Involvement of hyaluronan in the adaptive changes of the rat small intestine neuromuscular function after ischemia/reperfusion injury

Abstract

Intestinal ischemia/reperfusion (I/R) injury has severe consequences on myenteric neurons, which can be irreversibly compromised resulting in slowing of transit and hindered food digestion. Myenteric neurons synthesize hyaluronan (HA) to form a well-structured perineuronal net, which undergoes derangement when myenteric ganglia homeostasis is perturbed, i.e. during inflammation. In this study we evaluated HA involvement in rat small intestine myenteric plexus after in vivo I/R injury induced by clamping a branch of the superior mesenteric artery for 60 min, followed by 24 h of reperfusion. In some experiments, 4-methylumbelliferone (4-MU, 25 mg/kg), a HA synthesis inhibitor, was intraperitoneally administered to normal (CTR), sham-operated (SH) and I/R animals for 24 h. In longitudinal muscle myenteric plexus (LMMP) whole-mount preparations, HA binding protein staining as well as HA levels were significantly higher in the I/R group, and were reduced after 4-MU treatment. HA synthase 1 and 2 (HAS1 and HAS2) labelled myenteric neurons and mRNA levels in LMMPs increased in the I/R group with respect to CTR, and were reduced by 4-MU. The efficiency of the gastrointestinal transit was significantly reduced in I/R and 4-MU-treated I/R groups with respect to CTR and SH groups. In the 4-MU-treated I/R group gastric emptying was reduced with respect to the CTR, SH and I/R groups. Carbachol (CCh) and electrical field (EFS, 0.1-40 Hz) stimulated contractions and EFS-induced (10 Hz) NANC relaxations were reduced in the I/R group with respect to both CTR and SH groups. After I/R, 4-MU treatment increased EFS contractions towards control values, but did not affect CCh-induced contractions. NANC on-relaxations after I/R were not influenced by 4-MU treatment. Main alterations in the neurochemical coding of both excitatory (tachykinergic) and inhibitory pathways (iNOS, VIPergic) were also observed after I/R, and were influenced by 4-MU administration. Overall, our data suggest that, after an intestinal I/R damage, changes of HA homeostasis in specific myenteric neuron populations may influence the efficiency of the gastrointestinal transit. We cannot exclude that modulation of HA synthesis in these conditions may ameliorate derangement of the enteric motor function preventing, at least in part, the development of dysmotility. The gut is one of the most sensitive organs to ischemia-reperfusion (I/R) injury, which may occur in multiple clinical conditions, such as sepsis, shock, trauma, surgery, and is associated with high morbidity and mortality 1 .

Impact of Microbial Metabolites on Microbiota–Gut–Brain Axis in Inflammatory Bowel Disease

“…Major features of neuroplasticity involving the ENS during inflammation encompass structural changes, ranging from nerve rearrangement (i.e., hypertrophy and hyperplasia) to degeneration and loss of enteric ganglion cells as well as altered neurotransmission, leading to gastrointestinal dysfunction characterized by sensory-motor and secretory impairment of the gut, which may also occur in segments of the gastrointestinal tract remote from the site of the original inflammation. Such neuroplastic changes result from a dynamic interplay between enteric neurons and different cell types within the enteric microenvironment, including immune cells, enteric glial cells, and commensal bacteria [ 7 , 8 , 9 , 122 ]. It is well established that the microbiota may influence both sensory and motor gut functions as well as the development of the ENS in critical postnatal life periods [ 123 , 124 ].…”

“…An issue that needs to be explored is whether KYN derivatives may represent a possible novel signaling pathways to target visceral hyperalgesia in IBD, as suggested for IBS [ 307 ]. KynA by modulating NMDA receptor pathways may influence mechanosensitive pathways, transducing sensory stimuli deriving from pelvic and splanchnic afferents in response to neuroinflammation and hyperalgesia [ 91 , 122 , 308 ]. NMDA receptors located on complex neuronal networks in the spinal cord may promote the amplification of nociceptive signals and the “wind-up” of central responses to nociceptive stimuli [ 90 , 309 ].…”

Dopamine Transporter Genetic Reduction Induces Morpho-Functional Changes in the Enteric Nervous System

“…Total RNA was extracted from small intestine wall segments after removing the mucosa with TRIzol (Invitrogen; Monza, Italy), as described by Bistoletti et al (2020) [ 22 ]. cDNA was obtained by retrotranscribing 2.5 µg of total RNA using the High-Capacity cDNA synthesis kit (Applied Biosystems, Milan, Italy).…”

The microbiota-gut-brain axis: Focus on the fundamental communication pathways

“…Major features of neuroplasticity involving the ENS during inflammation encompass structural changes, ranging from nerve rearrangement (i.e., hypertrophy and hyperplasia) to degeneration and loss of enteric ganglion cells as well as altered neurotransmission, leading to gastrointestinal dysfunction characterized by sensory-motor and secretory impairment of the gut, which may also occur in segments of the gastrointestinal tract remote from the site of the original inflammation. Such neuroplastic changes result from a dynamic interplay between enteric neurons and different cell types within the enteric microenvironment, including immune cells, enteric glial cells, and commensal bacteria [7][8][9]122]. It is well established that the microbiota may influence both sensory and motor gut functions as well as the development of the ENS in critical postnatal life periods [123,124].…”