Inflammasome Signaling Regulates the Microbial-Neuroimmune Axis and Visceral Pain in Mice.

Interactions between the intestinal microbiota, immune system and nervous system are essential for homeostasis in the gut. Inflammasomes contribute to innate immunity and brain-gut interactions, but their role in microbiota-neuro-immune interactions is not clear. Therefore, we investigated the effect of the inflammasome on visceral pain and local and systemic neuroimmune responses after antibiotic-induced changes to the microbiota. Wild-type (WT) and caspase-1/11 deficient (Casp1 KO) mice were orally treated for 2 weeks with an antibiotic cocktail (Abx, Bacitracin A and Neomycin), followed by quantification of representative fecal commensals (by qPCR), cecal short chain fatty acids (by HPLC), pathways implicated in the gut-neuro-immune axis (by RT-qPCR, immunofluorescence staining, and flow cytometry) in addition to capsaicin-induced visceral pain responses. Abx-treatment in WT-mice resulted in an increase in colonic macrophages, central neuro-immune interactions, colonic inflammasome and nociceptive receptor gene expression and a reduction in capsaicin-induced visceral pain. In contrast, these responses were attenuated in Abx-treated Casp1 KO mice. Collectively, the data indicate an important role for the inflammasome pathway in functional and inflammatory gastrointestinal conditions where pain and alterations in microbiota composition are prominent.

Impact of Chronic Hypertension and Antihypertensive Treatment on Adverse Perinatal Outcomes: Systematic Review and Meta-Analysis.

Background Maternal chronic hypertension is associated with adverse pregnancy outcomes. Previous studies examined the association between either chronic hypertension or antihypertensive treatment and adverse pregnancy outcomes. We aimed to synthesize the evidence on the effect of chronic hypertension/antihypertensive treatment on adverse pregnancy outcomes. Methods and Results Medline/PubMed, EMBASE, and Web of Science were searched; we included observational studies and assessed the effect of race/ethnicity, where possible, following a registered protocol (CRD42019120088). Random-effects meta-analyses were used. A total of 81 studies were identified on chronic hypertension, and a total of 16 studies were identified on antihypertensive treatment. Chronic hypertension was associated with higher odds of preeclampsia (adjusted odd ratio [aOR], 5.43; 95% CI, 3.85-7.65); cesarean section (aOR, 1.87; 95% CI, 1.6-2.16); maternal mortality (aOR, 4.80; 95% CI, 3.04-7.58); preterm birth (aOR, 2.23; 95% CI, 1.96-2.53); stillbirth (aOR, 2.32; 95% CI, 2.22-2.42); and small for gestational age (SGA) (aOR, 1.96; 95% CI, 1.6-2.40). Subgroup analyses indicated that maternal race/ethnicity does not influence the observed associations. Women with chronic hypertension on antihypertensive treatment (versus untreated) had higher odds of SGA (aOR, 1.86; 95% CI, 1.38-2.50). Conclusions Chronic hypertension is associated with adverse pregnancy outcomes, and these associations appear to be independent of maternal race/ethnicity. In women with chronic hypertension, those on treatment had a higher risk of SGA, although the number of studies was limited. This could result from a direct effect of the treatment or because severe hypertension during pregnancy is a risk factor for SGA and women with severe hypertension are more likely to be treated. The effect of antihypertensive treatment on SGA needs to be further tested with large randomized controlled trials.

Chronic intrahippocampal interleukin-1ß overexpression in adolescence impairs hippocampal neurogenesis but not neurogenesis-associated cognition.

Both neuroinflammation and adult hippocampal neurogenesis (AHN) are implicated in many neurodegenerative disorders as well as in neuropsychiatric disorders, which often become symptomatic during adolescence. A better knowledge of the impact that chronic neuroinflammation has on the hippocampus during the adolescent period could lead to the discovery of new therapeutics for some of these disorders. The hippocampus is particularly vulnerable to altered concentrations of the pro-inflammatory cytokine interleukin-1ß (IL-1ß), with elevated levels implicated in the aetiology of neurodegenerative disorders such as Alzheimer's and Parkinson's, and stress-related disorders such as depression. The effect of acutely and chronically elevated concentrations of hippocampal IL-1ß have been shown to reduce AHN in adult rodents. However, the effect of exposure to chronic overexpression of hippocampal IL-1ß during adolescence, a time of increased vulnerability, hasn't been fully interrogated. Thus, in this study we utilized a lentiviral approach to induce chronic overexpression of IL-1ß in the dorsal hippocampus of adolescent male Sprague Dawley rats for 5 weeks, during which time its impact on cognition and hippocampal neurogenesis were examined. A reduction in hippocampal neurogenesis was observed along with a reduced level of neurite branching on hippocampal neurons. However, there was no effect of IL-1ß overexpression on performance in pattern separation, novel object recognition or spontaneous alternation in the Y maze. Our study has highlighted that chronic IL-1ß overexpression in the hippocampus during the adolescent period exerts a negative impact on neurogenesis independent of cognitive performance, and suggests a degree of resilience of the adolescent hippocampus to inflammatory insult.

Chronic interleukin-1ß in the dorsal hippocampus impairs behavioural pattern separation.

Understanding the long-term consequences of chronic inflammation in the hippocampus may help to develop therapeutic targets for the treatment of cognitive disorders related to stress, ageing and neurodegeneration. The hippocampus is particularly vulnerable to increases in the pro-inflammatory cytokine interleukin-1ß (IL-1ß), a mediator of neuroinflammation, with elevated levels implicated in the aetiology of neurodegenerative diseases such as Alzheimer's and Parkinson's, and in stress-related disorders such as depression. Acute increases in hippocampal IL-1ß have been shown to impair cognition and reduce adult hippocampal neurogenesis, the birth of new neurons. However, the impact of prolonged increases in IL-1ß, as evident in clinical conditions, on cognition has not been fully explored. Therefore, the present study utilized a lentiviral approach to induce long-term overexpression of IL-1ß in the dorsal hippocampus of adult male Sprague Dawley rats and examine its impact on cognition. Following three weeks of viral integration, pattern separation, a process involving hippocampal neurogenesis, was impaired in IL-1ß-treated rats in both object-location and touchscreen operant paradigms. This was coupled with a decrease in the number and neurite complexity of immature neurons in the hippocampus. Conversely, tasks involving the hippocampus, but not sensitive to disruption of hippocampal neurogenesis, including spontaneous alternation, novel object and location recognition were unaffected. Touchscreen operant visual discrimination, a cognitive task involving the prefrontal cortex, was largely unaffected by IL-1ß overexpression. In conclusion, these findings suggest that chronically elevated IL-1ß in the hippocampus selectively impairs pattern separation. Inflammatory-mediated disruption of adult hippocampal neurogenesis may contribute to the cognitive decline associated with neurodegenerative and stress-related disorders.