Microbiome in Critical Care: An Unconventional and Unknown Ally.

BACKGROUND: The digestive tract represents an interface between the external environment and the body where the interaction of a complex polymicrobial ecology has an important influence on health and disease. The physiological mechanisms that are altered during hospitalization and in the intensive care unit (ICU) contribute to the pathobiota's growth. Intestinal dysbiosis occurs within hours of being admitted to ICU. This may be due to different factors, such as alterations of normal intestinal transit, administration of various medications, or alterations in the intestinal wall, which causes a cascade of events that will lead to the increase of nitrates and decrease of oxygen concentration, and the liberation of free radicals. OBJECTIVE: This work aims to report the latest updates on the microbiota's contribution to developing sepsis in patients in the ICU department. In this short review, the latest scientific findings on the mechanisms of intestinal immune defenses performed both locally and systemically have been reviewed. Additionally, we considered it necessary to review the literature on the basis of the many studies carried out on the microbiota in the critically ill as a prevention to the spread of the infection in these patients. MATERIALS AND METHODS: This review has been written to answer four main questions: 1- What are the main intestinal flora's defense mechanisms that help us to prevent the risk of developing systemic diseases? 2- What are the main Systemic Abnormalities of Dysbiosis? 3- What are the Modern Strategies Used in ICU to Prevent the Infection Spreading? 4- What is the Relationship between COVID-19 and Microbiota? We reviewed 72 articles using the combination of following keywords: "microbiota" and "microbiota" and "intensive care", "intensive care" and "gut", "critical illness", "microbiota" and "critical care", "microbiota" and "sepsis", "microbiota" and "infection", and "gastrointestinal immunity" in: Cochrane Controlled Trials Register, Cochrane Library, Medline and Pubmed, Google Scholar, Ovid/Wiley. Moreover, we also consulted the site ClinicalTrials.com to find out studies that have been recently conducted or are currently ongoing. RESULTS: The critical illness can alter intestinal bacterial flora leading to homeostasis disequilibrium. Despite numerous mechanisms, such as epithelial cells with calciform cells that together build a mechanical barrier for pathogenic bacteria, the presence of mucous associated lymphoid tissue (MALT) which stimulates an immune response through the production of interferon-gamma (IFN-y) and THN-a or or from the production of anti-inflammatory cytokines produced by lymphocytes Thelper 2. But these defenses can be altered following hospitalization in ICU and lead to serious complications, such as acute respiratory distress syndrome (ARDS), health care associated pneumonia (HAP) and ventilator associated pneumonia (VAP), systemic infection and multiple organ failure (MOF), but also to the development of coronary artery disease (CAD). In addition, the microbiota has a significant impact on the development of intestinal complications and the severity of the SARS-COVID-19 patients. CONCLUSION: The microbiota is recognized as one of the important factors that can worsen the clinical conditions of patients who are already very frail in the intensive care unit. At the same time, the microbiota also plays a crucial role in the prevention of ICU-associated complications. By using the resources that are available, such as probiotics, synbiotics or fecal microbiota transplantation (FMT), we can preserve the integrity of the microbiota and the GUT, which will later help maintain homeostasis in ICU patients.

Exploiting the Lymph-Node-Amplifying Effect for Potent Systemic and Gastrointestinal Immune Responses via Polymer/Lipid Nanoparticles.

Parenteral vaccinations are not able to elicit effective systemic and gastrointestinal immune protection simultaneously because the lymphocytes are typically restricted to primed tissues. Although all-trans retinoic acid (atRA) was reported to trigger the gut-homing of immunocytes, the bioavailability and systemic immune responses remain limited for use in robust enteric vaccinations. Here, we show that co-delivery of atRA, CpG oligodeoxynucleotides (CpG), and antigens via engineered polymer/lipid nanoparticles (PLNPs) could exploit the amplifying function of draining lymph nodes (DLNs) for potent gut tropism and immune activations. After intramuscular injection, forming an immune-potentiated environment at the injection site, the PLNPs induced the designated transfer of primed dendritic cells (DCs) to the DLNs instead of the gastrointestinal tissues. Within the DLNs, the immune-potentiated environment markedly amplified the antigen presentation and homing receptor switch among immunocytes, which simultaneously stimulated the preferential dissipation of activated lymphocytes in the peripheral and gastrointestinal tissues, that is, exerted a DLN-amplifying effect. Compared with current atRA-containing formulations, the PLNPs not only boosted potent IgG secretions and T cell activations in the peripheral tissue but also provoked robust T cell homing and antigen-specific IgA levels in the gastrointestinal tracts in both ovalbumin and EV71 vaccinations. These data indicate that exploiting DLN amplification can stimulate potent systemic and gastrointestinal responses for more efficient enteric vaccinations.

Oral vaccination with influenza hemagglutinin combined with human pulmonary surfactant-mimicking synthetic adjuvant SF-10 induces efficient local and systemic immunity compared with nasal and subcutaneous vaccination and provides protective immunity in mice.

We reported previously that a synthetic mucosal adjuvant SF-10, which mimics human pulmonary surfactant, delivers antigen to mucosal dendritic cells in the nasal cavity and promotes induction of humoral and cellular immunity. The aim of the present study was to determine the effects of oral administration of antigen combined with SF-10 (antigen-SF-10) on systemic and local immunity. Oral administration of ovalbumin, a model antigen, combined with SF-10 enhanced ovalbumin uptake into intestinal antigen presenting MHC II+CD11c+ cells and their CD11b+CD103+ and CD11b+CD103- subtype dendritic cells, which are the major antigen presenting subsets of the intestinal tract, more efficiently compared to without SF-10. Oral vaccination with influenza hemagglutinin vaccine (HAv)-SF-10 induced HAv-specific IgA and IgG in the serum, and HAv-specific secretory IgA and IgG in bronchoalveolar lavage fluid, nasal washes, gastric extracts and fecal material; their levels were significantly higher than those induced by subcutaneous HAv or intranasal HAv and HAv-SF-10 vaccinations. Enzyme-linked immunospot assay showed high numbers of HAv-specific IgA and IgG antibody secreting cells in the gastrointestinal and respiratory mucosal lymphoid tissues after oral vaccination with HAv-SF-10, but no or very low induction following oral vaccination with HAv alone. Oral vaccination with HAv-SF-10 provided protective immunity against severe influenza A virus infection, which was significantly higher than that induced by HAv combined with cholera toxin. Oral vaccination with HAv-SF-10 was associated with unique cytokine production patterns in the spleen after HAv stimulation; including marked induction of HAv-responsive Th17 cytokines (e.g., IL-17A and IL-22), high induction of Th1 cytokines (e.g., IL-2 and IFN-γ) and moderate induction of Th2 cytokines (e.g., IL-4 and IL-5). These results indicate that oral vaccination with HAv-SF-10 induces more efficient systemic and local immunity than nasal or subcutaneous vaccination with characteristically high levels of secretory HAv-specific IgA in various mucosal organs and protective immunity.

Gastrointestinal immune and microbiome changes during parenteral nutrition.

Parenteral nutrition (PN) is a lifesaving therapy that provides intravenous nutrition support to patients who cannot, or should not, feed via the gastrointestinal (GI) tract. Unfortunately, PN also carries certain risks related to infection and metabolic complications compared with enteral nutrition. In this review, an overview of PN and GI immune and microbiome changes is provided. PN impacts the gut-associated lymphoid tissue functions, especially adaptive immune cells, changes the intestinal epithelium and chemical secretions, and significantly alters the intestinal microbiome. Collectively, these changes functionally result in increased susceptibility to infectious and injurious challenge. Since PN remains necessary in large numbers of patients, the search to improve outcomes by stimulating GI immune function during PN remains of interest. This review closes by describing recent advances in using enteric nervous system neuropeptides or microbially derived products during PN, which may improve GI parameters by maintaining immunity and physiology.

Microbiome-Linked Crosstalk in the Gastrointestinal Exposome towards Host Health and Disease.

The gastrointestinal exposome represents the integration of all xenobiotic components and host-derived endogenous components affecting the host health, disease progression and ultimately clinical outcomes during the lifespan. The human gut microbiome as a dynamic exposome of commensalism continuously interacts with other exogenous exposome as well as host sentineling components including the immune and neuroendocrine circuit. The composition and diversity of the microbiome are established on the basis of the luminal environment (physical, chemical and biological exposome) and host surveillance at each part of the gastrointestinal lining. Whereas the chemical exposome derived from nutrients and other xenobiotics can influence the dynamics of microbiome community (the stability, diversity, or resilience), the microbiomes reciprocally alter the bioavailability and activities of the chemical exposome in the mucosa. In particular, xenobiotic metabolites by the gut microbial enzymes can be either beneficial or detrimental to the host health although xenobiotics can alter the composition and diversity of the gut microbiome. The integration of the mucosal crosstalk in the exposome determines the fate of microbiome community and host response to the etiologic factors of disease. Therefore, the network between microbiome and other mucosal exposome would provide new insights into the clinical intervention against the mucosal or systemic disorders via regulation of the gut-associated immunological, metabolic, or neuroendocrine system.