Mechanisms of Vascular Permeability in the Gut

In the last decade, the role of intestinal permeability in a range of conditions, from autoimmunity to food reactions, has drawn increasing attention. New research suggests that increased gut vascular permeability may play a role in inflammatory bowel disease (IBD) pathogenesis.1 A single layer of endothelial cells lines the blood vessels, and they are the gatekeepers for permeability of the vessels to molecules and cells. This suggests that protecting the dynamic barrier in blood vessels may have benefits for patients with IBD.

Microvascular alterations may be maladaptive in IBD. 2

As the name states, inflammation plays a large role in inflammatory bowel diseases like Crohn’s and ulcerative colitis. Inflammatory cytokines have been named as causative agents for increased vascular permeability outside the GI tract.3,4 To support nutrient absorption, fluid homeostasis, and immune function, the gastrointestinal tract is highly vascularized.

In a November 2019 article, German researchers identified that a particular cytokine, interferon-gamma (IFN-gamma), which plays a role in cell signaling, was present at high concentrations in IBD patients.1 When present, IFN-gamma impaired endothelial cell-to-cell signaling, resulting in vascular permability.1 When seven people with IBD in remission were compared to eight with active IBD and three controls, increased vascular permeability was detected in the active group.1 Results were “strikingly” similar to those found in mouse models.1

These results may have two implications for working with patients with IBD. First, the acute effects of cytokines may be the cause of short-term worsening of symptoms. Both acute and chronic inflammation are known to increase vascular permeability.5 Chronic inflammation is associated with angiogenesis, and ongoing gastrointestinal inflammation and intestinal wall injury results in new microvasculature in the gut.6 Anti-inflammatory treatments (although not NSAIDs, which are known to worsen IBD7) may be beneficial in reducing symptoms. Second, the structural changes that are present in vascular tissues of IBD patients, even when the disease is in remission, suggest that there may be an ongoing need to support vascular health after diagnosis and successful treatment.

In patients with ulcerative colitis who are in remission, confocal laser endomicroscopy has documented “abnormal vascular architecture” and increased vascular permeability compared to controls.8 This may explain the increased translocation of molecules into the bloodstream in patients with IBD, which leads to overall immune activation and inflammation.1 Other signaling mechanisms, such as Wnt/beta-catenin signaling, are likely affected in other conditions.9

The increased translocation of bacteria may explain how impaired intestinal vascular barriers can lead to damage of other organs, like the liver.10 Furthermore, patients suffering from IBD are at elevated risk of a range of cardiovascular conditions.11 Management of cardiovascular risk factors may not only assist in reducing disease progression and repairing the GI tract for patients in remission, but may also help to improve cardiovascular outcomes in the long run. Anti-inflammatory foods and botanicals may not only reduce inflammation, but also help to repair the blood vessels in patients with IBD.

References

  1. Langer V, Vivi E, Regensburger D, et al. IFN-? drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption. J Clin Invest. 2019;129(11):4691-4707. doi:1172/JCI124884
  2. Cromer WE, Mathis JM, Granger DN, Chaitanya GV, Alexander JS. Role of the endothelium in inflammatory bowel diseases. World J Gastroenterol. 2011;17(5):578-593. doi:3748/wjg.v17.i5.578
  3. Claesson-Welsh L. Vascular permeability—the essentials. Ups J Med Sci. 2015;120(3):135-143. doi:3109/03009734.2015.1064501
  4. Fahey E, Doyle SL. IL-1 family cytokine regulation of vascular permeability and angiogenesis. Front Immunol. 2019;10:1426. doi:3389/fimmu.2019.01426
  5. Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis. 2008;11(2):109-119. doi:1007/s10456-008-9099-z
  6. Alkim C, Alkim H, Koksal AR, Boga S, Sen I. Angiogenesis in inflammatory bowel disease. Int J Inflam. 2015;2015:970890. doi:1155/2015/970890
  7. Matsuoka K, Kobayashi T, Ueno F, et al. Evidence-based clinical practice guidelines for inflammatory bowel disease. J Gastroenterol. 2018;53(3):305-353. doi:1007/s00535-018-1439-1
  8. Macé V, Ahluwalia A, Coron E, et al. Confocal laser endomicroscopy: a new gold standard for the assessment of mucosal healing in ulcerative colitis. J Gastroenterol Hepatol. 2015;30(Suppl 1):85-92. doi:1111/jgh.12748
  9. Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol. 2019;25(39):5897-5917. doi:3748/wjg.v25.i39.5897
  10. Spadoni I, Zagato E, Bertocchi A, et al. A gut-vascular barrier controls the systemic dissemination of bacteria. 2015;350(6262):830-834. doi:10.1126/science.aad0135
  11. Bunu DM, Timofte CE, Ciocoiu M, et al. Cardiovascular manifestations of inflammatory bowel disease: pathogenesis, diagnosis, and preventive strategies. Gastroenterol Res Pract. 2019;2019:3012509. doi:1155/2019/3012509

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