AJP - Gastrointestinal and Liver Physiology

Kronsten, Victoria T.; Woodhouse, Charlotte A.; Zamalloa, Ane; Lim, Tiong Yeng; Edwards, Lindsey A.; Martinez-Llordella, Marc; Sanchez-Fueyo, Alberto; Shawcross, Debbie L.

doi: 10.1152/ajpgi.00012.2022pmid: 35195033

Cirrhosis-associated immune dysfunction (CAID) contributes to disease progression and organ failure development. We interrogated immune system function in non-septic compensated and decompensated cirrhotic patients using the TruCultureÔ whole-blood stimulation system, a novel technique that allows a more accurate representation than traditional methods, such as peripheral blood mononuclear cell culture, of the immune response in vivo. 30 cirrhotics (21 decompensated, 9 compensated) and 7 healthy controls (HC) were recruited. Whole blood was drawn directly into 3 TruCultureÔ tubes [unstimulated, pre-loaded with heat-killed E.Coli 0111:B4 (HKEB) or lipopolysaccharide (LPS)] and incubated in dry heat blocks at 37°C for 24 hours. Cytokine analysis of the supernatant was performed by multiplex assay. Cirrhotic patients exhibited a robust pro-inflammatory response to HKEB compared to HCs, with increased production of IP-10 and IFNλ1, and to LPS, with increased production of IFNλ1. Decompensated patients demonstrated an augmented immune response compared to compensated patients, orchestrated by an increase in type I, II and III interferons, and higher levels of IL-1b, IL-6 and IL-8 post-LPS stimulation. IL-1b, TNF-a and IP-10 post-HKEB stimulation and IP-10 post-LPS stimulation negatively correlated with biochemical markers of liver disease severity and liver disease severity scores. Cirrhotic patients exposed to bacterial products exhibit an exaggerated inflammatory response orchestrated by IFNs, IL-6 and IL-8. Post-stimulation levels of a number of pro-inflammatory cytokines negatively correlate with markers of liver disease severity raising the possibility that the switch to an immunodeficient phenotype in CAID may commence earlier in the course of advanced liver disease.

Dodds, Kelsi N.; Travis, Lee; Kyloh, Melinda A.; Jones, Lauren A.; Keating, Damien J.; Spencer, Nick J.

doi: 10.1152/ajpgi.00019.2022pmid: 35293258

Cross-talk between the gastrointestinal tract and brain is of significant relevance for human health and disease. However, our understanding of how the gut and brain communicate has been limited by a lack of techniques to identify the precise spatial relationship between extrinsic nerve endings and their proximity to specific cell types that line the inner surface of the gastrointestinal tract. We used an in vivo anterograde tracing technique, previously developed in our laboratory, to selectively label single spinal afferent axons and their nerve endings in mouse colonic mucosa. The closest 3-dimensional distances between spinal afferent nerve endings and axonal varicosities to enterochromaffin (EC) cells, which contain serotonin (5-hydroxytryptamine; 5-HT), were then measured. The mean distances (± standard deviation) between any varicosity along a spinal afferent axon or its nerve ending, and the nearest EC cell, was 5.7 ± 6.0 μm (median: 3.6 μm) and 26.9 ± 18.6 μm (median: 24.1 μm), respectively. Randomization of the spatial location of EC cells revealed similar results to this actual data. These distances are ~200-1000 times greater than those between pre- and post-synaptic membranes (15-25 nm) that underlie synaptic transmission in the vertebrate nervous system. Our findings suggest that colonic 5-HT-containing EC cells release substances to activate centrally-projecting spinal afferent nerves likely via diffusion, as such signaling is unlikely to occur with the spatial fidelity of a synapse.

Halder, Sourav; Acharya, Shashank; Kou, Wenjun; Campagna, Ryan A. J; Triggs, Joseph R.; Carlson, Dustin A.; Aadam, Abdul Aziz; Hungness, Eric S.; Kahrilas, Peter J.; Pandolfino, John E.; Patankar, Neelesh A.

doi: 10.1152/ajpgi.00281.2021pmid: 35170365

We used in-silico models to investigate the impact of the dimensions of myotomy, contraction pattern, the tone of the esophagogastric junction (EGJ), and musculature at the myotomy site on esophageal wall stresses potentially leading to the formation of a blown-out myotomy (BOM). We performed three sets of simulations with an in-silico esophagus model, wherein the myotomy influenced region was modeled as an elliptical section devoid of muscle fibers. Longer myotomy was found to be accompanied by a higher bolus volume accumulated at the myotomy site. With respect to esophageal contractions, deformation at the myotomy site was greatest with propagated peristalsis, followed by combined peristalsis and spasm, and pan-esophageal pressurization. Stronger EGJ tone with respect to the wall stiffness at the myotomy site was found to aid in increasing deformation at the myotomy site. Additionally, we found that an esophagus with a shorter myotomy performed better at emptying the bolus compared to that with a longer myotomy. Shorter myotomies decrease the chance of BOM formation. Propagated peristalsis with EGJ outflow obstruction has the highest chance of BOM formation. We also found that abnormal residual EGJ tone may be a co-factor in the development of BOM while remnant muscle fibers at myotomy site reduce the risk of BOM formation.

Jiang, Yanyan; Zimmerman, Julia E.; Browning, Kirsteen N.; Travagli, R. Alberto

doi: 10.1152/ajpgi.00347.2021pmid: 35170350

Abstract Previous studies have shown that pharmacological manipulations with stress-related hormones such as corticotropin releasing factor and thyrotropin releasing hormone induce neuroplasticity in brainstem vagal neurocircuits which modulate gastric tone and motility. The prototypical anti-stress hormone, oxytocin (OXT), has been shown to modulate gastric tone and motility via vagal pathways, and descending hypothalamic oxytocinergic inputs play a major role in the vagally-dependent gastric-related adaptations to stress. The aim of this study was to investigate the possible cellular mechanisms through which OXT modulates central vagal brainstem and peripheral enteric neurocircuits of male Sprague-Dawley rats in response to chronic repetitive stress. Following chronic (five consecutive days) of homotypic or heterotypic stress load, the response to exogenous brainstem administration of OXT was examined using whole cell patch clamp recordings from gastric-projecting vagal motoneurons and in vivo recordings of gastric tone and motility. GABAergic currents onto vagal motoneurons were decreased by OXT in stressed, but not in naïve rats. In naïve rats, microinjections of OXT in vagal brainstem nuclei induced gastroinhibition via peripheral release of nitric oxide (NO). In stressed rats, however, the OXT-induced gastroinhibition was determined by release of both NO and vasoactive intestinal peptide (VIP). Taken together, our data indicate that stress induces neuroplasticity in the response to OXT in the neurocircuits that modulate gastric tone and motility. In particular, stress uncovers the OXT-mediated modulation of brainstem GABAergic currents and alters the peripheral gastric response to vagal stimulation.

Juneja, Pinky; Tripathi, Dinesh M.; Kaur, Savneet

doi: 10.1152/ajpgi.00271.2021pmid: 35195034

The lymphatic vascular system runs parallel to the blood vascular system, comprising a network of lymphatic vessels and secondary lymphoid organs. The intestinal lymphatic capillaries (lacteals) and the associated collecting vessels in the mesentery form the gut lymphatic system. The gut lymphatic vasculature comprises the longest-studied lymphatic vessel bed and plays a significant role in the uptake and transport of dietary fat, abdominal fluid balance, and gut immunosurveillance. Gut is closely connected to liver through the portal circulation. In several experimental and clinical studies, the 'gut-liver-axis' has been demonstrated to contribute to the pathogenesis of portal hypertension, liver cirrhosis, and its complications. Given a significant impact of gut health on the liver, in the current review, we highlight 'gut-liver axis' in context to the circulatory physiology of gut lymphatic vessels. Despite their paramount importance in maintaining fluid and immune homeostasis in the gut, gut lymphatic vessels remain one of the most understudied physiological systems in liver disease pathology. In the current review, we delineate the connections of gut lymphatics with abdominal fluid homeostasis and bacterial translocation in the pathogenesis of liver cirrhosis and portal hypertension. We describe mechanisms and factors that drive gut lymphangiogenesis and lymphatic vessel dysfunction during inflammation. The review also underscores the role of gut lymphatic endothelial cells in regulating gut and liver immunity. We finally discuss the prognostic and therapeutic prospects of studying gut lymphatic vessels in advanced liver cirrhosis.

Camilleri, Michael

doi: 10.1152/ajpgi.00011.2022pmid: 35258349

Bile acids are amphipathic, detergent molecules. The detergent effects of di-α-hydroxy bile acids are relevant to several colonic diseases. The aims were to review the concentrations of bile acids reaching the human colon in health and disease, the molecular structure of bile acids that determine detergent functions and the relationship to human diseases (neuroendocrine tumors, microscopic colitis, active celiac disease and ulcerative colitis, Crohn's disease and ileal resection), the relationship to bacterial uptake into mucosa, mucin depletion and epithelial damage, the role of bile acids in mucosal inflammation and microscopic colitis, and the role of sulfation of bile salts in detoxification or prevention of the detergent effects of bile acids. The concentrations of bile acids reaching the human colon range from 2-10mM; di-alpha-hydroxy bile acids are the only bile acids with detergent effects that include mucin depletion, mucosal damage, bacterial uptake, and microscopic inflammation that may be manifest in diseases associated with no overt inflammation of the mucosa, such as bile acid diarrhea, ileal diseases such as neuroendocrine tumors, ileal resection, and non-alcoholic steatohepatitis. Sulfation inactivates colonic secretion due to primary bile acids, but it may render secondary bile acids pro-inflammatory in the colon. Other evidence in preclinical models of IBD suggests reduced sulfation causes barrier dysfunction, inflammation, or carcinogenesis. These advances emphasize relevance and opportunities afforded by greater understanding of the chemistry and metabolism of bile acids, which stands to be further enhanced by research into the metabolic interactions of microbiota with bile acids.