Every year, millions of people die from abdominal sepsis, making it a real global health emergency regardless age, ethnicity, location and access to therapeutic care. Sepsis is an uncontrolled systemic inflammation of the organism in response to pathogens invasion. Although the survival rate is significantly increased in the last years because of the improvements of hospitalization conditions and the appropriate antibiotic therapy, the full recovery is dramatically impaired by late manifestations of neurological dysfunctions and cognitive impairments, causing a permanent disability in patients. Understanding the molecular mechanism at the basis of this neurocognitive decline might guarantee a higher quality of life in association with the survival rate of the pathology. Neurocognitive impairment induced by sepsis are not completely understood, and in the last years the possible involvement of the enteric nervous system (ENS) and gut microbiota alterations following sepsis have been highlighted as primitive etiology of tardive neurological dysfunctions in septic patients. It is believed that following the migration of pathogenic bacteria from the gut lumen to the ENS, a marked immune/inflammatory response is activated by enteric glial cells (EGC) that, behaving as antigen presenting cells in the gut, significantly amplify the enteric cytokine response to the brain by a vagal connection. Altered microbiota, works thus as an immune priming of EGC, that reverberates from gut to the spinal cord hence affecting selective brain areas such as cortex and hippocampus. The present research aims at investigate thus the connection among microbiota challenge, EGC priming and tardive neurological dysfunction in the brain in a model of mice sepsis induced by cecal ligation and puncture (CLP). By molecular, micro-biomics and behavioral approaches we will aim at identify novel targets to address for future medical approaches reducing cognitive impairment due to sepsis.
The characteristic neurocognitive complications arising in the post-infectious phase of sepsis are weakening clinic manifestations occurring several years after the recovery from the disease [Iwashyna et al, Jama 2010, 304(16):1787-1794]. The molecular mechanisms responsible for these neurological decline and cognitive impairment have not been investigated yet. A possible interplay among gut microbiota changes, ENS immune priming and enteric inflammation sustained by EGC have been hypothesized to promote a gut-brain axis connection bridging gut alterations to tardive brain dysfunction. The exact mechanism(s) at the basis of this hypothesis are largely unknown. To shed light on this point, the present research projects intends to clarify the exact process by which, following a septic challenge by CLP method, the EGC/ENS might be altered by septic-induced microbiota challenge, and how this reverberates along a vagal-spinal cord-to brain axis in the cortex and hippocampal neurodegeneration. According to the etiology of different neurological conditions ranging from Parkinson¿s disease (PD) [Bullich et al., Mov Disord Clin Pract. 2019 Oct 23;6(8):639-651] to HIV-1-Tat protein-induced dementia [Esposito et al., Sci Rep. 2017 Aug 10;7(1):7735] an intimate entanglement between enteric glia and CNS-glia has been reported. We hypothesize that such connection is also featuring the basis of neurocognitive dysfunctions occurring in sepsis. EGC are very sensitive to detrimental noxiae, as pathogenic bacteria featuring altered microbiota, inducing and supporting a marked immune-inflammatory response through the release of proinflammatory cytokines and signaling molecules [Ruhl A, Neurogastroenterol Motil 2005,17:777-90; Von Boyen BGT, Gut 2004,53:222-228). This in turn, may not restricted in the gut, but it might expand to the CNS by vagal route. Data provided by this project will give important information concerning both clinical and educational field. In a clinical point of view, this study will elucidate the exact involvement of 1. Altered microbiota strains during sepsis; 2; correlation with ENS and EGC priming in the intestinal sepsis course and 3. How these data correlate with the outbreak of neurological complications by behavioral and neuropathological hallmarks investigation in mice. Targeting the gut dysfunction with brain alteration during sepsis, and crossing data provided by microbiota analysis, ENS alteration and behavioral changes, this research project will identify new possible preventive targets of intervention to possibly reduce, in translational way in humans, the economics costs for medical care and diagnostics besides to a significant improvement of the life quality of people survived to sepsis.