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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.

•Higher sympathetic and lower parasympathetic activity 2 h after LPS-injection.•2 h Post-baseline difference in HEP amplitude lower in placebo compared to LPS group.•Reduced HEP amplitudes after 2 h in placebo group compared to LPS group.•ANS activity (HRV variables) correlated with HEP amplitudes under LPS. Interoception, or the perception of internal somatic states, is crucial for signaling the individual to take care of the body when needed. It enables behavioral adaptations to sickness states, which further impact autonomic nervous system (ANS) activity. Whether acute inflammation affects interoceptive processing and how this relates to sickness behavior remains unknown. Therefore, we investigated interoceptive processing in participants undergoing experimental endotoxemia. In neuroimaging research, heartbeat-evoked potentials (HEP) - defined as event-related potentials time-locked to electrocardiogram (ECG) R-waves during electroencephalogram (EEG) recordings - have emerged as a promising metric for cardiac interoceptive processing. We analyzed the effects of intravenous administration of lipopolysaccharide (LPS; 0.4 ng/kg) or placebo, on HEP amplitudes and ANS functioning in healthy, female participants (n = 52) during 8 min resting-state EEG and ECG recordings before and 2 h after injections. Our results showed increased cortisol and cytokine levels in the LPS group, along with increased sympathetic and decreased parasympathetic activity 2 h after injections compared to the placebo group. Placebo-injected participants exhibited lower post injection-baseline differences in HEP amplitudes in an early timeframe (255–455 ms), indicating lower HEPs 2 h after administrations. Moreover, post-injection HEP amplitudes differed between groups, suggesting that while participants in the placebo group showed altered HEP amplitudes after injection, HEPs remained unresponsive to LPS administration. These findings are discussed in the context of predictive processing, expectation violation and attention direction to external and interoceptive cues. Future research should further investigate the role of LPS dose and explore behavioral measures of interoception under experimental inflammation. [Display omitted]

Circadian variation in bodily functions has been shown to impact health in acute and chronic medical conditions. Little is known about the relationship between circadian rhythm and sepsis in humans. We aimed to investigate circadian variations in the host response in a human endotoxaemia model. A cross-over study, where 12 healthy young men received E. coli endotoxin (lipopolysaccharide, LPS) 0.3 ng/kg at 12 noon and, on another day, at 12 midnight. Blood samples were analysed for pro- and anti-inflammatory cytokines: tumour-necrosis factor (TNF)-alpha, soluble TNF receptors (sTNF-R)-1 and -2, interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, and IL-10 as well as YKL-40 and the oxidative stress markers malondialdehyde (MDA), ascorbic acid (AA) and dehydroascorbic acid (DHA) before and at 2, 4, 6 and 8 hours after LPS administration. The levels of MDA and IL-10 where significantly higher during the day time (P<0.05) whereas levels of TNF-alpha, sTNF-RI, sTNF-RII, IL-1Ra, IL-6, and YKL-40 were higher (P<0.01 for all comparisons) during the night time. No significant differences were seen in the levels of AA and DHA. A day-night difference in the acute phase response to endotoxaemia exists in healthy volunteers with a more pronounced inflammatory response during the night time. This circadian difference in the response to endotoxaemia may play an important role in the clinical setting and should be investigated further.

The autonomic nervous system (ANS) plays an important role in regulating the metabolic homeostasis and controlling immune function. ANS alterations can be detected by reduced heart rate variability (HRV) in conditions like diabetes and sepsis. We determined the effects of experimental conditions mimicking inflammation and hyperlipidemia on HRV and heart rate (HR) in relation to the immune, metabolic, and hormonal responses resulting from these interventions. Sixteen lean healthy subjects received intravenous (i.v.) low-dose endotoxin (lipopolysaccharide [LPS]), i.v. fat, oral fat, and i.v. glycerol (control) for 6 hours, during which immune, metabolic, hormonal, and five HRV parameters (pNN50, RMSSD, low-frequency (LF) and high-frequency (HF) power, and LF/HF ratio) were monitored and energy metabolism and insulin sensitivity (M-value) were assessed. LPS infusion induced an increase (AUC) in HR and LF/HF ratio and decline in pNN50 and RMSSD, while oral fat resulted in elevated HR and a transient (hours 1-2) decrease in pNN50, RMSSD, and HF power. During LPS infusion, ΔIL-1ra levels and ΔIL-1ra and ΔIL-1ß gene expression correlated positively with ΔLF/HF ratio and inversely with ΔRMSSD. During oral fat intake, ΔGLP-1 tended to correlate positively with ΔHR and inversely with ΔpNN50 and ΔRMSSD. Following LPS infusion, lipid oxidation correlated positively with HR and inversely with pNN50 and RMSSD, whereas HRV was not related to M-value. In conclusion, suppression of vagal tone and sympathetic predominance during endotoxemia are linked to anti-inflammatory processes and lipid oxidation but not to insulin resistance, while weaker HRV changes in relation to the GLP-1 response are noted during oral fat load. ClinicalTrials.gov NCT01054989.

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. In this study, we sought to compare fluid resuscitation with vasopressors with the use of vasopressors alone in a hyperdynamic model of ovine endotoxemia. 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. 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). 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-associated acute kidney injury (AKI) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AKI are therefore less clear. Here we have shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells. Tubular mitochondria were swollen, and their function was impaired. Expression profiling showed that oxidative phosphorylation genes were selectively suppressed during sepsis-associated AKI and reactivated when global function was normalized. PPARγ coactivator-1α (PGC-1α), a major regulator of mitochondrial biogenesis and metabolism, not only followed this pattern but was proportionally suppressed with the degree of renal impairment. Furthermore, tubular cells had reduced PGC-1α expression and oxygen consumption in response to TNF-α; however, excess PGC-1α reversed the latter effect. Both global and tubule-specific PGC-1α-knockout mice had normal basal renal function but suffered persistent injury following endotoxemia. Our results demonstrate what we believe to be a novel mechanism for sepsis-associated AKI and suggest that PGC-1α induction may be necessary for recovery from this disorder, identifying a potential new target for future therapeutic studies.

Abstract Study Objectives: Intermittent hypoxia (IH) mimicking obstructive sleep apnea (OSA) significantly modifies gut microbiota in mice. However, whether these IH-induced gut microbiome changes are reversible after restoring normal oxygenation (the equivalent of effective OSA therapy) is unknown. The aim of this study was to investigate gut microbiota composition and circulating endotoxemia after a post-IH normoxic period in a mouse model of OSA. Methods: Ten mice were subjected to IH (40 sec 21% O2-20 sec 5% O2) for 6 h/day for 6 w and 10 mice breathing normoxic air (NM) were used as controls. After exposures, both groups were subjected to 6 w in normoxia. Microbiome composition of fecal samples was determined by 16S ribosomal RNA (rRNA) pyrosequencing. Bioinformatic analysis was performed by Quantitative Insights into Microbial Ecology. Plasma lipopolysaccharide (LPS) levels were measured by endotoxin assay. Results: After normoxic recovery, the Chao and Shannon indices of each group suggested similar bacterial richness and diversity. 16S rRNA pyrosequencing analysis showed that IH-exposed mice had a significant decrease in the abundance of Bacteroidetes and a significant increase of Firmicutes and Deferribacteres compared to the NM group. After normoxic recovery, circulating LPS concentrations were higher in the IH group (P < 0.009). Moreover, the IH group showed a negative and significant correlation between the abundance of Lactobacillus and Ruminococcus and significant positive correlations between the abundance of Mucispirillum and Desulfovibrio and plasma LPS levels, respectively. Conclusions: Even after prolonged normoxic recovery after IH exposures, gut microbiota and circulating endotoxemia remain negatively altered, suggesting that potential benefits of OSA treatment for reversing OSA-induced changes in gut microbiota may either require a longer period or alternative interventions.

The glycocalyx is a layer of proteoglycans and complex carbohydrates that lines the endothelial cell surface in blood vessels. Schmidt et al . show that in mouse models of sepsis, lung inflammation and injury depend on glycocalyx degradation, which increases neutrophil access to endothelial adhesion molecules. The authors also provide data indicating the potential relevance of this mechanism of lung injury to humans with sepsis. Sepsis, a systemic inflammatory response to infection, commonly progresses to acute lung injury (ALI), an inflammatory lung disease with high morbidity. We postulated that sepsis-associated ALI is initiated by degradation of the pulmonary endothelial glycocalyx, leading to neutrophil adherence and inflammation. Using intravital microscopy, we found that endotoxemia in mice rapidly induced pulmonary microvascular glycocalyx degradation via tumor necrosis factor-α (TNF-α)-dependent mechanisms. Glycocalyx degradation involved the specific loss of heparan sulfate and coincided with activation of endothelial heparanase, a TNF-α–responsive, heparan sulfate–specific glucuronidase. Glycocalyx degradation increased the availability of endothelial surface adhesion molecules to circulating microspheres and contributed to neutrophil adhesion. Heparanase inhibition prevented endotoxemia-associated glycocalyx loss and neutrophil adhesion and, accordingly, attenuated sepsis-induced ALI and mortality in mice. These findings are potentially relevant to human disease, as sepsis-associated respiratory failure in humans was associated with higher plasma heparan sulfate degradation activity; moreover, heparanase content was higher in human lung biopsies showing diffuse alveolar damage than in normal human lung tissue.

In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiacsuperior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity.

Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice Patrice D. Cani 1 2 , Rodrigo Bibiloni 3 , Claude Knauf 2 , Aurélie Waget 2 , Audrey M. Neyrinck 1 , Nathalie M. Delzenne 1 and Rémy Burcelin 2 1 Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Université catholique de Louvain, Brussels, Belgium 2 Rangueil Institute of Molecular Medicine, Toulouse, France 3 Nestlé Research Center, Department of Nutrition and Health, Lausanne, Switzerland Corresponding author: Prof. Rémy Burcelin, Rangueil Institute of Molecular Medicine, I 2 MR, IFR31, Toulouse, France. E-mail: burcelin{at}toulouse.inserm.fr Abstract OBJECTIVE— Diabetes and obesity are characterized by a low-grade inflammation whose molecular origin is unknown. We previously determined, first, that metabolic endotoxemia controls the inflammatory tone, body weight gain, and diabetes, and second, that high-fat feeding modulates gut microbiota and the plasma concentration of lipopolysaccharide (LPS), i.e., metabolic endotoxemia. Therefore, it remained to demonstrate whether changes in gut microbiota control the occurrence of metabolic diseases. RESEARCH DESIGN AND METHODS— We changed gut microbiota by means of antibiotic treatment to demonstrate, first, that changes in gut microbiota could be responsible for the control of metabolic endotoxemia, the low-grade inflammation, obesity, and type 2 diabetes and, second, to provide some mechanisms responsible for such effect. RESULTS— We found that changes of gut microbiota induced by an antibiotic treatment reduced metabolic endotoxemia and the cecal content of LPS in both high-fat–fed and ob/ob mice. This effect was correlated with reduced glucose intolerance, body weight gain, fat mass development, lower inflammation, oxidative stress, and macrophage infiltration marker mRNA expression in visceral adipose tissue. Importantly, high-fat feeding strongly increased intestinal permeability and reduced the expression of genes coding for proteins of the tight junctions. Furthermore, the absence of CD14 in ob/ob CD14 − / − mutant mice mimicked the metabolic and inflammatory effects of antibiotics. CONCLUSIONS— This new finding demonstrates that changes in gut microbiota controls metabolic endotoxemia, inflammation, and associated disorders by a mechanism that could increase intestinal permeability. It would thus be useful to develop strategies for changing gut microbiota to control, intestinal permeability, metabolic endotoxemia, and associated disorders. DGGE, denaturing gradient gel electrophoresis FITC, fluorescein isothiocyanate IL, interleukin LPS, lipopolysaccharide MDA, malondialdehyde MCP, monocyte chemotactic protein PAI-1, plasminogen activator inhibitor 1 RPL19, ribosomal protein L19 TBARS, thiobarbituric acid reactive substances TNF-α, tumor necrosis factor-α ZO-1, zonula occludens-1 Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 27 February 2008. DOI: 10.2337/db07-1403. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1403 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 25, 2008. Received October 3, 2007. DIABETES