The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum
BACKGROUND. Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing...
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MDPI AG
2024-01-01
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| author | Mingju Cao Shikha Kuthiala Keven Jason Jean Hai Lun Liu Marc Courchesne Karen Nygard Patrick Burns André Desrochers Gilles Fecteau Christophe Faure Martin G. Frasch |
| author_facet | Mingju Cao Shikha Kuthiala Keven Jason Jean Hai Lun Liu Marc Courchesne Karen Nygard Patrick Burns André Desrochers Gilles Fecteau Christophe Faure Martin G. Frasch |
| author_sort | Mingju Cao |
| collection | DOAJ |
| description | BACKGROUND. Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. METHODS. Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3–54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages’ CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for <i>p</i> < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). RESULTS. Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. CONCLUSIONS. The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses. |
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| language | English |
| last_indexed | 2024-03-08T11:04:39Z |
| publishDate | 2024-01-01 |
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| series | Biology |
| spelling | doaj.art-b216455a8bb54f20831a7f13123665072024-01-26T15:06:58ZengMDPI AGBiology2079-77372024-01-011313810.3390/biology13010038The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal IleumMingju Cao0Shikha Kuthiala1Keven Jason Jean2Hai Lun Liu3Marc Courchesne4Karen Nygard5Patrick Burns6André Desrochers7Gilles Fecteau8Christophe Faure9Martin G. Frasch10Department of Obstetrics and Gynaecology and Department of Neurosciences, CHU Ste-Justine Research Centre, Université de Montréal, Montréal, QC H3T 1C5, CanadaDepartment of Obstetrics and Gynaecology and Department of Neurosciences, CHU Ste-Justine Research Centre, Université de Montréal, Montréal, QC H3T 1C5, CanadaDepartment of Obstetrics and Gynaecology and Department of Neurosciences, CHU Ste-Justine Research Centre, Université de Montréal, Montréal, QC H3T 1C5, CanadaDepartment of Obstetrics and Gynaecology and Department of Neurosciences, CHU Ste-Justine Research Centre, Université de Montréal, Montréal, QC H3T 1C5, CanadaBiotron Microscopy, Western University, London, ON N6A 3K7, CanadaBiotron Microscopy, Western University, London, ON N6A 3K7, CanadaClinical Sciences, CHUV, Université de Montréal, St-Hyacinthe, QC J2S 2M2, CanadaClinical Sciences, CHUV, Université de Montréal, St-Hyacinthe, QC J2S 2M2, CanadaClinical Sciences, CHUV, Université de Montréal, St-Hyacinthe, QC J2S 2M2, CanadaDepartment of Pediatrics, CHU Ste-Justine Research Centre, Université de Montréal, Montréal, QC H3T 1C5, CanadaDepartment of Obstetrics and Gynaecology and Department of Neurosciences, CHU Ste-Justine Research Centre, Université de Montréal, Montréal, QC H3T 1C5, CanadaBACKGROUND. Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. METHODS. Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3–54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages’ CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for <i>p</i> < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). RESULTS. Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. CONCLUSIONS. The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.https://www.mdpi.com/2079-7737/13/1/38vagus nerveimmunometabolisminflammationfetus |
| spellingShingle | Mingju Cao Shikha Kuthiala Keven Jason Jean Hai Lun Liu Marc Courchesne Karen Nygard Patrick Burns André Desrochers Gilles Fecteau Christophe Faure Martin G. Frasch The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum Biology vagus nerve immunometabolism inflammation fetus |
| title | The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum |
| title_full | The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum |
| title_fullStr | The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum |
| title_full_unstemmed | The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum |
| title_short | The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum |
| title_sort | vagus nerve regulates immunometabolic homeostasis in the ovine fetus near term the impact on terminal ileum |
| topic | vagus nerve immunometabolism inflammation fetus |
| url | https://www.mdpi.com/2079-7737/13/1/38 |
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