Hypothesis and Theory: A Pathophysiological Concept of Stroke-Induced Acute Phase Response and Increased Intestinal Permeability Leading to Secondary Brain Damage

Over my head. So we need the smartest stroke researchers out there to see what followup is needed and put it in the stroke strategy such that regular researchers just have to solve the exact questions and create a stroke protocol on this.  THAT IS WHAT REAL STROKE LEADERSHIP WOULD DO.  But since we have none, nothing will happen and 10 million survivors every year will be screwed forever.   Rather than the milquetoast term of secondary brain damage, it should be the neuronal cascade of death. That is least sounds important to solve. NOW.

Hypothesis and Theory: A Pathophysiological Concept of Stroke-Induced Acute Phase Response and Increased Intestinal Permeability Leading to Secondary Brain Damage

Fabienne Ferrara^1*, Vilia Zeisig², Sören Pietsch³, Rita Rütten¹, Antje Y. Dreyer¹, Laura Pieper⁴, Ann-Kathrin Schatzl¹, Damian D. McLeod^5,6, Henryk Barthel², Johannes Boltze⁷, Wieland Schrödl⁸ and Björn Nitzsche²

• ¹Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany
• ²Clinic and Policlinic for Nuclear Medicine, University of Leipzig, Leipzig, Germany
• ³Klinik und Poliklinik für Kinder und Jugendmedizin, Universitätsklinikum Leipzig, Leipzig, Germany
• ⁴Institut für Veterinär-Epidemiologie und Biometrie, Freie Universität Berlin, Berlin, Germany
• ⁵OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital CG Carus, TU Dresden, HZDR, Dresden, Germany
• ⁶School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, and Hunter Medical Research Institute, The University of Newcastle, Callaghan, NSW, Australia
• ⁷School of Life Sciences, Faculty of Science, University of Warwick, Coventry, United Kingdom
• ⁸Faculty of Veterinary Medicine, Institute of Bacteriology and Mycology, University of Leipzig, Leipzig, Germany

Gut integrity impairment leading to increased intestinal permeability (IP) is hypothesized to be a trigger of critically illness. Approximately 15–20% of human ischemic stroke (IS) victims require intensive care, including patients with impaired level of consciousness or a high risk for developing life-threatening cerebral edema. Local and systemic inflammatory reactions are a major component of the IS pathophysiology and can significantly aggravate brain tissue damage. Intracerebral inflammatory processes following IS have been well studied. Until now, less is known about systemic inflammatory responses and IS consequences apart from a frequently observed post-IS immunosuppression. Here, we provide a hypothesis of a crosstalk between systemic acute phase response (APR), IP and potential secondary brain damage during acute and subacute IS stages supported by preliminary experimental data. Alterations of the acute phase proteins (APPs) C-reactive protein and lipopolysaccharide-binding protein and serum level changes of antibodies directed against Escherichia coli-cell extract antigen (IgA-, IgM-, and IgG-anti-E. coli) were investigated at 1, 2, and 7 days following IS in ten male sheep. We found an increase of both APPs as well as a decrease of all anti-E. coli antibodies within 48 h following IS. This may indicate an early systemic APR and increased IP, and underlines the importance of the increasingly recognized gut-brain axis and of intestinal antigen release for systemic immune responses in acute and subacute stroke stages.

Introduction

Gut integrity (GI) plays an important role in balancing permeable gut functions required for the uptake of nutritional components versus preventive functions such as forming a barrier against pathogen egress (Doig et al., 1998; Otani and Coopersmith, 2019). GI impairment and subsequently increased intestinal permeability (IP) are believed to be a major pathophysiological elements in a number of severe conditions. They have been described in chronic heart failure (Doig et al., 1998; Sandek et al., 2014), complications in intensive care unit (ICU) patients (Klehmet et al., 2009) and in individuals undergoing cardiopulmonary bypass (Riddington et al., 1996), as well as after traumatic brain injury (Bansal et al., 2009). GI impairment and increased IP are supposed to be related to inadequate mucosal perfusion (Doig et al., 1998; Klehmet et al., 2009; Sandek et al., 2014) or a potential epithelial disruption by proinflammatory cytokines such as TNF-α (Triantafilou and Triantafilou, 2002). Decreased intestinal blood flow and increased proliferation of mucosal bacteria were correlated with a higher level of systemic anti-lipopolysaccharide (LPS) IgA in patients with critical chronic heart failure (Sandek et al., 2014).

Despite the recent advances in acute ischemic stroke (IS) management and care (Saver et al., 2016), IS is still a leading cause of chronic disability and death (Zazulia, 2009). Next to primary ischemic and secondary neuroinflammatory brain damage, IS patients also suffer from systemic stroke sequelae such as stroke-induced systemic immune suppression (SIIS) leading to pneumonia or severe gut alterations including dysmotility, microbiotic dysbiosis, and bleedings (Arya and Hu, 2018). While SIIS and related pulmonary infections have been investigated decently (Prass et al., 2003; Dirnagl et al., 2007; Klehmet et al., 2009), not much is known about intestinal epithelial barrier dysfunction following IS. Since GI and increased IP could serve as an important systemic immunological and inflammation trigger, they have recently been discussed as potential elements of systemic IS pathophysiology and as potential therapeutic targets (Zazulia, 2009; Wen and Wong, 2017). Based on a set of preliminary experimental data, we hypothesize that an impaired GI with increased IP can emerge after IS and could potentially pave the way for endogenous gut-borne infections, or fuel reciprocal immune responses leading to secondary brain damage.

Intestinal Permeability and Stroke Models

Recent investigations on the role of the microbiome in mouse IS models suggested a protective function of bacteria in the conventional gut flora as intestinal dysbiosis was associated with poor outcome (Winek et al., 2016; Sadler et al., 2017). However, rodent data on disturbed GI and increased IP following IS are controversial. Some studies report bacterial translocation and sepsis after IS in rats and aged mice (Crasper et al., 2016), while others did not find evidence for increased IP and bacterial translocation 3 days after transient middle cerebral artery occlusion (Oyama et al., 2018). This may raise the question whether these findings from rodent IS models might be breed-, supplier- or even model-specific.

The Stroke Treatment Academic Industry Roundtable (STAIR) expert consortium recommends the additional use of suitable gyrencephalic models of focal cerebral ischemia to increase the validity of experimental findings (Fisher et al., 2009). Due to a closer similarity to humans regarding neuroanatomical and physiological features, large animal models are believed to mimic the clinical situation of human stroke patients realistically (Dirnagl et al., 2013). In particular, large animals might be useful to investigate GI breakdown and increased IP after IS. Ruminants, for which IS models are available (Boltze et al., 2008; Wells et al., 2012), possess a much larger gastrointestinal tract than rodents and humans in both absolute and relative terms, and a higher physiological bacteria load, what may be an advantage when aiming to detect potential systemic immunological consequences.

Hypothesis: Stroke-Induced Acute Phase Response and Increased Intestinal Permeability Lead to Secondary Brain Damage

The mechanism behind a potential GI impairment and increased IP after IS remain poorly understood. Hypothetically, impaired GI and increased IP can be caused by inadequate mucosal perfusion or epithelial breakdown mediated by proinflammatory cytokines such as TNF-α or zonulin. This has been described in the context of ischemic diseases and reduced organ motility (Rahman et al., 2018). Indeed, inflammatory cytokines can compromise intestinal mucosa integrity by affecting endothelial (gate) and tight junction (fence) functions (Bruewer et al., 2003).

Within minutes, IS leads to a four-step process of ischemia-related blood-brain barrier breakdown (BBB) in peri-infarct regions (Ballabh et al., 2004; Sandoval and Witt, 2008; Krueger et al., 2015), accompanied by endothelial cell damage and loss (Krueger et al., 2015). BBB disruption then facilitates exchange of blood components and brain antigens such as brain myelin basic protein (del Zoppo and Mabuchi, 2003; Offner et al., 2006; Krueger et al., 2015). Inflammatory cytokines are released into the circulation in large amounts after IS and hence could inflict “off-site” damage to the intestinal mucosa. Moreover, inflammatory cytokines induce the production of acute phase proteins (APPs) in the liver, but interestingly also in intestinal epithelium (Molmenti et al., 1993; Wang et al., 1998). Some APPs, such as serum amyloid A (SAA) stimulate inflammatory cytokine production themselves, providing a positive feedback mechanism. SAA, once present in the circulation, also increases the recruitment of immune cells to inflammatory sites. Other APPs, such as coagulation factors and plasminogen activator-inhibitor foster coagulation and might negatively affect perfusion, contributing to thromboinflammation in cerebral and intestinal capillaries. A vicious circle finally leading to increased secondary brain damage might evolve (Figure 1).

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