Protective effects of fecal microbiota transplantation in sepsis are independent of the modulation of the intestinal flora.

OBJECTIVE: The aim of this study was to investigate the protective effects of probiotics and fecal transplantation on inflammatory and oxidative parameters in the intestines of two rat models of sepsis. METHODS: Rats were treated with prebiotics, probiotics, or symbiotics and exposed to lipopolysaccharide (LPS) or zymosan after 15 d to induce endotoxemia. Oxidative damage and inflammation were analyzed, and histologic examination of the intestinal tissue was performed. Fecal microbiota transplantation (FMT) was carried out in LPS- and zymosan-induced rat models of sepsis. RESULTS: Supplementation with symbiotics for 15 d effectively reduced the inflammatory parameters compared with supplementation for 7 d. Probiotics, prebiotics, and symbiotics exerted different effects on the evaluated parameters. In general, Lactobacillus rhamnosus and L. casei exerted better local protective effects. Evaluation of the role of the intestinal microbiota through FMT revealed its protective effects irrespective of the previous treatment with probiotics. CONCLUSION: Probiotic strains significantly differ among themselves and exert different effects on the host's health. Symbiotics and FMT could offer additional immunomodulatory benefits to drug therapy, thus serving as a new therapeutic alternative in pediatric patients with sepsis.

Anxious phenotype potentiates damage in peripheral organs of animals submitted to sepsis / Fenótipo ansioso potencializa danos em órgãos periféricos de animais submetidos à sepse

Introduction: Anxiety and sepsis are important public health problems that present high morbidity, mortality and significant economic repercussions. The present study investigated the presence of oxidative damage in peripheral organs in two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with foot shock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]) associated to sepsis. Methods: Animals were subject to sepsis by the cecal ligation and perforation (CLP) or sham operated. 24 hours and 10 days after sepsis animals were euthanized and removed adrenal, kidney, lung, serum, heart for the determination of carbonyl protein levels and adrenal for check weight this structure. Results: Sepsis increased oxidative damage in different systemic organs, included serum. There wasn't a significant increase in protein carbonyls in heart and kidney. Anxious phenotype potentiates this damage. Conclusion: These findings suggest that an anxious phenotype plus sepsis may induce more pronounced organs damage, and promote more alterations in the HPA axis. These findings may help to explain, at least in part, the common point of the mechanisms involved with the pathophysiology of sepsis and anxiety.

Introdução: Ansiedade e sepse são importantes problemas de saúde pública que apresentam alta morbidade, mortalidade e repercussões econômicas significativas. O presente estudo investigou a presença de dano oxidativo em órgãos periféricos em duas linhagens de animais criados para respostas de alta (CHF) e baixa (CLF) ansiedade associado a sepse. Métodos: Os animais foram submetidos a sham (controle) ou sepse por ligação e perfuração cecal (CLP). 24 horas e 10 dias após a sepse os animais foram eutanasiados e estruturas foram removidas: adrenal, rim, pulmão, soro e coração para a determinação dos níveis de proteínas carboniladas e adrenal para verificação do peso dessa estrutura. Resultados: A sepse aumentou o dano oxidativo em diferentes órgãos sistêmicos, incluindo o soro. Não houve um aumento significativo de proteínas carbonilas no coração e nos rins. Fenótipo ansioso potencializa esse dano. Conclusão: Esses achados sugerem que um fenótipo ansioso associado a sepse pode induzir dano mais pronunciado aos órgãos e promover mais alterações no eixo HPA. Esses achados podem ajudar a explicar, pelo menos em parte, o ponto comum dos mecanismos envolvidos na fisiopatologia da sepse e da ansiedade.

Receptor for advanced glycation end products mediates sepsis-triggered amyloid-ß accumulation, Tau phosphorylation, and cognitive impairment.

Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-ß peptide (Aß) and Ser-202-phosphorylated Tau (p-TauSer-202) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1ß, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, Nϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aß and p-TauSer-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aß and p-TauSer-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation.

The impact of chronic mild stress on long-term depressive behavior in rats which have survived sepsis.

The present study was created to investigate the effects of chronic mild stress (CMS) on the depressive behavior and neurochemical parameters of rats that were subjected to sepsis. Wistar rats were subjected to a CMS protocol, and sepsis was induced by cecal ligation and perforation (CLP). The animals were then divided into 4 separate groups; Control + Sham (n = 20), Control + CLP (n = 30), CMS + Sham (n = 20) and CMS + CLP (n = 30). Body weight, food and water intake and mortality were measured on a daily basis for a period of 10 days after the induction of sepsis. Locomotor activity, splash and forced swimming tests were performed ten days after CLP. At the end of the test period, the animals were euthanized, and the prefrontal cortex and hippocampus were removed to determine the levels of cytokines and oxidative damage. Our results show that there was no significant interaction between CMS and CLP in relation to locomotor activity and the forced swimming test. However, we did observe a significant decrease in total grooming time in the Control + CLP and CMS + Sham groups, with the CMS + CLP group showing behavior similar to that of the control animals. This was found to be related to a decrease in the levels of brain cytokines, and not to oxidative damage parameters. Collectively, our results suggest that a previous stress caused by CMS can protect the brain against the systemic acute and severe stress elicited by sepsis.

Estresse oxidativo e parâmetros inflamatórios em pacientes com doença celíaca / Oxidative stress and inflammatory parameters inpatients presenting celiac disease

Objetivos: Determinar a presença de estresse oxidativo e inflamação no intestino de pacientes com doença celíaca. Método: Foi realizado estudo transversal que incluiu pacientes submetidos à endoscopia gastrointestinal. A população do estudo consistiu em 24 casos e 26 controles. Foram medidos os níveis duodenais de proteínas carboniladas, espécies reativas ao ácido tiobarbitúrico, bem como catalase (CAT), superóxido dismutase (SOD). Também foram determinados os níveis intestinais de interleucina (IL) 6, 10 e 8. A classificação de Marsh foi registrada e utilizada como parâmetro de gravidade da doença. Resultados: Tanto a IL-6 como a IL-10, mas não a IL8, aumentaram nos pacientes com doença celíaca quando comparados com indivíduos saudáveis. Os parâmetros de dano oxidativo foram aumentados,enquanto que as defesas antioxidantes foram reduzidas em nossa amostra. Os níveis de IL6 ea atividade do SOD foram relacionados com a pontuação de Marsh. Conclusões: Diferentes marcadores de inflamação e estresse oxidativo estão alterados no intestino de pacientes com doença celíaca, e alguns deles estão relacionados à gravidade da doença.(AU)

Objectives: Determine the presence of oxidative stress and inflammation in the gut of patients with celiac disease. Methods: Transversal study that included patients undergoing upper gastrointestinal endoscopy was performed. The study population consisted 24 cases and 26 controls. The duodenal levels of protein carbonyls, thiobarbituric acid reactive species, as well as catalase, superoxide dismutase (SOD) activities were measured. Gut levels of interleukin (IL) 6, 10 and 8 were also determined.The Marsh classification was recorded and used as a parameter of disease severity. Results: Both IL-6 and IL-10, but not IL8, were increased in celiac disease patients when compared to healthy individuals. Oxidative damage parameters were increased while antioxidant defenses were decreased in our sample. Both IL6 levels and SOD activity were related to Marsh score. Conclusions: Different markers of inflammation and oxidative stress are altered in the gut of celiac disease patients, and some of them are related to disease severity.(AU)

Polarization of microglia and its role in bacterial sepsis.

Microglial polarization in response to brain inflammatory conditions is a crescent field in neuroscience. However, the effect of systemic inflammation, and specifically sepsis, is a relatively unexplored field that has great interest and relevance. Sepsis has been associated with both early and late harmful events of the central nervous system, suggesting that there is a close link between sepsis and neuroinflammation. During sepsis evolution it is supposed that microglial could exert both neurotoxic and repairing effects depending on the specific microglial phenotype assumed. In this context, here it was reviewed the role of microglial polarization during sepsis-associated brain dysfunction.

Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex.

Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures.

Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma.

Asthma represents a public health problem and traditionally is classified as an atopic disease, where the allergen can induce clinical airway inflammation, bronchial hyperresponsiveness, and reversible obstruction of airways. Studies have demonstrated the presence of T-helper 2 lymphocytes in the lung of patients with asthma. These cells are involved in cytokine production that regulates immunoglobulin synthesis. Recognizing that T cell interaction with antigens/allergens is key to the development of inflammatory diseases, the aim of this study is to evaluate the anti-inflammatory potential of cannabidiol (CBD) in this setting. Asthma was induced in 8-week-old Wistar rats by ovalbumin (OVA). In the last 2 days of OVA challenge animals received CBD (5 mg/kg, i.p.) and were killed 24 hours after. The levels of IL-4, IL-5, IL-13, IL-6, IL-10, and TNF-α were determinate in the serum. CBD treatment was able to decrease the serum levels of all analyzed cytokines except for IL-10 levels. CBD seems to be a potential new drug to modulate inflammatory response in asthma.

CD40-CD40 Ligand Pathway is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis.

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40-CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40-CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40-CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40-CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis.