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MicroRNA-132 Modulates Cholinergic Signaling and Inflammation in Human Inflammatory Bowel Disease

Maharshak, Nitsan MD*; Shenhar-Tsarfaty, Shani PhD†,‡; Aroyo, Nimrod MD*; Orpaz, Naama MD*; Guberman, Irene; Canaani, Jonathan MD*; Halpern, Zamir MD*; Dotan, Iris MD*; Berliner, Shlomo MD; Soreq, Hermona PhD

doi: 10.1097/MIB.0b013e318281f47d
Original Basic Science Article

Background: MicroRNA-132 (miR-132) targets acetylcholinesterase (AChE) and potentiates the cholinergic blockade of inflammatory reactions in cultured cells and experimental mice, but the implications of this interaction to human inflammatory disease remained unexplored. This study aimed to test whether miR-132 is causally involved in anti-inflammatory reactions of patients with inflammatory bowel disease (IBD) and modulates vagal tone and consequently inflammation in patients with IBD.

Methods: We prospectively measured inflammation readouts and the cholinergic status (total capacity for hydrolyzing acetylcholine in one's circulation), and AChE activity in 2 independent cohorts of patients with IBD and quantified miR-132 levels in intestinal tissue biopsies removed at colonoscopy from inflamed and apparently quiescent tissues of tested volunteers.

Results: MiR-132 levels are higher in inflamed compared with apparently quiescent intestinal biopsies from patients with IBD. Correspondingly, the cholinergic status and AChE activity was significantly lower in patients with IBD suffering from moderate–severe disease as compared with healthy controls or patient with IBD presenting low disease severity. Patients with IBD (n = 16) presented lower AChE activity compared with healthy controls (n = 33; 289 ± 128 AU versus 391 ± 102 AU, P = 0.001), and a negative correlation between AChE activity and C-reactive protein levels (r = −0.47, P = 0.01). Corroborating these observations in an additional cohort of participants, C-reactive protein and AChE activity were negatively correlated in patients with moderate–severe disease (n = 16; r = −0.6, P = 0.04) and positively correlated in healthy controls (n = 74, r = 0.24, P = 0.046).

Conclusions: Taken together, these findings support an inflammation-dependent homeostatic role for the regulation by miR-132 of AChE in IBD, opening new venues for therapeutic interference.

Article first published online 17 April 2013

*Department of Gastroenterology and Hepatology, Tel Aviv Sourasky Medical Center, The Sackler School of Medicine, Tel Aviv University, Israel;

Department of Chemical Biology, The Edmond and Lily Safra Center of Brain Sciences, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel; and

Department of Internal Medicine ‘H’, Tel Aviv Sourasky Medical Center, The Sackler School of Medicine, Tel Aviv University, Israel.

Reprints: Hermona Soreq, PhD, The Edmond and Lily Safra Center of Brain Sciences, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel (e-mail: soreq@cc.huji.ac.il).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

N.Maharshak and S.Shenhar-Tsarfaty equally contributed to this work.

Supported by the Rose Trees foundation (to H.S) and by an internal grant from. Tel Aviv Sourasky Medical Center. S.S-T is the incumbent of a post-doctoral fellowship by the Edmond and Lily Safra Center of Brain science.

The authors have no conflicts of interest to disclose.

Received October 28, 2012

Accepted November 15, 2012

© Crohn's & Colitis Foundation of America, Inc.
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