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Hippocampal neural stem cells and microglia response to experimental inflammatory bowel disease (IBD)

A Correction to this article was published on 01 September 2020

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Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a disease associated with dysbiosis, resulting in compromised intestinal epithelial barrier and chronic mucosal inflammation. Patients with IBD present with increased incidence of psychiatric disorders and cognitive impairment. Hippocampus is a brain region where adult neurogenesis occurs with functional implications in mood control and cognition. Using a well-established model of experimental colitis based on the administration of dextran sodium sulfate (DSS) in the drinking water, we sought to characterize the short and long-term effects of colitis on neurogenesis and glia responses in the hippocampus. We show that acute DSS colitis enhanced neurogenesis but with deficits in cell cycle kinetics of proliferating progenitors in the hippocampus. Chronic DSS colitis was characterized by normal levels of neurogenesis but with deficits in the migration and integration of newborn neurons in the functional circuitry of the DG. Notably, we found that acute DSS colitis-induced enhanced infiltration of the hippocampus with macrophages and inflammatory myeloid cells from the periphery, along with elevated frequencies of inflammatory M1-like microglia and increased release of pro-inflammatory cytokines. In contrast, increased percentages of tissue-repairing M2-like microglia, along with elevated levels of the anti-inflammatory cytokine, IL-10 were observed in the hippocampus during chronic DSS colitis. These findings uncover key effects of acute and chronic experimental colitis on adult hippocampal neurogenesis and innate immune cell responses, highlighting the potential mechanisms underlying cognitive and mood dysfunction in patients with IBD.

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Fig. 1: Acute DSS colitis induces hippocampal neurogenesis.
Fig. 2: Acute DSS colitis induces deficits in cell cycle kinetics of proliferating hippocampal progenitors.
Fig. 3: Chronic DSS colitis affects the migration of newborn neurons in the DG.
Fig. 4: Chronic DSS colitis affects the integration of newborn and mature dentate granule neurons in the functional circuitry of the DG.
Fig. 5: Innate immune cells in the hippocampus exhibit distinct phenotypes during acute and chronic DSS colitis.
Fig. 6: Cytokine profile in the brain and the periphery during acute and chronic DSS colitis.

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Acknowledgements

We thank Panos Sarantis, and Marianna Orfanou at the Center for Experimental Surgery, Clinical and Translational Research, BRFAA, for their valuable technical assistance in the experiments performed. The study was partially supported by Bodossakis Foundation, Athens, Greece, Captain Fanourakis Foundation, Kos island, Greece, the General Secretariat for Research and Technology (GSRT), and the Hellenic Foundation for Research and Innovation (HFRI) (Code: 1030). KK was supported by Excellence II and the General Secretariat for Research and Technology (GSRT). GX was supported by a ‘Research Excellence’ Grant (# 5035) funded by the General Secretariat for Research and Technology (GSRT) and by a ‘Fondation Santé’ Research Grant in the Biomedical Sciences. AG and IC were supported by DINNESMIN (Τ1Ε∆Κ - 03186) co-financed by Greece and EU in the context of Operational Program “Competitiveness, Entrepreneurship and Innovation” (ΕΠΑΝΕΚ) of the NSRF 2014–2020.

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Correspondence to Katia P. Karalis.

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Gampierakis, IA., Koutmani, Y., Semitekolou, M. et al. Hippocampal neural stem cells and microglia response to experimental inflammatory bowel disease (IBD). Mol Psychiatry 26, 1248–1263 (2021). https://doi.org/10.1038/s41380-020-0651-6

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