Dietary monosodium glutamate increases visceral hypersensitivity in a mouse model of visceral pain.

BACKGROUND: Monosodium glutamate (MSG) has been identified as a trigger of abdominal pain in irritable bowel syndrome (IBS), but the mechanism is unknown. This study examined whether MSG causes visceral hypersensitivity using a water-avoidance stress (WAS) mouse model of visceral pain. METHODS: Mice were divided into four groups receiving treatment for 6 days: WAS + MSG gavage, WAS + saline gavage, sham-WAS + MSG gavage, and sham-WAS + saline gavage. The acute effects of intraluminal administration of 10 µM MSG on jejunal extrinsic afferent nerve sensitivity to distension (0-60 mmHg) were examined using ex vivo extracellular recordings. MSG was also applied directly to jejunal afferents from untreated mice. Glutamate concentration was measured in serum, and in the serosal compartment of Ussing chambers following apical administration. KEY RESULTS: Acute intraluminal MSG application increased distension responses of jejunal afferent nerves from mice exposed to WAS + MSG. This effect was mediated by wide dynamic range and high-threshold units at both physiologic and noxious pressures (10-60 mmHg, p < 0.05). No effect of MSG was observed in the other groups, or when applied directly to the jejunal afferent nerves. Serum glutamate was increased in mice exposed to WAS + MSG compared to sham-WAS + saline, and serosal glutamate increased using WAS tissue (p = 0.0433). CONCLUSIONS AND INFERENCES: These findings demonstrate that repeated exposure to MSG in mice leads to sensitization of jejunal afferent nerves to acute ex vivo exposure to MSG. This may contribute to visceral hypersensitivity reported in response to MSG in patients with IBS.

Small-molecule metabolome identifies potential therapeutic targets against COVID-19.

Respiratory viruses are transmitted and acquired via the nasal mucosa, and thereby may influence the nasal metabolome composed of biochemical products produced by both host cells and microbes. Studies of the nasal metabolome demonstrate virus-specific changes that sometimes correlate with viral load and disease severity. Here, we evaluate the nasopharyngeal metabolome of COVID-19 infected individuals and report several small molecules that may be used as potential therapeutic targets. Specimens were tested by qRT-PCR with target primers for three viruses: Influenza A (INFA), respiratory syncytial virus (RSV), and SARS-CoV-2, along with unaffected controls. The nasopharyngeal metabolome was characterized using an LC-MS/MS-based screening kit capable of quantifying 141 analytes. A machine learning model identified 28 discriminating analytes and correctly categorized patients with a viral infection with an accuracy of 96% (R2 = 0.771, Q2 = 0.72). A second model identified 5 analytes to differentiate COVID19-infected patients from those with INFA or RSV with an accuracy of 85% (R2 = 0.442, Q2 = 0.301). Specifically, Lysophosphatidylcholines-a-C18:2 (LysoPCaC18:2) concentration was significantly increased in COVID19 patients (P < 0.0001), whereas beta-hydroxybutyric acid, Methionine sulfoxide, succinic acid, and carnosine concentrations were significantly decreased (P < 0.0001). This study demonstrates that COVID19 infection results in a unique nasopharyngeal metabolomic signature with carnosine and LysoPCaC18:2 as potential therapeutic targets.

A maladaptive role for EP4 receptors in podocytes.

Inhibition of p38 mitogen-activated protein kinase and cyclooxygenase-2 reduces albuminuria in models of chronic kidney disease marked by podocyte injury. Previously, we identified a feedback loop in podocytes whereby an in vitro surrogate for glomerular capillary pressure (i.e., mechanical stretch) along with prostaglandin E(2) stimulation of its EP4 receptor induced cyclooxygenase-2 in a p38-dependent manner. Here we asked whether stimulation of EP4 receptors would exacerbate glomerulopathies associated with enhanced glomerular capillary pressure. We generated mice with either podocyte-specific overexpression or depletion of the EP4 receptor (EP4(pod+) and EP4(pod-/-), respectively). Glomerular prostaglandin E(2)-stimulated cAMP levels were eightfold greater for EP4(pod+) mice compared with nontransgenic (non-TG) mice. In contrast, EP4 mRNA levels were >50% lower, and prostaglandin E(2)-induced cAMP synthesis was absent in podocytes isolated from EP4(pod-/-) mice. Non-TG and EP4(pod+) mice underwent 5/6 nephrectomy and exhibited similar increases in systolic BP (+25 mmHg) by 4 weeks compared with sham-operated controls. Two weeks after nephrectomy, the albumin-creatinine ratio of EP4(pod+) mice (3438 µg/mg) was significantly higher than that of non-TG mice (773 µg/mg; P < 0.0001). Consistent with more severe renal injury, the survival rate for nephrectomized EP4(pod+) mice was significantly lower than that for non-TG mice (14 versus 67%). In contrast, 6 weeks after nephrectomy, the albumin-creatinine ratio of EP4(pod-/-) mice (753 µg/mg) was significantly lower than that of non-TG mice (2516 µg/mg; P < 0.05). These findings suggest that prostaglandin E(2), acting via EP4 receptors contributes to podocyte injury and compromises the glomerular filtration barrier.