Intraindividual Variation in Markers of Intestinal Permeability and Adipose Tissue Inflammation in Healthy Normal-Weight to Obese Adults

Kuzma, Jessica N.; Hagman, Derek K.; Cromer, Gail; Breymeyer, Kara L.; Roth, Christian; Foster-Schubert, Karen E.; Holte, Sarah; Weigle, David S.; Kratz, Mario

doi:10.1158/1055-9965.epi-18-0641

Cited by 14 publications

(3 citation statements)

References 36 publications

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“…A signi cant increase in serum LBP levels in MOH group was consistent with the presence of LPS in the blood circulation. Because of longer half-life and low intraindividual variation overtime, serum LBP is a reliable biomarker of intestinal permeability, endotoxemia and the presence of LPS in the systemic circulation [39].…”

Section: Discussionmentioning

confidence: 99%

Medication Overuse Headache is Associated with Elevated Lipopolysaccharide Binding Protein and Pro-inflammatory Molecules in the Bloodstream

Dağıdır,

Topa,

Vurallı

et al. 2023

Preprint

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Objective: Medication overuse headache (MOH) is secondary headache that accompanies chronic migraine and NSAIDs are the most frequently use analgesics in the word. NSAIDs are known to induce leaky gut and we aimed to investigate whether NSAID induced MOH is associated with altered circulating LBP levels and inflammatory molecules. Materials and Methods: Piroxicam (10 mg /kg, po) for 5 weeks was used to induce MOH in female Sprague Dawley rats. Pain was tested by evaluating periorbital von Frey thresholds, grooming, freezing and headshake behavior. Serum samples and brain tissues were collected to measure circulating LPS binding protein (LBP), tight junction protein occludin, adherence junction protein vascular endothelial (VE)-cadherin, CGRP, IL-6, levels. HMGB1 and IL-17 were determined in brain tissues. Results: Chronic piroxicam exposure resulted in decreased periorbital mechanical thresholds, increased grooming, freezing and headshake behavior compared to vehicle administration. Serum LBP, CGRP, IL-6, IL-17, occludin, VE-cadherin levels and brain IL-17 and HMGB1 levels were significantly higher in piroxicam group compared to controls. Serum LBP was correlated positively with occludin (r = 0.611), VE-cadherin (r = 0.588), CGRP (r = 0.706), HMGB1 (r = 0.618), headshakes (r = 0.921), and negatively with von Frey thresholds (r=-0.740). Conclusion: Chronic piroxicam induced MOH is associated with elevated serum LPS, VE- cadherin and occludin levels indicating disrupted intestinal barrier function and leakage of LPS into the systemic circulation. LPS induced low-grade inflammation and elevated nociceptive and/or pro-inflammatory molecules of HMGB1, IL-6, IL-17, CGRP and may play a role in development and maintaining of MOH. Interference with leaky gut and pro- inflammatory nociceptive molecules could also be a target for sustained management of MOH.

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Section: Discussionmentioning

confidence: 99%

Medication Overuse Headache is Associated with Elevated Lipopolysaccharide Binding Protein and Pro-inflammatory Molecules in the Bloodstream

Dağıdır,

Topa,

Vurallı

et al. 2023

Preprint

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“…Over the past decade, several studies have examined serum zonulin levels in various diseases, and along with that, many of these publications have demonstrated that zonulin cannot be used as a biomarker of increased intestinal permeability [ 253 , 254 , 255 , 256 ]. Emerging evidence has revealed that the controversial results of these studies may be due to some commercially available enzyme-linked immunosorbent assays (ELISAs) to specifically detect zonulin [ 93 , 257 , 258 , 259 , 260 ].…”

Section: Considerationsmentioning

confidence: 99%

Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions

Veres-Székely

Szász

Pap

et al. 2023

IJMS

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The relationship between dysbiosis and central nervous diseases has been proved in the last 10 years. Microbial alterations cause increased intestinal permeability, and the penetration of bacterial fragment and toxins induces local and systemic inflammatory processes, affecting distant organs, including the brain. Therefore, the integrity of the intestinal epithelial barrier plays a central role in the microbiota–gut–brain axis. In this review, we discuss recent findings on zonulin, an important tight junction regulator of intestinal epithelial cells, which is assumed to play a key role in maintaining of the blood–brain barrier function. In addition to focusing on the effect of microbiome on intestinal zonulin release, we also summarize potential pharmaceutical approaches to modulate zonulin-associated pathways with larazotide acetate and other zonulin receptor agonists or antagonists. The present review also addresses the emerging issues, including the use of misleading nomenclature or the unsolved questions about the exact protein sequence of zonulin.

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“…Innate immunity and damage-associated molecular pattern molecule HMGB1, and IL-6 were higher in COVID-19 headache patients and were correlated with headache severity and paracetamol unresponsiveness [ 17 ]. LBP is a dynamically regulated protein that binds to LPS and can be used as a marker to monitor LPS in circulation [ 18 – 20 ]. Tight junction (occludin) and adherens junction (VE-cadherin) proteins are core elements in the intestinal barrier and their detection in the bloodstream may indicate the disruption in intestinal permeability.…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation

Vuralli,

Ceren Akgor,

Gok Dagidir

et al. 2024

J Headache Pain

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Objective Medication overuse headache (MOH) was recently shown to be associated with leaky gut in rodents. We aimed to investigate whether chronic migraine (CM) patients with MOH have elevated lipopolysaccharide levels and inflammatory molecules in blood circulation. Materials and methods The study included women participants (40 CM patients with NSAID overuse headache, 35 episodic migraine (EM) patients, and 20 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, MigSCog, HADS-D, HADS-A, and HIT-6 scores were recorded. Serum samples were collected to measure circulating LPS, LPS binding protein (LBP), tight junction protein occludin, adherens junction protein vascular endothelial cadherin (VE-cadherin), CGRP, HMGB1, HIF-1α, IL-6, and IL-17 levels. Results Serum LPS, VE-Cadherin, CGRP, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the EM group and healthy controls while serum LBP and HMGB1 were higher in the CM + MOH group compared to healthy controls. IL-17 and occludin levels were comparable between the three groups. Serum HMGB1 levels in EM patients were higher compared to the control group. Mig-SCog and HIT-6 scores were higher in the CM + MOH group compared to EM patients. HADS-A and HADS-D scores were significantly higher in the CM + MOH group compared to EM patients and healthy controls, and they were also higher in EM patients compared to healthy subjects. LPS levels were correlated with VE-cadherin and occludin levels. The number of monthly migraine headache days was positively correlated with serum LPS, HIF-1α, VE-cadherin, and IL-6 levels, HADS-A, HADS-D, HIT-6, and MigSCog scores. Conclusion We have evidence for the first time that CM + MOH is associated with elevated serum LPS and LBP levels suggestive of LPS leak into the systemic circulation. Higher levels of nociceptive and/or pro-inflammatory molecules such as HMGB1, HIF-1α, IL-6, and CGRP may play a role in trigeminal sensitization and neurobiology of MOH. Intestinal hyperpermeability and consequent inflammatory response should be considered as a potential contributory factor in patients with MOH. Graphical Abstract

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Intraindividual Variation in Markers of Intestinal Permeability and Adipose Tissue Inflammation in Healthy Normal-Weight to Obese Adults

Cited by 14 publications

References 36 publications

Medication Overuse Headache is Associated with Elevated Lipopolysaccharide Binding Protein and Pro-inflammatory Molecules in the Bloodstream

Medication Overuse Headache is Associated with Elevated Lipopolysaccharide Binding Protein and Pro-inflammatory Molecules in the Bloodstream

Zonulin as a Potential Therapeutic Target in Microbiota-Gut-Brain Axis Disorders: Encouraging Results and Emerging Questions

Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation

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