Altered intestinal barrier contributes to cognitive impairment in old mice with constipation after sevoflurane anesthesia

Tianyun Zhao; Junming Lu; Jingwen Qin; Yanxin Chen; Ziwen Shi; Wei Wei; Peng Xiong; Daqing Ma; Xingrong Song

doi:10.3389/fnut.2023.1117028

Altered intestinal barrier contributes to cognitive impairment in old mice with constipation after sevoflurane anesthesia

Front Nutr. 2023 Sep 12:10:1117028. doi: 10.3389/fnut.2023.1117028. eCollection 2023.

Authors

Tianyun Zhao^{1

2}, Junming Lu³, Jingwen Qin², Yanxin Chen³, Ziwen Shi², Wei Wei², Peng Xiong⁴, Daqing Ma^{5

6}, Xingrong Song^{1

2

7}

Affiliations

¹ The First Affiliated Hospital of Jinan University, Guangzhou, China.
² Department of Anesthesiology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
³ Department of Anesthesiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
⁴ Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China.
⁵ Division of Anaesthetics, Pain Medicine & Intensive Care, Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.
⁶ National Clinical Research Center for Child Health, Zhejiang, China.
⁷ Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou, China.

Abstract

Background: Elderly patients have a high risk of developing postoperative cognitive dysfunction (POCD). Gastrointestinal disorders, such as constipation, in the elderly population may be involved in the pathogenesis of neurological disorders by promoting inflammatory responses due to a 'leaky gut'. General anesthetic sevoflurane may impair gastrointestinal function in elderly patients to trigger neurological complications following surgery. Therefore, we hypothesized that elderly individuals with gastrointestinal dysfunction may be more vulnerable to sevoflurane and consequently develop POCD.

Methods: Aged mice were randomly divided into four groups: control (CTRL), CTRL+sevoflurane (Sev), slow transit constipation (STC), and STC + Sev. Mice in the STC and STC + Sev groups were intra-gastrically administrated loperamide (3 mg/kg, twice a day for 7 days) to induce a slow transit constipation (STC) model determined with fecal water content and the time of first white fecal pellet, whereas mice in the other groups received the similar volume of saline. One week later, mice in the CTRL+Sev group and STC + Sev group received 2% sevoflurane for 2 h. The gut permeability evaluated with 4-kDa fluorescein isothiocyanate (FITC)-dextran, serum cytokines, microglia density, TLR4/NF-κB signaling expression, and POCD-like behavioral changes were determined accordingly.

Results: The loperamide-induced STC mice had decreased fecal water content and prolonged time of first white fecal pellet. Sevoflurane exposure caused significantly increased gut permeability and serum cytokines, as well as the activation of microglia and the TLR4/NF-κB signaling pathway in the prefrontal cortex of the aged STC mice. Sevoflurane also caused cognitive impairment and emotional phenotype abnormality in aged STC mice.

Conclusion: Aged STC mice were more vulnerable to sevoflurane anesthesia and consequently developed POCD-like behavioral changes. Our data suggest that gastrointestinal disorders including constipation may contribute to the development of POCD.

Keywords: gastrointestinal dysfunction; gut permeability; microglia; perioperative neurocognitive dysfunction; slow transit constipation.