Brain-immune axis regulation is responsive to cognitive behavioral therapy and mindfulness intervention: Observations from a randomized controlled trial in patients with Crohn's disease

Anna Nemirovsky^{1

2}, Karny Ilan¹, Livnat Lerner¹, Liel Cohen-Lavi^{2

3}, Doron Schwartz⁴, Ganit Goren⁵, Ruslan Sergienko⁶, Dan Greenberg⁷, Vered Slonim-Nevo⁵, Orly Sarid⁵, Michael Friger⁶, Shirley Regev⁵, Shmuel Odes⁴, Tomer Hertz^{1

2

8}, Alon Monsonego^{1

2}; Israeli IBD Research Nucleus (IIRN)

Affiliations

¹ The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
² The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel.
³ Department of Industrial Engineering and Management, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel.
⁴ Dept. of Gastroenterology and Hepatology, Soroka Medical Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
⁵ Spitzer Department of Social Work Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
⁶ Department of Public Health, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
⁷ Department of Health Systems Management, School of Public Health, Guilford Glazer Faculty of Business and Management, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
⁸ Vaccine and Infectious Disease Division, Fred Hutch Cancer Research Center, Seattle, WA, USA.

PMID: 35024638
PMCID: PMC8728050
DOI: 10.1016/j.bbih.2021.100407

Brain-immune axis regulation is responsive to cognitive behavioral therapy and mindfulness intervention: Observations from a randomized controlled trial in patients with Crohn's disease

Anna Nemirovsky et al. Brain Behav Immun Health. 2021.

. 2021 Dec 23:19:100407.

doi: 10.1016/j.bbih.2021.100407. eCollection 2022 Feb.

Authors

Affiliations

¹ The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
² The National Institute of Biotechnology in the Negev, Zlotowski Neuroscience Center, and Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel.
³ Department of Industrial Engineering and Management, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel.
⁴ Dept. of Gastroenterology and Hepatology, Soroka Medical Center, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
⁵ Spitzer Department of Social Work Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
⁶ Department of Public Health, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
⁷ Department of Health Systems Management, School of Public Health, Guilford Glazer Faculty of Business and Management, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
⁸ Vaccine and Infectious Disease Division, Fred Hutch Cancer Research Center, Seattle, WA, USA.

PMID: 35024638
PMCID: PMC8728050
DOI: 10.1016/j.bbih.2021.100407

Abstract

Background and aims: Crohn's disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the hypothalamus-pituitary-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) impacts their inflammatory process.

Methods: Circulating inflammatory markers and a wide range of psychological parameters related to stress and well-being were measured in CD patients before and after COBMINDEX. Inflammatory markers in CD patients were also compared to age- and sex-matched healthy controls (HCs).

Results: CD patients exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by interconnected inflammatory modules represented by IL-6, TNFα, IL-17, MCP-1 and IL-18. Notably, higher IL-18 levels correlated with higher score of stress and a lower score of wellbeing in CD patients. COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 and IFNα and negatively with those of MCP-1. Furthermore, inflammatory markers of CD patients at baseline predicted COBMINDEX efficacy, as higher levels of distinct cytokines and cortisol at baseline, correlated negatively with changes in disease activity (by Harvey-Bradshaw Index) and psychological distress (global severity index measure) following COBMINDEX.

Conclusion: CD patients have a characteristic immunological profile that correlates with psychological stress, and disease severity. We suggest that COBMINDEX induces stress resilience in CD patients, which impacts their well-being, and their disease-associated inflammatory process.

Keywords: CD, Crohn's disease; COBMINDEX, Cognitive-behavioral and mindfulness-based stress reduction; Crohn's disease; Cytokines; HC, Healthy controls; HPA axis; HPA, Hypothalamus-pituitary-adrenal; IBD; IBD, Inflammatory bowel disease; Mindfulness; Psychological intervention; Stress.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Doron Schwartz reports a relationship with Takeda Pharmaceutical Co Ltd that includes: consulting or advisory and speaking and lecture fees. Doron Schwartz reports a relationship with AbbVie Inc that includes: consulting or advisory and speaking and lecture fees. Doron Schwartz reports a relationship with Pfizer Inc that includes: consulting or advisory. Doron Schwartz reports a relationship with Janssen Pharmaceuticals Inc that includes: speaking and lecture fees. Doron Schwartz reports a relationship with Ferring Pharmaceuticals Inc that includes: speaking and lecture fees. Doron Schwartz reports a relationship with Neopharm Labs Inc that includes: speaking and lecture fees. Ganit Goren reports a relationship with Ferring Pharmaceuticals Inc that includes: speaking and lecture fees.

Figures

**Fig. 1**
**CD patients demonstrate higher levels of the inflammatory cytokines IL-6 and IL-18.** Increased levels of IL-6 (A) and IL-18 (B) in serum samples of CD patients (n=92) in comparison to healthy controls (n=55). p-values were calculated with Mann-Whitney Test.

**Fig. 2**
**Cytokine interactions modules among CD patients at baseline.** A heatmap portraying Spearman correlations and their p-values corrected using family-wise error rate (FWER) for multiple hypothesis adjustment (Methods). Numbers indicate the correlations and asterisks indicate the FWER-adjusted p-values of these correlations: ∗p < 0.05, ∗∗p < 0.005 and ∗∗∗ for p < 0.0005. The colored stripes represent the assignment of cytokines to modules (M1-M5) by their correlations using the CytoMod algorithm (Cohen et al., 2019).

**Fig. 3**
**Psychological, biological and clinical variables are interconnected in CD patients. A.** Score ranges of medical and psychological characteristics: visualization of lowest and highest potential scores of 6 main parameters (HBI, GSI, PSS4, SIBDQ, SF12MH and FACIT, details in Materials and Methods) as they relate to the patients' well being. B. A network graph visualizing the correlations between inflammatory and psychological variables. Each variable is represented by a node and each correlation by a line, with varying of width according to the correlation magnitude. SFMH=SF12MH, SFPH=SF12PH, SIB=SIBDQ.

**Fig. 4**
**IL-18 as a biomarker for declined well-being in CD patients**. Visualization of the overall interactions between IL-18 levels and the psychological parameters of CD patients at baseline (Table S2). The red line denotes the negative correlation coefficients, the blue line denotes a positive correlation coefficients, and the thickness of the line stands for the correlation coefficients that are significant at the level of 5% (p < 0.05). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

See this image and copyright information in PMC

References

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Brain-immune axis regulation is responsive to cognitive behavioral therapy and mindfulness intervention: Observations from a randomized controlled trial in patients with Crohn's disease

Affiliations

Brain-immune axis regulation is responsive to cognitive behavioral therapy and mindfulness intervention: Observations from a randomized controlled trial in patients with Crohn's disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources

Miscellaneous