Chronic Ultrasound (‘Emotional’) Stress in Mice Exacerbates Colitis Through GSK3β-Mediated Neuroimmune Dysregulation and Is Ameliorated by Probiotic Intervention
10 affiliations
- 1Department of Psychiatry and Neuropsychology, Maastricht University, 6211 LK Maastricht, The Netherlands
- 2Research and Education Resource Center, Peoples Friendship University of Russia (RUDN University), 117198 Moscow, Russia
- 3Hotchkins Brain Institute, University of Calgary, Calgary, AB T2N 1N4, Canada
- 4Department of Anesthesiology,The Ohio State University, Columbus, OH 43210, USA
- 5Department of Biology, Lomonosov Moscow State University, 119991 Moscow, Russia
- 6Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan
- 7Department of Normal Physiology, Sechenov University, 119048 Moscow, Russia
- 8Institute of General Pathology and Pathophysiology, 125315 Moscow, Russia
- 9Laboratory of Genetic Technology and Gene Editing for Biomedicine and Veterinary, National Research Belgorod State University, 308015 Belgorod, Russia
- 10Division of Molecular Psychiatry, Center of Mental Health, University of Hospital Würzburg, Magarete Höppel-Platz 1, 97080 Würzburg, Germany
Abstract
Background: Growing evidence supports a bidirectional relationship between ‘emotional’ (psychological) stress and intestinal inflammation. ‘Emotional stress’, a form of stress that is triggered by negative information and experiences of non-physical nature, is an established risk factor for the development of subclinical intestinal inflammation, called irritable bowel syndrome (IBS), to inflammatory bowel disease (IBD). However, the underlying mechanisms of this transition remain unclear, owing to the limited availability of appropriate animal models. Glycogen synthase kinase-3β (GSK3β), a molecular hub of ‘emotional stress’ response, as shown particularly in the ultrasound stress (US) model, and an important player in gut inflammation, may underlie this transition. Here, we propose a mouse paradigm for the progression from IBS to IBD-like syndrome by combining the US with dextran sulfate sodium (DSS)-induced colitis paradigm in mice and investigate the role of GSK3β signaling under these conditions. Methods: C57BL/6 mice were subjected to a 21-day US consisting of irradiation of alternating ‘negative’ and ‘neutral’ frequencies, followed by 5 days of 0.5% DSS exposure via drinking water. A standardized anti-inflammatory probiotic VSL#3 whose efficacy was shown in DSS-based models was administered to a subgroup of mice. Behavioral, histological, and molecular outcomes previously established in US and IBS models were evaluated. This included parameters of anxiety, anhedonia, time of intestinal transit, fecal water content, and brain and gut neutrophil infiltration, as well as gene expression of pro-inflammatory cytokines and of GSK3β, and serum levels of pro-inflammatory molecules. Given the important role of the nervus vagus in brain–gut interactions, molecular changes were studied in the nervus vagus as well. Results: Mice exposed to the combined US and DSS challenge had impaired intestinal transit and increased fecal water content, neutrophil infiltration, the upregulation of pro-inflammatory mediators and GSK3β in the gut that together manifested the IBD-like state. In this group, upregulated gene expression of these markers was found in the prefrontal cortex and the hippocampus, as well as in the vagus. The combined US and DSS challenge exacerbated anxiety- and anhedonia-like behaviors and elevated blood cytokine and chemokine levels. In comparison to these changes, solitary exposures to US or DSS exerted smaller effects on the majority of measured parameters. Probiotic treatment attenuated most of the physiological, inflammatory, and behavioral abnormalities induced by the combined US and DSS intervention. Conclusions: The mouse model employed here using both US and DSS recapitulated the progression of IBS to the IBD associated with ‘emotional stress’ and demonstrated upregulated gut and brain Gsk3β expression accompanying this transition. The described model provides a useful paradigm for investigating the mechanisms underlying the disease development from IBS- to IBD-like pathology.
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BibTeX
@article{gorlova2026chronic,
title = {{Chronic Ultrasound (‘Emotional’) Stress in Mice Exacerbates Colitis Through GSK3β-Mediated Neuroimmune Dysregulation and Is Ameliorated by Probiotic Intervention}},
author = {Anna Gorlova and Abrar Haque and Nathaniel Reid and Anatoly Inozemtsev and Sholpan Askarova and Aleksei Umriukhin and Anna Obleukhova and Elena Zakharova and Johannes P. M. de Munter and Alexander M. Dudchenko and Almagul Kushugulova and Alexey V. Deykin and Tatyana Cherdyntseva and Dmitrii Pavlov and Tatyana Strekalova},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209092},
url = {https://www.mdpi.com/1422-0067/27/20/9092},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Chronic Ultrasound (‘Emotional’) Stress in Mice Exacerbates Colitis Through GSK3β-Mediated Neuroimmune Dysregulation and Is Ameliorated by Probiotic Intervention
AU - Anna Gorlova
AU - Abrar Haque
AU - Nathaniel Reid
AU - Anatoly Inozemtsev
AU - Sholpan Askarova
AU - Aleksei Umriukhin
AU - Anna Obleukhova
AU - Elena Zakharova
AU - Johannes P. M. de Munter
AU - Alexander M. Dudchenko
AU - Almagul Kushugulova
AU - Alexey V. Deykin
AU - Tatyana Cherdyntseva
AU - Dmitrii Pavlov
AU - Tatyana Strekalova
PY - 2026
DA - 2026/10/14
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209092
UR - https://www.mdpi.com/1422-0067/27/20/9092
AB - Background: Growing evidence supports a bidirectional relationship between ‘emotional’ (psychological) stress and intestinal inflammation. ‘Emotional stress’, a form of stress that is triggered by negative information and experiences of non-physical nature, is an established risk factor for the development of subclinical intestinal inflammation, called irritable bowel syndrome (IBS), to inflammatory bowel disease (IBD). However, the underlying mechanisms of this transition remain unclear, owing to the limited availability of appropriate animal models. Glycogen synthase kinase-3β (GSK3β), a molecular hub of ‘emotional stress’ response, as shown particularly in the ultrasound stress (US) model, and an important player in gut inflammation, may underlie this transition. Here, we propose a mouse paradigm for the progression from IBS to IBD-like syndrome by combining the US with dextran sulfate sodium (DSS)-induced colitis paradigm in mice and investigate the role of GSK3β signaling under these conditions. Methods: C57BL/6 mice were subjected to a 21-day US consisting of irradiation of alternating ‘negative’ and ‘neutral’ frequencies, followed by 5 days of 0.5% DSS exposure via drinking water. A standardized anti-inflammatory probiotic VSL#3 whose efficacy was shown in DSS-based models was administered to a subgroup of mice. Behavioral, histological, and molecular outcomes previously established in US and IBS models were evaluated. This included parameters of anxiety, anhedonia, time of intestinal transit, fecal water content, and brain and gut neutrophil infiltration, as well as gene expression of pro-inflammatory cytokines and of GSK3β, and serum levels of pro-inflammatory molecules. Given the important role of the nervus vagus in brain–gut interactions, molecular changes were studied in the nervus vagus as well. Results: Mice exposed to the combined US and DSS challenge had impaired intestinal transit and increased fecal water content, neutrophil infiltration, the upregulation of pro-inflammatory mediators and GSK3β in the gut that together manifested the IBD-like state. In this group, upregulated gene expression of these markers was found in the prefrontal cortex and the hippocampus, as well as in the vagus. The combined US and DSS challenge exacerbated anxiety- and anhedonia-like behaviors and elevated blood cytokine and chemokine levels. In comparison to these changes, solitary exposures to US or DSS exerted smaller effects on the majority of measured parameters. Probiotic treatment attenuated most of the physiological, inflammatory, and behavioral abnormalities induced by the combined US and DSS intervention. Conclusions: The mouse model employed here using both US and DSS recapitulated the progression of IBS to the IBD associated with ‘emotional stress’ and demonstrated upregulated gut and brain Gsk3β expression accompanying this transition. The described model provides a useful paradigm for investigating the mechanisms underlying the disease development from IBS- to IBD-like pathology.
SN - 1422-0067
ER -