1211CHAPTER 102 Critical Illness and the Microbiome remains relatively stable over time 57 A disrupted microbiome early in life (during a so called critical window) has been linked to abnormal develop[.]
CHAPTER 102 Critical Illness and the Microbiome Pregnancy Metabolic state: insulin resistance Infection 1211 Early childhood Infection Allergy, atopy Autoimmunity Cystic fibrosis Cancer Adolescence–adulthood Infection Metabolic state (obesity, diabetes) Allergy, atopy Inflammatory bowel disease Autoimmunity Cystic fibrosis Cancer Infancy Infection Immune development Brain development Allergy, atopy • Fig 102.2 Physiologic and pathologic roles of the microbiome relevant to pediatrics (From Kliegman R, St Geme J Nelson Textbook of Pediatrics, 21st ed Philadelphia: Elsevier; 2020.) remains relatively stable over time.57 A disrupted microbiome early in life (during a so-called critical window) has been linked to abnormal development of the immune system, risk of obesity, and atopic diseases, including asthma53 (Fig 102.2) TABLE 102.2 ICU Factors Affecting the Microbiome Factor Intensive care unit environment Development of Intensive Care Unit Dysbiosis in Children Following the launch of the HMP, most initial studies investigating links between dysbiosis and disease focused on outpatients with chronic diseases As also seen in adults, children with chronic medical conditions can harbor different microbiota in their mouth, colon, and skin relative to healthy controls.58 For example, patients dependent on enteral tube feeds have been found to be depleted of commensal microbiota and enriched with pathogenic bacteria.59 A well-studied topic is the dysbiosis observed in children undergoing hematopoietic stem cell transplant (HSCT) Studies are beginning to describe the impact of these changes In addition to the risk of infection, HSCT patients with dysbiosis may be more likely to develop graft-versus-host disease.60 In recent years, studies of the microbiome and disease have been extended to critical illness, where alterations in the microbiome are particularly susceptible to rapid temporal variation Disruptions to the microbiome in critical illness are likely unavoidable due to a combination of factors related to the host, illness, ICU environment, and ICU therapies Preclinical models of critical care—which include starvation, preoperative antibiotics, Sedation Acid suppression (proton pump inhibitor and histamine H2 receptor antagonist) References 22, 63–66 67 62, 68, 69 Catecholamines 70 Antibiotic therapy 71–75 Intubation 76–79 Enteral nutrition 59, 80 Parenteral nutrition 81, 82 Head position 83, 84 Selective decontamination of the digestive tract Vascular catheterization 85 86, 87 and abdominal surgery—reliably cause severe dysbiosis 61 A landmark article recently demonstrated that many classes of medications—including proton pump inhibitors, antipsychotics, and calcium channel blockers—have unanticipated antimicrobial effects.62 A list of ICU factors affecting the microbiome is presented in Table 102.2 1212 S E C T I O N X I Pediatric Critical Care: Immunity and Infection Older culture-dependent microbiome studies in the ICU,88,89 which focused narrowly on specific pathogens such as S aureus and P aeruginosa, have reproducibly shown that the risk of colonization with pathogens increases over time in the ICU and that such colonization is associated with risk of a hospital-acquired infection More recently, the application of culture-independent techniques to longitudinal studies of oral, tracheal, skin, and rectal samples from critically ill children have identified changes in multiple pathogenic organisms as well as healthy commensal bacteria over time in the pediatric intensive care unit (PICU) In one study, which enrolled a population with 95% of patients requiring mechanical ventilation, samples were collected within 48 hours of admission and then every to days and compared to a healthy volunteer database and children admitted for minor trauma.90 The findings of this study showed that children admitted to the PICU rapidly develop (1) loss of diversity, (2) loss of body-site specificity, and (3) presence of pathogens at high levels Perhaps equally important, critical illness was characterized by a depletion of commensal microorganisms, such as Ruminococcus from the gastrointestinal tract and Rothia and Haemophilus from the mouth These results are similar to those seen in studies of the microbiome in critically ill adults.25 The natural history of ICU dysbiosis is not yet known According to some reports, ICU dysbiosis appears to improve but not completely resolve during hospitalization For example, in a 2-year old chronically ill child admitted with culture-positive sepsis caused by Enterococcus, enterococcal populations at three body sites disappeared with time and initiation of appropriate antibiotics.90 By day 15, the skin and oral communities had adopted a more healthy configuration However, there is little if any long-term data assessing the microbiota of ICU patients months or years after hospital discharge It seems likely that the resilience of an individual’s microbiome—that is, whether the microbiome ultimately returns to its baseline configuration—impacts the risk of adverse outcomes, including hospital readmission The resilience of the gut microbiome has been characterized in the context of antibiotic treatment for healthy volunteers but has not been characterized after ICU discharge Known and Potential Clinical Consequences of Intensive Care Unit Dysbiosis Studies in the past several years have succeeded in characterizing temporal and spatial changes in the microbiome during critical illness However, the correlations between dysbiosis and clinical outcomes are unclear To date, the available data does strongly suggest that aberrant colonization profiles predispose patients to bloodstream infections, ventilator-associated pneumonia (VAP), and urinary infections.91–96 The gut of patients in the neonatal ICU (NICU) are frequently colonized by bacterial communities present on room surfaces touched by caregivers These frequently contain pathogenic bacteria, including E faecalis and K pneumonia.64,65 Disruptions in the normal colonization of infants, rather than growth of a single pathogen, has been associated with necrotizing enterocolitis and late-onset sepsis in neonates.97 In acute respiratory distress syndrome (ARDS), recent research using culture-independent techniques has begun to characterize changes in the lung microbiome A study of adults with sepsis and ARDS observed that the lung microbiome was enriched with bacteria from the gastrointestinal tract, including Bacteroides spp., and correlated with the degree of inflammation as determined by A Bacterial growth + – – Local inflammation B Nutrient abundance + Endothelial and epithelial injury E + + + D Intraalveolar edema C • Fig 102.3 Factors that promote or inhibit bacterial growth in the lower respiratory tract (From Du Moulin GC, Hedley-Whyte J, Paterson DG, Lisbon A Aspiration of gastric bacteria in antacid-treated patients: a frequent cause of postoperative colonisation of the airway Lancet 1982;319:242–245.) measurement of cytokines in bronchoalveolar lavage fluid.98 Research is ongoing to determine whether translocation of enteric bacteria to the lung precedes the development of ARDS Intubated trauma patients were found to have significant loss of diversity over the initial 48 hours of mechanical ventilation and that community characteristics at 48 hours was associated with the subsequent risk of ARDS.95 A positive feedback mechanism that has been proposed for development of pneumonia and ARDS is shown in Fig 102.3 As depicted, local inflammation and nutrient supply inhibit further bacterial growth under normal conditions However, in cases in which local inflammation causes sufficient endothelial and epithelial injury to allow leakage of protein-rich fluid into the alveolar space, the nutrient abundance may be restored, leading to development of pneumonia and collapse of the commensal microbial communities, in turn, leading to growth of a dominant pathogen in a “low-diversity high-biomass” state.99 Future studies should apply culture-independent methods of microbiome analysis to mechanically ventilated children and determine whether the lung microbiome can be targeted directly or indirectly via the gut to prevent the development of ARDS or to reduce symptoms in patients with established ARDS Beyond immune dysfunction and infection, there are many problems experienced among ICU patients that are likely impacted by ICU dysbiosis but have not yet been studied This applies both to normal physiologic functions that deteriorate in the ICU and to ICU complications that are probably more likely in the setting of dysbiosis For example, important and compelling research has demonstrated the contributions of the gut microbiota to gut motility, cognitive function, and circadian rhythm.100–102 An example of a complication with unexpected association with the microbiome is thrombosis risk Elegant studies have demonstrated how the gut microbial metabolite trimethylamine N-oxide (TMAO) induces platelet hyperresponsiveness and predicts thrombotic event risk (myocardial infarction and stroke).103 Interestingly, in murine studies, platelet hyperresponsiveness and thrombosis potential were transmissible by cecal microbial transplantation of high-TMAO-producing organisms.103 This relationship has not been studied in the ICU A major challenge in the ICU remains clarifying and optimizing the relationship between dysbiosis, malnutrition, and supplemental nutrition The relationship between the microbiome, energy balance, and malnutrition is now well established as a result CHAPTER 102 Critical Illness and the Microbiome of seminal research from Gordon and others.5,24 The relevance of recent lessons learned on this subject is not yet clear in the context of the microbiome-modifying variables in Table 102.2 in patients who are unable to eat, patients who cannot eat but can tolerate enteral nutrition delivered by tube, and patients receiving only parenteral nutrition Since any acute dietary change appears to alter the gut microbiome, it seems almost certain that these dietary changes in the ICU impact the onset and recovery from dysbiosis Moreover, the chemically defined formulas often provided as the source of supplemental enteral nutrition have features shown to promote inflammation and dysbiosis, including low fiber content, high sugar content, and addition of artificial emulsifiers.104,105 Two recent publications indicated that natural plantbased enteral nutrition offers advantage over artificial formulas in preventing dysbiosis and reducing intestinal inflammation.59,106 An emerging topic undoubtedly related to ICU care and outcomes is the contribution of microbes to metabolism of medications (xenobiotics) For example, enzymes produced by the gut bacteria Eggerthella lenta have been found to inactive digoxin and, together with changes in dietary protein intake, significantly affect serum drug concentration.107 Even the response to probiotic therapy is contingent on the presence or absence of indwelling gut microbes prior to initiation of treatment.108 It is not surprising to see infectious complications in ICU patients with dysbiosis However, importantly, many ICU patients with dysbiosis never develop such complications For this reason, open questions include whether biomarkers can be identified to predict infection prior to onset, and whether specific subgroups of patients are more or less likely to benefit from the microbiometargeted interventions discussed in the next section Microbiome-Based Therapeutics in the Intensive Care Unit The explosion of knowledge regarding contributions of the microbiota to homeostasis and disease pathogenesis has led to a dramatic parallel increase in microbiome-based therapeutics.109 These consist of at least two broad categories of therapeutics: those that seek to directly modify the microbiome or reverse dysbiosis, either preemptively or in the setting of complications, and those that seek to deliver important microbial metabolites with or without the organisms that typically produce these metabolites Probiotics Probiotics are live microbes that can be administered to patients, which represents one of the most common strategies to reverse dysbiosis The mechanisms whereby probiotics may improve outcomes from critical illness include immunomodulation, stimulation of mucus and IgA production, and reduction of overgrowth by pathogenic species.110 A meta-analysis of 19 published studies in hospitalized adults observed that administration of probiotics closer to the initiation of antibiotics reduced the incidence of Clostridium difficile infection (CDI) by greater than 50%.111 A Cochrane systematic review found low-quality evidence to suggest that the use of probiotics is associated with lower incidence of VAP in adult ICU patients.112 The Canadian Clinical Practice Guidelines Committee now recommends the consideration of probiotics in critically ill patients The utility of probiotics in pediatric critical care has been evaluated in two single-center randomized controlled trials 1213 (RCTs) First, in a study of children in Northern India with severe sepsis randomized to usual care plus placebo or a multistrain probiotic containing Lactobacillus, Bifidobacterium, and Streptococcus species, patients receiving probiotics had a reduction in systemic inflammation and organ dysfunction scores at days as well as a trend toward fewer HAIs and shorter length of stay.113 An earlier study in which all children admitted to the PICU were eligible for enrollment randomized patients to receive placebo or Lactobacillus rhamnosus strain GG (Culturelle) daily observed no difference in the incidence of HAI Thus, with limited data available from PICUs, future studies of probiotic administration with targeted enrollment of patients at highest risk for dysbiosis may be most appropriate Fecal Microbiota Transplantation Fecal microbiota transplantation (FMT), the procedure of transplanting stool from healthy individuals to a patient, is another method to restore eubiosis in patients FMT has been primarily studied outside of the ICU in patients with chronic C difficile colitis In a multicenter study of 335 children who underwent FMT for CDI, 87% had a positive outcome The incidence of serious adverse events was 5%; therefore, FMT was deemed to be an effective and safe therapy overall In critically ill patients, concerns associated with giving a bacterial load to patients with disrupted epithelium, who may be immunosuppressed, and who receive or may receive antibiotics with anaerobic activity against transplanted bacteria have thus far limited its use and reported studies to case reports.114 Case reports of the use of FMT for patients with sepsis have been published.115,116 FMT in two cases was used in patients with multiple-organ dysfunction syndrome (MODS) after completing antibiotic course and refractory to standard medical management Hypothesizing that dysbiosis (confirmed by analysis of the gut microbiome) was contributing to persistent organ dysfunction, antibiotics were held and FMT performed The patients subsequently had resolution of MODS and a reduction in serum markers of inflammation Notably, MODS after shock recovery is the second most common cause of death in children with severe sepsis/septic shock Current treatment options for this patient population are limited to supportive care.117 Selective Gut Decontamination In contrast to probiotics or FMT, selective decontamination of the digestive tract (SDD) or the oral cavity (SOD) aims to prevent nosocomial infection in critically ill patients with dysbiosis by administering nonabsorbable antibiotics expected to have activity against opportunistic pathogens but minimal toxicity against commensal bacteria In one commonly used SDD protocol, patients are administered colisitin, tobramycin, and amphotericin B as a paste in the oropharynx and via feeding tube to the lower gastrointestinal tract A meta-analysis of four RCTs in critically ill children found a significant reduction in the incidence of VAP in patients receiving SDD.118 Significant concern remains regarding the risk of developing multidrug-resistant organisms and cost of therapy related to SDD Regarding the risk of antibiotic resistance, a systematic review of 64 studies from adult critical care found no association between SDD and colonization with antibiotic-resistant organisms.119 The cost of therapy is difficult to determine but is likely to be offset by a reduction in cultures sent to evaluate for nosocomial infection A survey of Canadian 1214 S E C T I O N X I Pediatric Critical Care: Immunity and Infection pediatric intensivists observed that SDD is not performed routinely in PICUs in Canada and emphasized the need for additional pediatric-specific studies.120 Supplementing/Repleting Microbial Metabolites Dysbiosis leading to altered patient levels of metabolites secreted or otherwise modified by commensal microbiota has been associated with multiple disease states, including IBD, depression, cardiovascular disease, and nonalcohol fatty liver disease.109,121 Examples include short- and long-chain fatty acids, bile acids, biogenic amines, and amino acids Short-chain fatty acids are produced by bacterial fermentation of dietary fiber in the gut and have a variety of effects on the host, including regulation of metabolism and immune function.122 Monitoring of microbial metabolites in patients with suspected dysbiosis and repleting those metabolites that are deficient or supplementing beneficial microbial metabolites to supranormal levels may represent a novel therapeutic approach to critically ill patients Metabolite treatment allows direct effect on the host, downstream of the microbiome, and may overcome limitations of other microbiome-targeted therapies Targeted Interventions Against Enterobacteriaceae A novel approach to treating Enterobacteriaceae in the setting of murine colitis models was shown using tungstate treatment, which inhibited grown of pathogenic bacteria during episodes of inflammation by inhibiting molybdenum-cofactor-dependent processes, but had minimal effect on commensal bacteria within a healthy microbiome.123 In contrast, traditional antibiotic therapies with anaerobic activity that are commonly used in the ICU to treat gastrointestinal infection are not selective for pathogenic versus commensal bacteria Termed precision editing of the microbiota, therapies such as tungstate may be used to treat infection without compromising healthy microbiota Monitoring the Intensive Care Unit Microbiome Monitoring the microbiome is not currently available in a highthroughput or real-time fashion Such capability would be useful either for simple observation analogous to common laboratory tests, such as C-reactive protein, or for determining whether microbiome-based interventions have yielded the intended consequences For example, reports have indicated that successful antibiotic administration for a documented infection ought to generate a significant change in the gut microbiome; failure to observe such a change with antibiotics may indicate a high likelihood of failure of antibiotic therapy.20 The reasons behind our inability to monitor the microbiome in real time include cost-effectiveness, the turnaround time of currently available methods, and the complexity of data processing of 16S sequencing However, a recent publication in synthetic biology has proposed a cost-effective paper-based solution to this problem.124 The authors describe a cost-effective synthetic biology platform that is able to identify several bacterial strains based on 16S rRNA, human mRNA, and C difficile toxin mRNA.124 Although the use of these technologies requires further study, they represent a promising start that will allow healthcare providers to bring microbiome science to the bedside Future of Microbiome Science Because the study of the human microbiome has been highly interdisciplinary since its beginning, advances in molecular biology, bioinformatics, or microbiology accelerate microbiome science These developments drive down the costs and increase the efficiency of microbiome studies, making the design of longitudinal studies more feasible.13 The multiomics approach coupled with longitudinal data will provide greater insights into a patient’s microbiome and move the field toward more mechanistic explanations of health and disease Furthermore, advances in microbial culture techniques have significantly expanded the microorganisms that can be cultured in a laboratory setting The function of these new taxa can now be characterized and studied in cell lines and animal models.125 Strain-level studies can also be useful for the discovery of keystone species and disease-relevant strains A better understanding of strain-specific behavior can help design novel community-level experiments and verify hypotheses based on community-level data The study of microbial biomarkers of disease is another particularly promising application of microbiome science Recent publications describing the use of the microbiome in colorectal cancer risk assessment and melanoma immunotherapy efficacy highlight sometimes unforeseen relationships between gut microbes and disease prognosis.31,126–128 Because the number of diseases that involve the microbiome is constantly being expanded, the probability that diagnostic, prognostic, and therapeutic roles are identified is ever increasing Key References NIH HMP Working Group, Peterson J, Garges S, et al The NIH Human Microbiome Project Genome Res 2009;19:2317-2323 Integrative HMP Research Network Consortium The integrative human microbiome project: Dynamic analysis of microbiome-host omics profiles during periods of human health and disease corresponding author Cell Host Microbe 2014;16:276-289 Thaiss CA, Zmora N, Levy M, Elinav E The microbiome and innate immunity Nature 2016;535:65-74 Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R Current understanding of the human microbiome Nat Med 2018;24:392-400 Rogers MB, Firek B, Shi M, et al Disruption of the microbiota across multiple body sites in critically ill children Microbiome 2016;4(1):66 Yeh A, Rogers MB, Firek B, Neal MD, Zuckerbraun BS, Morowitz MJ Dysbiosis across multiple body sites in critically ill adult surgical patients Shock 2016;46:649-654 Byndloss MX, Bäumler AJ The germ-organ theory of non-communicable diseases Nat Rev Microbiol 2018;16:103-110 Wolff NS, Hugenholtz F, Wiersinga WJ The emerging role of the microbiota in the ICU Crit Care 2018;22(1):78 Ihekweazu FD, Versalovic J Development of the pediatric gut microbiome: impact on health and disease Am J Med Sci 2018;356:413-423 Alverdy JC, Krezalek MA Collapse of the microbiome, emergence of the pathobiome, and the immunopathology of sepsis Crit Care Med 2017;45:337-347 David LA, 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Database Project: improved alignments and new tools for rRNA analysis Nucleic Acids Res 2008;37:141-145 45 Pruesse E, Quast C, Knittel K, et al SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB Nucleic Acids Res 2007;35:7188-7196 46 Schloss PD, Westcott SL, Ryabin T, et al Introducing mothur: Open-source, platform-independent, community-supported software for describing and comparing microbial communities Appl Environ Microbiol 2009;75:7537-7541 47 Hamady M, Lozupone C, Knight R Fast UniFrac: Facilitating highthroughput phylogenetic analyses of microbial communities including analysis of pyrosequencing and PhyloChip data ISME J 2010;4:17-27 48 Lozupone C, Knight R UniFrac: a New phylogenetic method for comparing microbial communities Appl Environ Microbiol 2005;71:8228-8235 49 Morgan XC, Huttenhower C Chapter 12: Human Microbiome Analysis PLoS Comput Biol 2012;8(12):e1002808 50 Mukherjee S, Seshadri R1, Varghese NJ, et al 1,003 Reference genomes of bacterial and archaeal isolates expand coverage of the tree of life Nat Biotechnol 2017;35:676-683 ... samples were collected within 48 hours of admission and then every to days and compared to a healthy volunteer database and children admitted for minor trauma.90 The findings of this study showed that... complex communities reveals many novel molecular species within the human gut Appl Environ Microbiol 1999;65(11):4799-4807 41 Magnúsdóttir S, Thiele I Modeling metabolism of the human gut microbiome... experienced among ICU patients that are likely impacted by ICU dysbiosis but have not yet been studied This applies both to normal physiologic functions that deteriorate in the ICU and to ICU complications