Increased IgA-mediated responses to the gut paracellular pathway and blood-brain barrier proteins predict delirium due to hip fracture in older adults

Paul Thisayakorn; Yanin Thipakorn; Saran Tantavisut; Sunee Sirivichayakul; Aristo Vojdani; Michael Maes

doi:10.3389/fneur.2024.1294689

Increased IgA-mediated responses to the gut paracellular pathway and blood-brain barrier proteins predict delirium due to hip fracture in older adults

Front Neurol. 2024 Feb 6:15:1294689. doi: 10.3389/fneur.2024.1294689. eCollection 2024.

Authors

Paul Thisayakorn¹, Yanin Thipakorn¹, Saran Tantavisut², Sunee Sirivichayakul³, Aristo Vojdani^{4

5}, Michael Maes^{6

7

8

9

10

11}

Affiliations

¹ Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
² Department of Orthopedics, Hip Fracture Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
³ Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
⁴ Immunosciences Lab Inc., Los Angeles, CA, United States.
⁵ Cyrex Labs LLC, Phoenix, AZ, United States.
⁶ Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
⁷ Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, China.
⁸ Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.
⁹ Research Institute, Medical University of Plovdiv, Plovdiv, Bulgaria.
¹⁰ Kyung Hee University, Seoul, Republic of Korea.
¹¹ Cognitive Impairment and Dementia Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Abstract

Introduction: Delirium is accompanied by immune response system activation, which may, in theory, cause a breakdown of the gut barrier and blood-brain barrier (BBB). Some results suggest that the BBB is compromised in delirium, but there is no data regarding the gut barrier. This study investigates whether delirium is associated with impaired BBB and gut barriers in elderly adults undergoing hip fracture surgery.

Methods: We recruited 59 older adults and measured peak Delirium Rating Scale (DRS) scores 2-3 days after surgery, and assessed plasma IgG/IgA levels (using ELISA techniques) for zonulin, occludin, claudin-6, β-catenin, actin (indicating damage to the gut paracellular pathway), claudin-5 and S100B (reflecting BBB damage), bacterial cytolethal distending toxin (CDT), LPS-binding protein (LBP), lipopolysaccharides (LPS), Porphyromonas gingivalis, and Helicobacter pylori.

Results: Results from univariate analyses showed that delirium is linked to increased IgA responses to all the self-epitopes and antigens listed above, except for LPS. Part of the variance (between 45-48.3%) in the peak DRS score measured 2-3 days post-surgery was explained by independent effects of IgA directed to LPS and LBP (or bacterial CDT), baseline DRS scores, and previous mild stroke. Increased IgA reactivity to the paracellular pathway and BBB proteins and bacterial antigens is significantly associated with the activation of M1 macrophage, T helper-1, and 17 cytokine profiles.

Conclusion: Heightened bacterial translocation, disruption of the tight and adherens junctions of the gut and BBB barriers, elevated CDT and LPS load in the bloodstream, and aberrations in cell-cell interactions may be risk factors for delirium.

Keywords: bacterial translocation; biomarkers; cytokines; inflammation; leaky gut; neuro-immune.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by a Ratchadapisek Sompoch Endowment Fund of the Faculty of Medicine, Chulalongkorn University (RA62/014).