Gut Microbiome Is Related to Cognitive Impairment in Peritoneal Dialysis Patients.

Gut microbiota disturbances may influence cognitive function, increasing uremic toxins and inflammation in dialysis patients; therefore, we aimed to evaluate the association of the gut microbiota profile with cognitive impairment (CI) in patients on automated peritoneal dialysis (APD). In a cross-sectional study, cognitive function was evaluated using the Montreal Cognitive Assessment in 39 APD patients and classified as normal cognitive function and CI. The gut microbiota was analyzed using the 16S rRNA gene sequencing approach. All patients had clinical, biochemical and urea clearance evaluations. Eighty-two percent of patients were men, with a mean age of 47 ± 24 years and 11 (7-48) months on PD therapy; 64% had mild CI. Patients with CI were older (53 ± 16 vs. 38 ± 14, p = 0.006) and had a higher frequency of diabetes mellitus (56% vs. 21%, p = 0.04) and constipation (7% vs. 48%, p = 0.04) and lower creatinine concentrations (11.3 ± 3.7 vs. 14.9 ± 5.4, p = 0.02) compared to normal cognitive function patients. Patients with CI showed a preponderance of S24_7, Rikenellaceae, Odoribacteraceae, Odoribacter and Anaerotruncus, while patients without CI had a greater abundance of Dorea, Ruminococcus, Sutterella and Fusobacteria (LDA score (Log10) > 2.5; p < 0.05). After glucose and age adjustment, Odoribacter was still associated with CI. In conclusion, patients with CI had a different gut microbiota characterized by the higher abundance of indole-producing and mucin-fermenting bacteria compared to normal cognitive function patients.

Current Understanding of the Roles of Gut-Brain Axis in the Cognitive Deficits Caused by Perinatal Stress Exposure.

The term 'perinatal environment' refers to the period surrounding birth, which plays a crucial role in brain development. It has been suggested that dynamic communication between the neuro-immune system and gut microbiota is essential in maintaining adequate brain function. This interaction depends on the mother's status during pregnancy and/or the newborn environment. Here, we show experimental and clinical evidence that indicates that the perinatal period is a critical window in which stress-induced immune activation and altered microbiota compositions produce lasting behavioral consequences, although a clear causative relationship has not yet been established. In addition, we discuss potential early treatments for preventing the deleterious effect of perinatal stress exposure. In this sense, early environmental enrichment exposure (including exercise) and melatonin use in the perinatal period could be valuable in improving the negative consequences of early adversities. The evidence presented in this review encourages the realization of studies investigating the beneficial role of melatonin administration and environmental enrichment exposure in mitigating cognitive alteration in offspring under perinatal stress exposure. On the other hand, direct evidence of microbiota restoration as the main mechanism behind the beneficial effects of this treatment has not been fully demonstrated and should be explored in future studies.

Experimental Pulmonary Tuberculosis in the Absence of Detectable Brain Infection Induces Neuroinflammation and Behavioural Abnormalities in Male BALB/c Mice.

Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.

Fish oil-rich lipid emulsion modulates neuroinflammation and prevents long-term cognitive dysfunction after sepsis.

OBJECTIVES: Sepsis is a severe organic dysfunction caused by an infection that affects the normal regulation of several organ systems, including the central nervous system. Inflammation and oxidative stress play crucial roles in the development of brain dysfunction in sepsis. The aim of this study was to determine the effect of a fish oil (FO)-55-enriched lipid emulsion as an important anti-inflammatory compound on brain dysfunction in septic rats. METHODS: Wistar rats were subjected to sepsis by cecal ligation and perforation (CLP) or sham (control) and treated orally with FO (600 µL/kg after CLP) or vehicle (saline; sal). Animals were divided into sham+sal, sham+FO, CLP+sal and CLP+FO groups. At 24 h and 10 d after surgery, the hippocampus, prefrontal cortex, and total cortex were obtained and assayed for levels of interleukin (IL)-1ß and IL-10, blood-brain barrier permeability, nitrite/nitrate concentration, myeloperoxidase activity, thiobarbituric acid reactive species formation, protein carbonyls, superoxide dismutase and catalase activity, and brain-derived neurotrophic factor levels. Behavioral tasks were performed 10 d after surgery. RESULTS: FO reduced BBB permeability in the prefrontal cortex and total cortex of septic rats, decreased IL-1ß levels and protein carbonylation in all brain structures, and diminished myeloperoxidase activity in the hippocampus and prefrontal cortex. FO enhanced brain-derived neurotrophic factor levels in the hippocampus and prefrontal cortex and prevented cognitive impairment. CONCLUSIONS: FO diminishes the negative effect of polymicrobial sepsis in the rat brain by reducing inflammatory and oxidative stress markers.

Prebiotics and probiotics as potential therapy for cognitive impairment.

Cognitive functions, such as learning and memory, may be impaired during aging. Age-related cognitive impairment is associated with selective neuronal loss, oxidative changes that lead to microglia activation and neuroinflammation. In addition, it is associated to alteration reduction in trophic factors affecting neurogenesis and synaptic plasticity. In recent years, attention has been paid to the relationship between gut microbiota and brain. In aging, there is an alteration in microbiota, gut microbiota diversity is perturbed with an increase in pathogenic bacteria at the expense of beneficial ones. Dysbiosis may lead to chronic inflammation, and a decrease in bacteria metabolites such as short-chain fatty acids which have been related to an upregulation of neurotrophic factors. Supplementation with prebiotics and probiotics can modulate gut microbiota, returning it to a more physiological state; thus, they may be considered as a possible treatment for age-related cognitive impairment.

Neonatal infection leads to increased susceptibility to Aß oligomer-induced brain inflammation, synapse loss and cognitive impairment in mice.

Harmful environmental stimuli during critical stages of development can profoundly affect behavior and susceptibility to diseases. Alzheimer disease (AD) is the most frequent neurodegenerative disease, and evidence suggest that inflammatory conditions act cumulatively, contributing to disease onset. Here we investigated whether infection early in life can contribute to synapse damage and cognitive impairment induced by amyloid-ß oligomers (AßOs), neurotoxins found in AD brains. To this end, wild-type mice were subjected to neonatal (post-natal day 4) infection by Escherichia coli (1 × 104 CFU/g), the main cause of infection in low-birth-weight premature infants in the US. E. coli infection caused a transient inflammatory response in the mouse brain starting shortly after infection. Although infected mice performed normally in behavioral tasks in adulthood, they showed increased susceptibility to synapse damage and memory impairment induced by low doses of AßOs (1 pmol; intracerebroventricular) in the novel object recognition paradigm. Using in vitro and in vivo approaches, we show that microglial cells from E. coli-infected mice undergo exacerbated activation when exposed to low doses of AßOs. In addition, treatment of infected pups with minocycline, an antibiotic that inhibits microglial pro-inflammatory polarization, normalized microglial response to AßOs and restored normal susceptibility of mice to oligomer-induced cognitive impairment. Interestingly, mice infected with by E. coli (1 × 104 CFU/g) during adolescence (post-natal day 21) or adulthood (post-natal day 60) showed normal cognitive performance even in the presence of AßOs (1 pmol), suggesting that only infections at critical stages of development may lead to increased susceptibility to amyloid-ß-induced toxicity. Altogether, our findings suggest that neonatal infections can modulate microglial response to AßOs into adulthood, thus contributing to amyloid-ß-induced synapse damage and cognitive impairment.