Introduction

Ileus, a slowing or halting of intestinal motility, develops in trauma, critically ill, and surgical patients, resulting in prolonged hospital and ICU stays, increased infectious complications, and more hospital readmissions. Inflammatory insult to the gastrointestinal smooth muscle is frequently brought on by direct manipulation of the intestines during surgery, but can also be caused by systemic inflammation, which activates mast cells and macrophages and increases the production of inflammatory cytokines. We have demonstrated that the chemokine (C-X-C motif) ligand 1 (CXCL1), which inhibits intestinal motility, is enhanced in rodent ileus models and in the blood of trauma patients who develop ileus. P21-activated kinase (PAK) 1, which is elevated in response to mechanical stretch, has also been connected to the emergence of ileus.

Aims & Methods

In this study, we focused on the relationship between mechanotransduction, CXCL1, and PAK1. We utilized both an organ bath system and cyclical stretch of cell models via a Flex cell apparatus to study the role of mechanotransduction. Both human intestinal smooth muscle cells (hiSMCs) and macrophages were subjected to physiological (control cyclical stretch, CCS) and pathological (edema cyclical stretch, ECS, as experienced during edema development or ileus) stretch. The role of NF-kB, which has been shown to regulate CXCL1 expression, was investigated. Intestinal tissue samples from wildtype and PAK1 knockout mice were also stretched in the presence or absence of IPA-3, a PAK1 inhibitor, and IMD-5304, an NF-kB inhibitor. The expression and secretion of CXCL-1 in intestinal smooth muscle cells and macrophages were determined by ELISA and RT-qPCR.

Results

In response to the induction of ileus (via gut manipulation), CXCL1 expression was increased in wild-type mice but not PAK1 knockout mice. PAK1 inhibition did not attenuate the inhibitory effects of CXCL1 on intestinal motility; however, the inhibitory effects of CXCL1 were partially inhibited in PAK1 knockout mice. Mechanical stretch increased CXCL1 in the media of macrophages and human intestinal smooth muscle cells. PAK1 inhibition did not prevent the increased CXCL1 secretion in human intestinal smooth muscle cells. NF-kB activation was increased in response to increased stretch, and NF-kB inhibition prevented stretch-induced increase in CXCL1 secretion.

Conclusion

We conclude that during the development of edema and/or ileus, pathological strain can stimulate CXCL1 release from both intestinal smooth muscle cells and macrophages. However, inhibition of NF-kB, but not PAK1, prevents stretch-induced CXCL1 secretion.

References

Asgeirsson, T., El-Badawi, K. I., Mahmood, A., Barletta, J., Luchtefeld, M., & Senagore, A. J. (2010). Postoperative Ileus: It Costs More Than You Expect. Journal of the American College of Surgeons, 210(2), 228–231. https://doi.org/10.1016/j.jamcollsurg.2009.09.028
Chu, J., Pham, N. T., Olate, N., Kislitsyna, K., Day, M. C., LeTourneau, P. A., Kotss, A., Stewart, R. H., Laine, G. A., Cox, C. S., & Uray, K. (2013). Biphasic regulation of myosin light chain phosphorylation by p21-activated kinase modulates intestinal smooth muscle contractility. Journal of Biological Chemistry, 288(2), 1200–1213. https://doi.org/10.1074/JBC.M112.370718
Docsa, T., Bhattarai, D., Sipos, A., Wade, C. E., Cox, C. S., & Uray, K. (2020). CXCL1 is upregulated during the development of ileus resulting in decreased intestinal contractile activity. Neurogastroenterology & Motility, 32(3), e13757. https://doi.org/10.1111/NMO.13757
Joshi, V., Strege, P. R., Farrugia, G., & Beyder, A. (2021). Mechanotransduction in gastrointestinal smooth muscle cells: Role of mechanosensitive ion channels. American Journal of Physiology - Gastrointestinal and Liver Physiology, 320(5), G897–G906. https://doi.org/10.1152/AJPGI.00481.2020/ASSET/IMAGES/MEDIUM/GI-00481-2020R01.PNG
Rychter, J., & Clavé, P. (2013). Intestinal inflammation in postoperative ileus: pathogenesis and therapeutic targets. Gut, 62(11), 1534–1535. https://doi.org/10.1136/gutjnl-2012-304176

Introduction

There is an ongoing paradigm shift toward serology-based diagnosis of celiac disease (CeD). It is essential to target potential endoscopies for those most likely to benefit. Anemia is a common symptom of CeD that may warrant further investigations, but the prevalence and clinical relevance of endoscopic findings in anemic CeD patients remain unclear.

Aims & Methods

The aim of this study was to compare the prevalence of upper and lower endoscopic findings between anemic patients and non-CeD controls, and to identify predictors of significant findings in CeD patients. Medical data, including upper and lower endoscopy findings, were collected from 162 CeD patients and 350 controls. Binary logistic regression analysis was used to identify predictors of findings.

Results

CeD patients were younger (median 49 vs 66 years, p<0.001) and had fewer risk factors such as smoking (14% vs 25%, p<0.001), alcohol abuse (4% vs 14%, p<0.001), chronic comorbidities (55% vs 83%, p<0.001), and previous malignancies (1% vs 8%, p=0.002).
In comparison of upper endoscopy findings, CeD patients had fewer significant findings (21% vs 53%, p<0.001), H. Pylori positive gastritis (6% vs 19%, p<0.001), gastric ulcers (0% vs 5%, p=0.006), and atrophic gastritis (3% vs 9%, p=0.005) compared to the controls.
Twenty-four patients and 208 controls had undergone lower endoscopy with celiac patients more frequently demonstrating significant findings (54% vs 28%, p=0.008), non-specific inflammation (21% vs 1%, p<0.001) and colorectal cancer (25% vs 9%, p=0.018).
Predictors of significant upper endoscopy findings in CeD patients were older age (OR 1.03, 95% CI 1.01-1.05), age >50 (2.44, 1.18-5.06), co-existing chronic conditions (3.45, 1.53-7.78), gastrointestinal symptoms (2.31, 1.07-4.98), and use of acetylsalicylic acid (2.38, 1.01-5.06), and of colonoscopy findings older age (1.01, 0.99-1.04), co-existing conditions (3.48, 1.12-10.8), and gastrointestinal symptoms (4.73, 1.34-16.7).

Conclusion

CeD patients had fewer findings on upper endoscopy but, despite being younger and having fewer risk factors, showed more findings on lower endoscopy compared to controls. In older CeD patients presenting with anemia, lower endoscopy should be strongly considered.