Alterations in the gut and immune function are proposed to play an important role in the pathophysiology and progression of critical illness, especially in sepsis. Because the treatment of most aspects of critical illness is supportive, significant research efforts are focused on targeting and preventing the changes that occur in these two complex systems in efforts to devise new therapeutic options. This review focuses on the changes that take place in the gut and therapeutic interventions that may be available in the future.
Defining the Gut
The gut is a complex ecosystem with multiple components that are altered in critical illness. Globally, the gut can be divided into two components: (1) the commensal bacterial microbiome and (2) the structures that provide intestinal integrity or barrier function. The two components are separated by a layer of mucus, which serves as the first barrier separating intraluminal contents and commensal bacteria from the epithelium ( Fig. 70-1 ). We analyze each in more detail to determine how therapeutic modulation of the intestinal microflora or gut integrity may be used to treat septic patients ( Fig. 70-2 ).
Understanding and Altering the Microbiome for Therapeutic Benefit
Perhaps the most striking aspect of the gut is that it plays host to nearly 100 trillion bacteria, which serve an important symbiotic function for the host. The multitude of organisms within the gut exist in differing populations over the life of the host and can be altered by diet, stress, disease, and iatrogenic methods. It is increasingly recognized that these bacterial populations play a key role in the pathogenesis and pathophysiology of critical illness, and they have become a target for therapeutic interventions. To understand how altering the gut bacteria can be beneficial, one must first understand how the microbiome is affected during critical illness and how it may contribute to propagating the disease.
Isolation of enteric bacteria from blood cultures suggests that bacteria are able to translocate across the intestinal barrier into the bloodstream via the portal circulation. However, this process has not been definitively confirmed because portal vein blood samples from trauma patients have failed to isolate enteric bacteria. Rather, bacteria have been isolated from mesenteric lymph nodes in cirrhosis, in portal hypertension, and after hepatectomy. These findings suggest that translocation may occur under specific disease states, but hematogenous spread of bacteria is unlikely.
In studying the intestinal microbial environment, a growing body of evidence suggests that changes in bacterial populations, gene expression, and microenvironment are able to potentiate illness. In mice, intestinal Pseudomonas alters its own gene expression and transforms into a more virulent form after hepatectomy, an effect that is directly potentiated by the administration of morphine. This virulent transformation can be halted by phosphate supplementation or by the prevention of hypophosphatemia, highlighting the importance of maintaining a “healthy” intestinal microbiome. Intestinal microbes constantly survey the surrounding bacterial populations and the microenvironment. Changes in either that may indicate “stress” will lead bacteria to alter their numbers and gene expression, a concept referred to as “quorum sensing.” During health, normal host bacteria produce bacteriocins that inhibit growth of other bacteria, particularly pathogenic ones. This response suggests that virulent transformation might be prevented by therapeutically altering the microbiome. Changes of this nature can be accomplished through supplementation of healthy bacteria, destruction/elimination of pathogenic organisms, or replacement of the entire microbiologic population.
The demonstration of changes in the microbiome led to the development of probiotics and synbiotics that supplement the gut with live bacteria and nutrients to support their growth. Prophylactic probiotic/synbiotic administration reduces the incidence of ventilator-associated pneumonias and infectious complications in trauma patients and those undergoing major abdominal surgery. In the setting of pediatric necrotizing enterocolitis, probiotics may also reduce the associated mortality. However, because probiotic/synbiotic administration has not been shown to significantly alter mortality and in rare instances has resulted in bacteremia, the therapeutic benefit of these agents remains to be determined.
In efforts to attack the problem from a different point of view, ongoing research has examined selective decontamination of the digestive tract (SDD) for critically ill patients. In SDD, broad-spectrum antibiotics are administered prophylactically to prevent bacterial overgrowth. Although SDD may reduce the incidence of ventilator-associated pneumonias, concerns over the development of bacterial resistance have limited its use. A detailed analysis of the risks, benefits, and application of SDD can be found in Chapter 46 .
Restoration of the distal gut microbiome to that of a healthy host via fecal transplantation has emerged as a novel and promising therapeutic option for critically ill patients with several disorders. Perturbations in the intestinal microbiome are inciting factors for several gastrointestinal diseases, of which Clostridium difficile infection is a prime example, and fecal transplantation seeks to target these disease processes. There is also growing evidence that fecal transplantation can correct alterations in the microbiome that play an important role in inflammatory bowel disease, with a reduction in symptoms and even disease remission in a select group of these patients. Although fecal transplantation may benefit select groups of patients, its role as a first-line therapy in critically ill patients remains unclear.
Critical Illness and alterations in Intestinal Integrity
The intestinal epithelium is made up of a single layer of columnar cells that are produced in the crypts of Lieberkühn and migrate upward toward the villous tip, where they are exfoliated into the intestinal lumen. These cells are responsible for nutrient absorption, they provide a barrier against intraluminal contents and bacteria, and they communicate with the immune system. Epithelial cells are held together by an intercellular junctional complex, forming a selective barrier allowing for paracellular transport of ions and solutes. Alterations in the mucus layer and the intercellular junctional complexes impair gut barrier function, whereas epithelial cell apoptosis impairs intestinal integrity ( Fig. 70-1 ).
Mucus-producing epithelial cells secrete a layer of glycosylated proteins that lines the gut and forms a hydrophobic barrier. This protective layer can be altered during states of stress. In critical illness, the mucous layer becomes thinner and loses its hydrophobicity, potentially increasing gut injury. The degree of intestinal injury directly correlates with the extent of mucous layer loss. This effect appears to result, in part, from mucous degradation by pancreatic proteases and digestive enzymes. The proteolytic effects of these compounds can then cause autodigestion (i.e., direct injury to intestinal epithelium). Although isolated loss of the mucous layer is not sufficient to cause systemic organ dysfunction, it does appear to play a synergistic role in the process.
In animal models, treatment with the protease inhibitors 6-amidino-2-naphtyl p -guanidinobenzoate di-methanesulfate, transexamic acid, or aprotinin-attenuated autodigestion and thus intestinal and systemic injury, a benefit that may be related to reduced reactive oxygen species. High molecular weight polyethylene glycol also preserved mucus-producing cells and maintained hydrophobicity. Female rates have preservation of the mucus layer, and this attenuates gut injury, suggesting a hormonal effect on the mucus barrier. Unfortunately, although many of these therapies have shown promise in preclinical models, additional translational and clinical data are needed before being implemented in clinical practice.
Role of Intestinal Lymph in Critical Illness
Although evidence has not supported a role for the hematogenous spread of gut bacteria in the pathogenesis of critical illness, data generated in the last decade indicate that mesenteric lymph may activate neutrophils and cause endothelial cell injury. In particular, pancreatic enzymes that damage the mucus layer may contribute to the generation of “toxic lymph,” although the mechanism, which may involve reactive oxygen species, remains poorly understood. In animal models, ligation of the mesenteric lymph duct prevents critical illness–induced myocardial dysfunction and lung injury. A practical treatment option would need to focus on preventing generation of toxic lymph, perhaps by minimized reactive oxygen species or inhibiting pancreatic proteases.
Gut Epithelial Layer and Intestinal Integrity
The gut and spleen are the only systems in which apoptosis is significantly increased in sepsis and critical illness. Toll-like receptor 4 expression by intestinal epithelial cells mediates proliferation and apoptosis. The relationship between gut epithelial apoptosis and survival from experimental sepsis is multifactorial, reflecting the model of sepsis, timing, and degree of cell death. In one animal model, gut epithelial apoptosis can be prevented through overexpression of the antiapoptotic protein Bcl-2.
The connection between intestinal epithelial cells includes a tight junction complex containing multiple proteins, including occludins, claudins, and junctional adherens molecules. Activation of myosin light chain kinase (MLCK) (an intracellular protein kinase) results in activation of intracellular zonula occludens (ZO) proteins, which leads to junctional complex contraction and allows paracellular molecular transport. This gut barrier function is altered during critical illness, leading to increased intestinal permeability. Proposed mechanisms include altered expression of intracellular ZO and intercellular proteins. In addition, increased expression and activation of MLCK during critical illness may lead to increased contraction of the junctional complex and increased intestinal permeability.
Although there are no clinically available agents that prevent gut epithelial apoptosis, two options have shown promise. Epidermal growth factor (EGF) is a cytoprotective peptide that improves intestinal integrity. In septic animals, EGF treatment normalized gut epithelial proliferation and apoptosis and provided a significant survival advantage. This protective benefit persists when EGF is selectively overexpressed in enterocytes, suggesting that the benefits arise from these cells. Another potential therapeutic option involves the cytokine interleukin 15 (IL-15), which exerts antiapoptotic effects on natural killer cells, dendritic cells, and CD8 T cells. Septic mice treated with IL-15 had improved survival and reduced intestinal apoptosis. Although EGF and IL-15 show promise, they require further study before clinical use. Preventing hyperpermeability may also improve intestinal integrity. ML-9, an MLCK inhibitor, attenuated burn-induced increases in intestinal permeability and normalization of claudin and occludin levels in mice. A similar effect was observed with PIK (membrane permeant inhibitor of MLCK), a second MLCK inhibitor. Therefore targeting the machinery responsible for the maintenance of intestinal integrity may be a potential therapy in critically ill patients.
Conclusions
The gut plays an important role in driving the mortality associated with sepsis and is considered the motor of critical illness. The process reflects alterations in the intestinal microbiome and loss of intestinal integrity and barrier function. Although the therapeutic options for critically ill patients are currently limited, improved understanding of the pathophysiology of critical illness has identified new potential targets for pharmacologic intervention. Additional translational and clinical research is needed to demonstrate clinical utility.
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