Title: A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function Running title: The role of Tenascin-X in murine gastric function Keywords: Gastric emptying, gastric hypersensitivity, enteric neurones

Tenascin X (TNX) is a glycoprotein that regulates tissue structure through anti-adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers Danlos Syndrome (hEDS) involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal (GI) dysfunction. Previously, we have shown TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX-deficient patients and mice. We set out to identify if TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report TNX was present in calretinin-immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice suggesting vagal afferent responses are likely due to altered peripheral mechanosensitivity. In TNXB-deficient patients significantly greater symptoms of reflux, indigestion, and abdominal pain was reported. Here we report the first role for TNX in gastric function and further studies are required in TNX deficient patients to determine if symptoms can be relieved using GABAB agonists.