The gut microbiota influences blood-brain barrier permeability in mice

Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life

Taurine blunts doxorubicin cardiotoxicity: chronic and acute effects

Aim. To study the functional statement of the isolated heart inherent to doxorubicin cardiotoxicity under the chronic and acute action of taurine. Material and methods. Doxorubicin (Dx) cardiotoxicity manifested by heart failure development was reproduced classically by anthracycline i/p administration in rats in cumulative dose of 16 mg/kg (4 mg/kg four times during 2 weeks) – Dx series. Series with chronic action of taurine (Tr) included rats receiving this aminoacid daily per os during Dx administration (100 mg/kg) – Dx + Tr series. Rats of both series were sacrificed by euthanasia and the isolated heart was perfused by Krebs solution according to Langendorff (isovolumic heart) and Neely-Rovetto (working heart) methods in conditions of diverse hemodynamic and neuroendocrine efforts applying. Acute action of taurine was studied during its infusion in the perfusate of isolated hearts in final concentration of 40 µM. The hearts of intact rats constituted the control series. Results. Chronic action of taurine has identified certain important functional benefits, the most important being underlined beneath. The first, taurine reversed the negative inotropic effect of isolated heart on endothelin-1 (ET-1) action (10-7 M), detected in Dx series and manifested by both systolic pressure of left ventricle (LV) and cardiac output fall by about 9,1%. Taurine assured increase of these indices during ET-1 stimulation. The second, Tr notably improved both isovolumic relaxation and contraction of myocardium exhibited by significant enhancement of Veragut index (118,6 ± 9,6 vs 94,8 ± 6,5 1/sec), +dP/dPmax (8389 ± 445 vs 7216 ± 363 mm Hg/sec) and -dP/dTmax (7526 ±  378 vs 5684 ± 322 mm Hg/sec) during efforts with volume and resistance. The third, Tr significantly decreased LV end diastolic pressure (LVSDP) when coronary pressure of isovolumic heart elevated by 50% (from 80 up to 120 cm H20 column): 16,2 ± 1,2 vs 18,8 ± 1,4 mm Hg. Acute Tr action manifested by: (i) significant LVSDP diminution during 30 min of ischemia (52,4 ± 3,1 vs 63,7 ± 4,4 mm Hg) and on 45th min of reperfusion (18,3 ± 1,3 vs 22,8 ± 1,4 mm Hg), (ii) increased time of LV extrasystole appearance when the glucose content of Krebs solution was reduced by 50% (28,6 ± 2,8 vs 22,5 ± 2,4 min), and (iii) increased time of LV tachyarrhythmia appearance when the potassium content of Krebs solution raised up to 6,5 meq/L (9,2 ± 0,5 vs 6,9 ± 0,3 min). Conclusion. Taurine, a natural calcium modulator of the heart, notably improves functional reserves of the myocardium exposed to cardiotoxic action of Dx, and could be seen as a relevant remedy of primary and secondary prophylaxis of Dx induced heart failure in oncologic patients

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients

Background: The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions. Results: Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected. Conclusion: These results demonstrate that age-associated shifts of the microbiota have an impact on protein expression and key functions of the CNS. Furthermore, these results highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions and the declining quality of life in the elderly

Estrogen-dependent regulation of sodium/hydrogen exchanger-3 (NHE3) expression via estrogen receptor β in proximal colon of pregnant mice

Although constipation is very common during pregnancy, the exact mechanism is unknown. We hypothesized that the involvement of estrogen receptor (ER) in the regulation of electrolyte transporter in the colon leads to constipation. In this study, the intestines of normal female ICR mouse and pregnant mice were examined for the expression of ERβ and ERβ by immunohistochemistry and in situ hybridization. ERα, but not ERα, was expressed in surface epithelial cells of the proximal, but not distal, colon on pregnancy days 10, 15, and 18, but not day 5, and the number of ERα-positive cells increased signiWcantly during pregnancy. Expression of NHE3, the gene that harbors estrogen response element, examined by immunohistochemistry and western blotting, was localized in the surface epithelial cells of the proximal colon and increased in parallel with ERβ expression. In ovariectomized mice, NHE3 expression was only marginal and was up-regulated after treatment with 17- estradiol (E2), but not E 2 + ICI 182,780 (estrogen receptor antagonist). Moreover, knock-down of ERβ expression by electroporetically transfected siRNA resulted in a signiWcant reduction of NHE3 expression. These results indicate that ERβ regulates the expression of NHE3 in the proximal colon of pregnant mice through estrogen action, suggesting the involvement of increased sodium absorption by up-regulated NHE3 in constipation during pregnancy

Microbiota and neurologic diseases : potential effects of probiotics

Background: The microbiota colonizing the gastrointestinal tract have been associated with both gastrointestinal and extra-gastrointestinal diseases. In recent years, considerable interest has been devoted to their role in the development of neurologic diseases, as many studies have described bidirectional communication between the central nervous system and the gut, the so-called "microbiota-gut-brain axis". Considering the ability of probiotics (i.e., live non-pathogenic microorganisms) to restore the normal microbial population and produce benefits for the host, their potential effects have been investigated in the context of neurologic diseases. The main aims of this review are to analyse the relationship between the gut microbiota and brain disorders and to evaluate the current evidence for the use of probiotics in the treatment and prevention of neurologic conditions. Discussion: Overall, trials involving animal models and adults have reported encouraging results, suggesting that the administration of probiotic strains may exert some prophylactic and therapeutic effects in a wide range of neurologic conditions. Studies involving children have mainly focused on autism spectrum disorder and have shown that probiotics seem to improve neuro behavioural symptoms. However, the available data are incomplete and far from conclusive. Conclusions: The potential usefulness of probiotics in preventing or treating neurologic diseases is becoming a topic of great interest. However, deeper studies are needed to understand which formulation, dosage and timing might represent the optimal regimen for each specific neurologic disease and what populations can benefit. Moreover, future trials should also consider the tolerability and safety of probiotics in patients with neurologic diseases

Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism.

The ligand-induced transcription factor, aryl hydrocarbon receptor (AhR) is known for its capacity to tune adaptive immunity and xenobiotic metabolism-biological properties subject to regulation by the indigenous microbiome. The objective of this study was to probe the postulated microbiome-AhR crosstalk and whether such an axis could influence metabolic homeostasis of the host. Utilising a systems-biology approach combining in-depth 1H-NMR-based metabonomics (plasma, liver and skeletal muscle) with microbiome profiling (small intestine, colon and faeces) of AhR knockout (AhR-/-) and wild-type (AhR+/+) mice, we assessed AhR function in host metabolism. Microbiome metabolites such as short-chain fatty acids were found to regulate AhR and its target genes in liver and intestine. The AhR signalling pathway, in turn, was able to influence microbiome composition in the small intestine as evident from microbiota profiling of the AhR+/+ and AhR-/- mice fed with diet enriched with a specific AhR ligand or diet depleted of any known AhR ligands. The AhR-/- mice also displayed increased levels of corticosterol and alanine in serum. In addition, activation of gluconeogenic genes in the AhR-/- mice was indicative of on-going metabolic stress. Reduced levels of ketone bodies and reduced expression of genes involved in fatty acid metabolism in the liver further underscored this observation. Interestingly, exposing AhR-/- mice to a high-fat diet showed resilience to glucose intolerance. Our data suggest the existence of a bidirectional AhR-microbiome axis, which influences host metabolic pathways

Bifidobacterium longum and Lactobacillus helveticus synergistically suppress stress-related visceral hypersensitivity through hypothalamic-pituitary-adrenal axis modulation

Visceral pain and hypothalamic-pituitary-adrenal axis (HPA) dysregulation is a common characteristic in irritable bowel syndrome (IBS) patients. Previously, we reported that a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) prevents chronic stress-mediated brain function abnormalities by attenuating the HPA axis response. Here, we compared the effect between different probiotic treatments on the perception of visceral pain during colorectal distension (CRD) following a chronic stress and the consequences to the activity of the HPA axis. After a 2-week treatment with a combined probiotic formulation, or L. helveticus or B. longum alone in stressed mice, the visceral pain in response to CRD was recorded. The expression of glucocorticoid receptors was determined in the different brain areas involved in the stress response (hypothalamus, hippocampus, and prefrontal cortex). The plasma levels of stress hormones were also measured. A pretreatment using the combination of probiotic formulation significantly reduces the chronic stress-induced visceral hypersensitivity respectively at 0.06, 0.08, and 0.10 mL CRD volume. However, a single probiotic (B. longum or L. helveticus) administration is less effective in reducing visceral pain in stressed mice. Moreover, the expression of the glucocorticoid receptor mRNA was consistently up-regulated in several brain areas after pretreatment with a combined probiotic, which correlated with the normalization of stress response compared to the inconsistent effects of a single probiotic. The combination of L. helveticus and B. longum is more effective in regulating glucocorticoid negative feedback on the HPA axis than probiotic alone and subsequently in treating stress-induced visceral pain