Modulation of lipopolysaccharide-induced neuronal response by activation of the enteric nervous system.

International audienceBackground:Evidence continues to mount concerning the importance of the enteric nervous system (ENS) incontrolling numerous intestinal functions in addition to motility and epithelial functions. Nevertheless, little isknown concerning the direct participation of the ENS in the inflammatory response of the gut during infectious orinflammatory insults. In the present study we analyzed the ENS response to bacterial lipopolysaccharide, inparticular the production of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α).Methods:TNF-αexpression (measured by qPCR, quantitative Polymerase Chain Reaction) and production(measured by ELISA) were measured in human longitudinal muscle-myenteric plexus (LMMP) and rat ENS primarycultures (rENSpc). They were either treated or not treated with lipopolysaccharide (LPS) in the presence or not ofelectrical field stimulation (EFS). Activation of extracellular signal-regulated kinase (ERK) and 5?-adenosinemonophosphate-activated protein kinase (AMPK) pathways was analyzed by immunocytochemistry and Westernblot analysis. Their implications were studied using specific inhibitors (U0126, mitogen-activated protein kinasekinase, MEK, inhibitor and C compound, AMPK inhibitor). We also analyzed toll-like receptor 2 (TLR2) expression andinterleukin-6 (IL-6) production after LPS treatment simultaneously with EFS or TNF-α-neutralizing antibody.Results:Treatment of human LMMP or rENSpc with LPS induced an increase in TNF-αproduction. Activation of theENS by EFS significantly inhibited TNF-αproduction. This regulation occurred at the transcriptional level. Signalinganalyses showed that LPS induced activation of ERK but not AMPK, which was constitutively activated in rENSpcneurons. Both U0126 and C compound almost completely prevented LPS-induced TNF-αproduction. In the presenceof LPS, EFS inhibited the ERK and AMPK pathways. In addition, we demonstrated using TNF-α-neutralizing antibody thatLPS-induced TNF-αproduction increased TLR2 expression and reduced IL-6 production.Conclusions:Our results show that LPS induced TNF-αproduction by enteric neurons through activation of thecanonical ERK pathway and also in an AMPK-dependent manner. ENS activation through the inhibition of thesepathways decreased TNF-αproduction, thereby modulating the inflammatory response induced by endotoxin

Maternal dietary omega-3 deficiency worsens the deleterious effects of prenatal inflammation on the gut-brain axis in the offspring across lifetime

Maternal immune activation (MIA) and poor maternal nutritional habits are risk factors for the occurrence of neurodevelopmental disorders (NDD). Human studies show the deleterious impact of prenatal inflammation and low n-3 polyunsaturated fatty acid (PUFA) intake on neurodevelopment with long-lasting consequences on behavior. However, the mechanisms linking maternal nutritional status to MIA are still unclear, despite their relevance to the etiology of NDD. We demonstrate here that low maternal n-3 PUFA intake worsens MIA-induced early gut dysfunction, including modification of gut microbiota composition and higher local inflammatory reactivity. These deficits correlate with alterations of microglia-neuron crosstalk pathways and have long-lasting effects, both at transcriptional and behavioral levels. This work highlights the perinatal period as a critical time window, especially regarding the role of the gut-brain axis in neurodevelopment, elucidating the link between MIA, poor nutritional habits, and NDD