Intestinal neuromuscular function adaptation to ischemia/reperfusion injury: relevance of the microbiota-gut interplay

Intestinal ischemia/reperfusion (IR) injury represents an important clinical problem, inducing severe damage to the enteric nervous system and to the neuromuscular intestinal function. Recently, we have focused on hyaluronan (HA), an extracellular matrix component, as a new modulator of the neuroadaptive changes of enteric neuronal circuitries in the inflamed gut. In this study, we evaluated HA involvement in myenteric neuron derangements after IR injury. After IR, a gradual deposition of HA was observed along the intestinal layers, with the highest deposition occurring in the external longitudinal muscle with the myenteric plexus, which was associated to HA synthase2 upregulation. IR-induced HA deposition was reduced by treatment with 4MU, a HA synthesis inhibitor. After IR, the expression levels of HA targets, TLR2, TLR4 and CD44 increased in the muscularis externa with the myenteric plexus more than in submucosal and mucosal layers and were sensitive to 4MU. The efficiency of the intestinal transit was significantly reduced in IR and further reduced in the 4MU-treated IR group. Carbachol (CCh), electrical field stimulated (EFS) contractions and EFSinduced non-adrenergic-non-cholinergic (NANC) relaxations were reduced after I/R. In this condition, 4MU increased EFS contractions towards control values, but did not affect CCh-induced contractions neither NANC on-relaxations. Main alterations in the neurochemical coding of excitatory (tachykinergic) and inhibitory pathways (iNOS, VIPergic) were also observed after IR and were influenced by 4MU administration. Overall, our data suggest that, after an intestinal IR damage, changes of HA homeostasis in specific myenteric neuron populations may participate in neuromuscular function derangement.