Nerve growth factor mediates alterations of colonic sensitivity and mucosal barrier induced by neonatal stress in rats

International audienc

Intestinal Flora Is Involved in the Physiologic Regulation of Colonic Paracellular Permeability: Role of Proteinase-Activated Receptor (PAR)-2

Intestinal Flora Is Involved in the Physiologic Regulation of Colonic Paracellular Permeability: Role of Proteinase-Activated Receptor (PAR)-2. Digestive Disease Week / 105th Annual meeting of the AG

Proteinase-activated receptor-4 evoked colorectal analgesia in mice: an endogenously activated feed-back loop in visceral inflammatory pain

Background Activation of proteinase-activated receptor-4 (PAR-4) from the colonic lumen has an antinociceptiveeffect to colorectal distension (CRD) in micein basal conditions. We aimed to determine thefunctional localization of the responsible receptorsand to test their role in two different hyperalgesiamodels. Methods Mice received PAR-4 activatingpeptide (PAR-4-AP, AYPGKF-NH2) or vehicle intraperitoneally(IP), and abdominal EMG response toCRD was measured. The next group received PAR-4-AP intracolonically (IC) with or without 2,4,6-triaminopyrimidine,a chemical tight junction blocker,before CRD. The SCID mice were used to test the roleof lymphocytes in the antihyperalgesic effect. Theeffects of PAR-4-AP and PAR-4-antagonist (P4pal-10)were evaluated in water avoidance stress (WAS)model and low grade 2,4,6-trinitrobenzene sulfonicacid (TNBS) colitis. Spinal Fos protein expression wasvisualized by immunohistochemistry. Key Results Theantinociceptive effect of PAR-4-AP disappeared whenwas administrered IP, or with the blockade of colonicepithelial tight junctions, suggesting that PAR-4-APneeds to reach directly the nerve terminals in the colon.The CRD-induced spinal Fos overexpression wasreduced by 43% by PAR-4-AP. The PAR-4-AP was antihyperalgesicin both hyperalgesia models and in micewith impaired lymphocytes. The PAR-4-antagonistsignificantly increased the TNBS, but not the WAS-inducedcolonic hyperalgesia. Conclusions & InferencesThe antinociceptive effect of PAR-4-AP dependson its penetration to the colonic mucosa. The PAR-4activation is endogenously involved as a feedback loopto attenuate inflammatory colonic hyperalgesia toCRD

Mice exposed to food-grade titanium dioxide from in utero life to adulthood show sex-specific gut microbiota and metabolic disorders which are aggravated under Western-diet

International audienceBackground: Food additives are one major hallmark of ultra-processed food in the Western diet, a food habit often associated with metabolic disorders. Among these additives, the whitener and opacifying agent titanium dioxide (TiO2, E171 in EU) raises public health issues due to systemic passage, organ accumulation (including placenta) and a maternofetal passage of TiO2 nanoparticles (found in the meconium) in human, showing early life exposure. In this context, exposure to TiO2 with biocidal properties could alter the gut colonization by the microbiota that plays a key role in intestinal and metabolic functions, leading to health effects at adulthood. Our aim in mice was to assess the fetal passage of TiO2 (E171) particles given to dams and the consequences on gut microbiota and metabolic functions of the offspring.Methods: Female mice (F0) were exposed to a control or E171-enriched normal diet at a human dose level (10 mg/kg bw/day) during pregnancy and lactation. At weaning, part of the descendants (F1) were fed with the same diet as their mother and the other part received a Western diet (WD) supplemented or not with the E171 (10 mg/kg bw/day) until postnatal day (PND) 150. Total fetal titanium (Ti) content was measured by ICP-MS at day 18 of pregnancy, and in the liver of F1 descendants at PND150. Intestinal inflammation and microbiota composition were studied at PND150 using ELISA for cytokines and 16S gene sequencing, respectively. Metabolic status was evaluated using oral glucose tolerance test and fasting insulin.Results: Compared to controls, high Ti level was detected in fetuses of E171-exposed mothers, while further liver Ti accumulation was evidenced at PND150 in F1 descendants fed with the same E171-enriched diet, regardless of the sex. Under normal diet, chronic E171 exposure starting in utero increased production of the pro-inflammatory cytokine IL1β in the colon of adult F1 males. Changes in the gut microbiota composition occurred in males only, showing an increase of β-diversity and Firmicutes/Bacteroidetes ratio. This occurred concomitantly to glucose intolerance and higher fasting insulin levels, while the same E171 treatment fostered WD-induced colon inflammation and glucose intolerance. In contrast, decreased secretion of pro- (IL1β, TNFα, IFNγ, IL17) and anti-(IL10) inflammatory cytokines occurred in the colon of E171-exposed F1 females under normal diet, while the metabolic alterations induced by WD showed no worsening.Conclusions: These results showed that a long-term exposure to food-grade TiO2 (E171) starting from in utero life alters intestinal and metabolic homeostasis in a sex-dependent manner, characterized by altered glucose metabolism, gut dysbiosis and worsening of WD-induced metabolic disorders in male mice only. Taken together, these data suggest that a lifespan exposure to TiO2 from dietary sources could both initiate and promote the development of metabolic disorders in humans

Mice exposed to food-grade TiO 2 from in utero life to adulthood show sex-specific gut microbiota and metabolic disorders

International audienceThe use of titanium dioxide (TiO 2) particles as a food additive (E171 in EU) in ultra-processed foods raises public health issues. Our previous study showed transplacental passage of TiO 2 nanoparticles in the human placenta, and presence of TiO 2 particles in meconium, demonstrating foetal exposure. Due to biocidal properties of TiO 2 , whether E171 exposure starting early during pregnancy may alter the establishment of gut microbiota homeostasis with potential deleterious effects at adulthood has not been explored. The current study in mice aimed to assess the perinatal fate of E171 given to dams and the consequences on gut microbiota and metabolic functions of the offspring. Female mice were exposed to a control or E171-enriched diet at a human relevant level (10 mg/kg bw/day) during pregnancy and lactation until weaning of pups, then the descendants were fed with the same diet as their mother until postnatal day (PND) 150. Oral glucose tolerance and fasting insulin were assessed at PND143. At PND150, all mice were sacrificed and gut microbiota composition as well as intestinal pro-and anti-inflammatory cytokine production were measured by 16S gene sequencing and ELISA, respectively. Biodistribution of TiO 2 particles was also studied by ICP-MS in fetus at day 18 of pregnancy, and in the liver at PND150. In E171-exposed mice, higher Ti level was first detected in fetus, and Ti accumulation was reported in liver at PND150 compared to controls regardless of the sex. Changes in gut microbiota composition occurred in E171-exposed male only, showing increased βdiversity and of the Firmicutes/Bacteroidetes ratio. Increased production of the pro-inflammatory cytokine IL1β in the colon as well as glucose intolerance and higher fasting insulin levels were also reported in E171-exposed male relative to controls. In contrast, decreased secretion of pro-(IL1β, TNFα, IFNγ, IL17) and anti-(IL10) inflammatory cytokines occurred in the colon of E171-exposed females, without other changes. These results showed that long term exposure to E171 from in utero life alters intestinal and metabolic homeostasis in a sex-dependent manner, characterized by altered glucose metabolism and gut dysbiosis in male mice only

Toxic effects of mineral oil saturated hydrocarbons (MOSH) and relation to accumulation in rat liver

acceptedVersio

Characterization of titanium dioxide nanoparticle intestinal absorption, in vivo and ex vivo, in the mouse

Titanium dioxide (TiO2) nanoparticles are ingested on a daily basis by millions of people, especially in western countries, being largely used as additive in manufactured foods or pharmaceutical drugs. Its oral administration was shown to exacerbate colitis, during UC or Crohn Diseases, by activating the NRLP3 inflammasome in gut and increasing its overall distribution in the blood or the spleen (Lomer MC Br J Nutr 2004;92:947, Ruiz PA, Gut. 2016 Feb 4. pii: gutjnl-2015-310297). Our study investigated the intestinal absorptive route of the alimentary TiO2 (E171) , after a unique gavage in mice, characterizing the major sites and kinetic of its absorption and distribution in the intestine and blood. The pathways of TiO2 absorption were also characterized ex vivo, in anesthetized mouse using specific inhibitors injected with the particles in ligatured loops of the jejunum. The TiO2 particles were detected using confocal microscopy and laser light reflection which uniquely permit to look at extended tissue area. The TiO2 particles from 100 nm to 1-2 micrometers showed a major absorption in the jejunum in both the villi and Peyer Patches and much lower uptake in ileon and colon. In villi the TiO2 absorption rose until 4 hours after feeding and returned to control levels at 8 h while Peyer patches contents remained low at 4h but are significantly increased at 8 h. TiO2 particles were also 4 time increased in the blood at 4 and 8 h, compared to controls, showing similar kinetics of accumulations as previously reported in human (Pele, L. C. et al. Part Fibre Toxicol, 2015 12, 26). In ex vivo experiments the absorption of TiO2 in ligatured loops of jejunum were found to be rapid, clearly visible after 15 or 30 minutes of incubation and is inhibited by 66 % in the presence of 100 mM of TAP (4,5,6-Triaminopyrimidine sulfate) a tight junction blocker suggesting a major absorption via a paracellular pathways across epithelial tight junctions. By contrast, the intestinal uptake of TiO2 was not modified in the presence of either 100 mM 5-(N-Ethyl-N-isopropyl) amiloride inhibiting pinocytosis, 30 µM pitstop 2 which blocks clathrin dependent endocytosis or17 µM methyl beta-cyclodextrin affecting raft-mediated endocytosis, showing little or no contribution of endocytosis in the absorptive process. We developed an easy method to rapidly follow the intestinal absorption of TiO2 by the intestine using confocal microscopy. The absorption occurred through out the intestine, being predominant in both villi and Peyer patches of the jejunum. Most TiO2 particles entered the intestine through a paracellular route, passed through it and were transferred to the blood in a few hours