The gut microbiome primes a cerebroprotective immune response after stroke

Singh, Vikramjeet; Sadler, Rebecca; Heindl, Steffanie; Llovera, Gemma; Roth, Stefan; Benakis, Corinne; Liesz, Arthur

doi:10.1177/0271678x18780130

Cited by 110 publications

(105 citation statements)

References 8 publications

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“…In the first 2-3 days after AIS, lymphocytes arrive at the ischemic lesion (adaptive response) ( 4 ). In particular, T helper-1 and-17 subpopulations activate neuroinflammation, whereas regulatory T-cells have a neuroprotective action due to their anti-inflammatory properties ( 50 ). The consequences of this remain unclear, as detrimental effects to regulatory T cells after AIS have been reported ( 51 ).…”

Section: Pathophysiologymentioning

confidence: 99%

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

et al. 2020

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The microbiota-gut-brain axis is considered a central regulator of the immune system after acute ischemic stroke (AIS), with a potential role in determining outcome. Several pathways are involved in the evolution of gut microbiota dysbiosis after AIS. Brain-gut and gut-brain signaling pathways involve bidirectional communication between the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, the enteric nervous system, and the immune cells of the gut. Alterations in gut microbiome can be a risk factor and may also lead to AIS. Both risk factors for AIS and gut-microbiome composition are influenced by similar factors, including diabetes, hypertension, hyperlipidemia, obesity, and vascular dysfunction. Furthermore, the systemic inflammatory response after AIS may yield liver, renal, respiratory, gastrointestinal, and cardiovascular impairment, including the multiple organ dysfunction syndrome. This review focus on biochemical, immunological, and neuroanatomical modulation of gut microbiota and its possible systemic harmful effects after AIS, as well as the role of ischemic stroke on microbiota composition. Finally, we highlight the role of gut microbiota as a potential novel therapeutic target in acute ischemic stroke.

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Section: Pathophysiologymentioning

confidence: 99%

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

et al. 2020

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“…Previous findings have shown that the induction of stroke in murine models of brain ischemia can activate immune cells and promote the progression of inflammatory heart disease . Moreover, brain injury can modulate the functions of the intestine and its immune components, supporting the hypothesis of multi-organ failure after stroke (Singh et al, 2016a;Singh et al, 2018). In addition, stroke patients may present signs of severe immunosuppression and inflammation that often lead to hospital-acquired respiratory infections (Shi et al, 2018).…”

Section: Introductionmentioning

confidence: 78%

Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

Singh

Beer

Kraus

et al. 2020

Preprint

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Highlights:Brain tissue injury increases ACE2 levels in the lungs Brain injury induces pro-inflammatory cytokine expression in the lungs Brain injury causes parenchymal inflammation and systemic lymphopeniaAbstract Background: The newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated.Methods: Mice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1β were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry.Results: Strikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1 in the lungs. Higher gene expression of cytokines IL-6 and IL-1 was found in ischemic brain hemispheres and a reduced number of Tlymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression. Conclusions:We demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions.

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“…This is a relationship that is fraught with peril as a nuanced system of checks and balances are required to limit invasive flora whilst restraining overtly inflammatory responses and allowing the host to reap the benefits of housing a commensal community. As a consequence of this intimate host-microbe relationship, it is unsurprising that shifts in the microbial communities inhabiting barrier surfaces are associated with disease states during inflammation, injury and aging (204–207). In this context, metabolites generated by the gastrointestinal microbial community have been demonstrated to calibrate homeostatic and anti-microbial immune networks in situ (208–211).…”

Section: Possible Mechanisms By Which Periodontitis Could Contributementioning

confidence: 99%

Distal Consequences of Oral Inflammation

Konkel

O’Boyle

Krishnan³

2019

Front. Immunol.

105

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Periodontitis is an incredibly prevalent chronic inflammatory disease, which results in the destruction of tooth supporting structures. However, in addition to causing tooth and alveolar bone loss, this oral inflammatory disease has been shown to contribute to disease states and inflammatory pathology at sites distant from the oral cavity. Epidemiological and experimental studies have linked periodontitis to the development and/or exacerbation of a plethora of other chronic diseases ranging from rheumatoid arthritis to Alzheimer's disease. Such studies highlight how the inflammatory status of the oral cavity can have a profound impact on systemic health. In this review we discuss the disease states impacted by periodontitis and explore potential mechanisms whereby oral inflammation could promote loss of homeostasis at distant sites.

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The gut microbiome primes a cerebroprotective immune response after stroke

Cited by 110 publications

References 8 publications

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

Gut Microbiota in Acute Ischemic Stroke: From Pathophysiology to Therapeutic Implications

Stroke increases the expression of ACE2, the SARS-CoV-2 binding receptor, in murine lungs

Distal Consequences of Oral Inflammation

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