Yihui Li1
You Shang
Jianfeng Xie
Huaibo Zhang
Hui Han
Hao Wang- 1Department of Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, China
- 2Department of Critical Care Medicine, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
- 3Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine Southeast University, Zhongda Hospital, Nanjing, China
- 4Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
Editorial on the Research Topic
Causative mechanism and potential pharmacological and non-pharmacological interventions in sepsis-associated encephalopathy
Sepsis is a life-threatening syndrome characterized by multi-organ dysfunction induced by a dysregulated host response to infection (1, 2). Sepsis-associated encephalopathy (SAE) is a widespread dysfunction of the brain that arises as a key complication of sepsis. The incidence of SAE is more than 70% in patients experiencing septic shock, with higher rates observed among elderly individuals, neonates, and those with chronic illnesses. It is associated with long-term neurological damage, including anxiety, memory impairment, and alterations in consciousness. Studies have reported a significantly higher mortality rate among septic patients with SAE (3–5).
A lack of objective and uniform indicators and diagnostic criteria, as well as the neglect of clinical researchers, have resulted in a dearth of epidemiological data on SAE in various populations, including incidence, mortality, risk factors, clinical outcomes, and social and economic burden. Furthermore, there are no animal models fully mimicking the characteristics of SAE (3, 4). Additional investigations are necessary to understand the underlying causative mechanisms of SAE and explore potential pharmacological and non-pharmacological interventions. The goal of this Research Topic is to expand the knowledge of SAE, with a focus on the role of immune disorders. The current issue comprises six articles covering the mechanisms and potential interventions for SAE, utilizing various approaches such as clinical cohort studies, animal models, and microbiome analyses.
SAE in the elderly and pediatric populations
The epidemiological data on SAE in ICU has consistently lacked on two special populations at both ends of the age spectrum: the elderly and children (6). This topic, for the first time, focuses on the clinical data of SAE in these two special populations. Zhao et al. develop a nomogram to predict SAE in elderly patients, while Chen et al. identify risk factors for SAE in children, which can present with unique symptoms. Depending on the different diagnostic criteria, sepsis affects 10% to over 70% of adult ICU patients (5). Elderly and pediatric populations are not spared from SAE. Zhao et al. review data from 22,361 elderly patients (age ≥ 65 years) in the Medical Information Mart for Intensive Care (MIMIC)-IV database and find that 290 patients (37.1%) had SAE. The in-hospital mortality rate was higher in the SAE group than in the non-SAE group (18.8 vs. 8.9%, p < 0.001). They develop a nomogram integrating age, sodium, Sequential Organ Failure Assessment (SOFA) score, heart rate, and body temperature to predict the occurrence of SAE in the elderly population. Chen et al. focus on another special group of sepsis patients, children. In a cohort of 210 children, 91 (43.33%) were diagnosed with SAE. Procalcitonin, calcium, septic shock, Pediatric Logistic Organ Dysfunction-2 (PELOD-2), and midazolam were identified as independent risk factors for SAE, while fentanyl was a protective factor. SAE in children presents unique symptoms, such as anterior fontanelle full/bulging/high tension, muscle hypertonia, muscle hypotonia, hyperreflexia, focal seizure, and generalized seizure.
Immune imbalance in SAE
Liu et al. and Gao et al. bring more cumulative evidence to this topic supporting dysregulated immune response possibly having a central role in SAE. The pathogenesis of SAE involves a dysregulated immune system in the central nervous system (CNS), disruption of the blood-brain barrier, mitochondrial dysfunction, oxidative stress, and other factors (4, 7). Liu et al. summarize the interactions between the brain and peripheral immune system in sepsis. They propose that SAE is mainly caused by neuronal ischemia, cell death, and the disruption of the “neurocentral-endocrine-immune” networks due to the over-activation of immune cells in the brain mediated by the neutrophils, microglia, astrocytes, and the hypothalamic-pituitary-adrenal axis.
Tregs are important anti-inflammatory cells, and Gao et al. emphasize the regulatory roles of Tregs in neurotransmitter modulation, inflammation resolution, regulation of glial cells, brain endothelial cells, and the brain-gut axis in the pathogenesis of SAE. They propose that adoptive cell transfer therapies with Tregs or derived small extracellular vesicles may be a potential treatment strategy for SAE in the future.
Microbiota-gut-brain axis drives SAE
The researchers within this topic have brought new perspectives to the mechanisms of SAE: the gut microbiota regulates normal brain function and mediates SAE, and suggests strategies such as probiotics, fecal microbiota transplantation, vagus nerve stimulation, and short-chain fatty acids (SCFAs) might be proposed to treat SAE by modulating the microbiota-gut-brain axis. The gut is the engine of sepsis, and the microbiota-gut-brain axis regulates normal brain function and mediates SAE (8). Barlow et al. summarize the changes in gut microbiota and metabolites in sepsis, including the production of gamma-aminobutyric acid (GABA) by endogenous gut microbiota such as Bifidobacterium and Lactobacillus. They also review the use of probiotics, fecal microbiota transplantation, and vagus nerve stimulation as strategies to regulate the microbiota-gut-brain axis and treat SAE.
Liao et al. propose another approach to modulate the microbiota-gut-brain axis: SCFAs produced by gut microbiota fermentation of indigestible dietary fiber. They find that the levels of acetate and propionate were significantly reduced in SAE mice, accompanied by gut microbiota dysbiosis, particularly a decrease in SCFA-producing bacteria. SCFAs can antagonize neuroinflammation and protect mouse cognition through G-protein-coupled receptor 43 (GPR43) in SAE.
Perspectives
In summary, sepsis is a life-threatening systemic disease. In terms of organs, the brain is not a survivor. Among the population, the elderly and children are not exempt from SAE. The gut microbiota-mediated immune dysregulation in sepsis may be an important pathological mechanism of SAE. Moreover, Treg immune cells, gut microbiota, and their metabolites may become promising therapeutic strategies for SAE. Nonetheless, there remain several challenges regarding SAE that require increased attention, as highlighted by the Surviving Sepsis Campaign project. The following recommendations are offered as guidelines for preclinical and clinical investigations:
1) Develop clinically efficient, concise, and easy-to-use diagnostic procedures and prognostic models for SAE by integrating multi-scale measures and analyses to better comprehend the underlying mechanisms of disease progression.
2) Establish animal models of SAE that accurately and comprehensively simulate the condition in humans, rather than relying on simple translations of conventional sepsis models. Additionally, the behavioral experiments in these animal models should be implementable without complex instruments or apparatuses.
3) Explore cost-effective and feasible technologies and drugs that can improve the performance of high-risk SAE patients, ideally while also enhancing their ultimate prognoses.
4) Establish interdisciplinary research teams that include critical care physicians, neurologists, internists, and neuroscientists to break down the barriers between bench and bedside, assist clinical practitioners in understanding the pathophysiological characteristics and research progress of SAE, and help neurologists and critical care scientists uncover more potential mechanisms of the disease.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
This work was supported by the National Natural Science Foundation of China (82072231) and the Taishan Scholars Program of Shandong Province (tsqn202103165). The funders were not involved in the collection, analysis, or interpretation of data, or the writing or submitting of this report.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. (2020) 395:200–11. doi: 10.1016/S0140-6736(19)32989-7
2. Yin M, Zheng Y, Zhang L, Qin W, Han H, Wu D, et al. The real-life performance of metagenomic next-generation sequencing in sepsis. J Infect. (2022) 84:418–67. doi: 10.1016/j.jinf.2021.11.018
3. Mazeraud A, Righy C, Bouchereau E, Benghanem S, Bozza FA, Sharshar T. Septic-associated encephalopathy: a comprehensive review. Neurotherapeutics. (2020) 17:392–403. doi: 10.1007/s13311-020-00862-1
4. Gofton TE, Young GB. Sepsis-associated encephalopathy. Nat Rev Neurol. (2012) 8:557–66. doi: 10.1038/nrneurol.2012.183
5. Sonneville R, de Montmollin E, Poujade J, Garrouste-Orgeas M, Souweine B, Darmon M, et al. Potentially modifiable factors contributing to sepsis-associated encephalopathy. Intensive Care Med. (2017) 43:1075–84. doi: 10.1007/s00134-017-4807-z
6. Yin M, Si L, Qin W, Li C, Zhang J, Yang H, et al. Predictive value of serum albumin level for the prognosis of severe sepsis without exogenous human albumin administration: a prospective cohort study. J Intensive Care Med. (2018) 33:687–94. doi: 10.1177/0885066616685300
7. van der Poll T, Shankar-Hari M, Wiersinga WJ. The immunology of sepsis. Immunity. (2021) 54:2450–64. doi: 10.1016/j.immuni.2021.10.012
Keywords: sepsis-associated encephalopathy (SAE), special populations, immune imbalance, microbiota-gut-brain axis, Treg cell
Citation: Li Y, Shang Y, Xie J, Zhang H, Han H and Wang H (2023) Editorial: Causative mechanism and potential pharmacological and non-pharmacological interventions in sepsis-associated encephalopathy. Front. Neurol. 14:1199840. doi: 10.3389/fneur.2023.1199840
Received: 04 April 2023; Accepted: 02 May 2023;
Published: 16 May 2023.
Edited and reviewed by: Sean Ruland, Loyola University Medical Center, United States
Copyright © 2023 Li, Shang, Xie, Zhang, Han and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hui Han, hxf0923@126.com; Hao Wang, wanghao@126.com