between n-3 PUFA anti-inflammatory action in vivo and cell-specific modulation of calgranulin expression during innate immune activation.

Background Systemic inflammation triggers a wide range of sickness symptoms, including bodily discomfort and affective symptoms, which are relevant to numerous health conditions. While extensive research in the placebo field demonstrates that positive expectations can improve symptoms, it remains unclear if interventions designed to augment positive treatment expectations can alleviate sickness symptoms in the context of immunomodulatory drug therapies. Methods In this randomized, controlled, fully balanced 2 × 2 factorial placebo design, N  = 124 healthy volunteers received either active ibuprofen treatment (600 mg per os) or placebo, combined with either a positive or neutral labeling of the treatment by the physician. All participants were intravenously injected with lipopolysaccharide (LPS, 0.8 ng per kg of body weight) as a translational model of inflammation-induced sickness symptoms. Primary outcomes were bodily and affective symptoms, assessed at baseline and up to 6 h after injection, along with a range of inflammatory markers. Results Ibuprofen substantially alleviated inflammation-induced symptoms. Positive labeling also improved bodily and affective symptoms of sickness, even in placebo-treated groups. Notably, positive labeling enhanced ibuprofen’s efficacy for alleviating affective symptoms, supporting that expectations can boost the efficacy of a highly effective anti-inflammatory treatment. However, labeling did not influence changes in physiological markers of inflammation, suggesting that the effects of expectations primarily act through mechanisms distinct from direct modulation of peripheral immune responses. Conclusions Placebo mechanisms engaged by physician communication can independently alleviate inflammation-induced symptom burden and enhance the efficacy of an anti-inflammatory medication. Results underscore the critical role of healthcare provider communication and pave the way for improved treatment strategies for conditions characterized by inflammation-driven symptoms. Trial registration DRKS00023088, registration website German Clinical Trials Register (date registered: 10/22/2020).

Abstract Rationale Fluid resuscitation is widely considered a life-saving intervention in septic shock; however, recent evidence has brought both its safety and efficacy in sepsis into question. Objectives In this study, we sought to compare fluid resuscitation with vasopressors with the use of vasopressors alone in a hyperdynamic model of ovine endotoxemia. Methods Endotoxemic shock was induced in 16 sheep, after which they received fluid resuscitation with 40 ml/kg of 0.9% saline or commenced hemodynamic support with protocolized noradrenaline and vasopressin. Microdialysis catheters were inserted into the arterial circulation, heart, brain, kidney, and liver to monitor local metabolism. Blood samples were recovered to measure serum inflammatory cytokines, creatinine, troponin, atrial natriuretic peptide, brain natriuretic peptide, and hyaluronan. All animals were monitored and supported for 12 hours after fluid resuscitation. Measurements and Main Results After resuscitation, animals that received fluid resuscitation required significantly more noradrenaline to maintain the same mean arterial pressure in the subsequent 12 hours (68.9 mg vs. 39.6 mg; P = 0.04). Serum cytokines were similar between groups. Atrial natriuretic peptide increased significantly after fluid resuscitation compared with that observed in animals managed without fluid resuscitation (335 ng/ml [256–382] vs. 233 ng/ml [144–292]; P = 0.04). Cross-sectional time-series analysis showed that the rate of increase of the glycocalyx glycosaminoglycan hyaluronan was greater in the fluid-resuscitated group over the course of the study (P = 0.02). Conclusions Fluid resuscitation resulted in a paradoxical increase in vasopressor requirement. Additionally, it did not result in improvements in any of the measured microcirculatory- or organ-specific markers measured. The increase in vasopressor requirement may have been due to endothelial/glycocalyx damage secondary to atrial natriuretic peptide–mediated glycocalyx shedding.

Sepsis is defined as life-threatening organ dysfunction caused by the dysregulated host response to infection. Despite serious mortality and morbidity, no sepsis-specific drugs exist. Endotoxemia is often used to model the hyperinflammation associated with early sepsis. This model classically uses lipopolysaccharide (LPS) from Gram-negative pathogens to activate the immune system, leading to hyperinflammation, microcirculatory disturbances and death. Other toxins may also be used to activate the immune system including Gram-positive peptidoglycan (PG) and lipoteichoic acid (LTA). In addition to these standard toxins, other bacterial components can induce inflammation. These molecules activate different signaling pathways and produce different physiological responses which can be taken advantage of for sepsis modeling. Endotoxemia modeling can provide information on pathways to inflammation in sepsis and contribute to preclinical drug development.