Effect of route and type of nutrition on intestine-derived inflammatory responses

BACKGROUND: Immunological links between the gastrointestinal (GI) tract and respiratory tract has been postulated in the development and maintenance of mucosal immunity. Route and type of nutrition affects mucosal immunity by reducing cell populations within the Peyer's patches of the small intestine and lamina propria as well as altering cytokine profiles within these sites. In addition to the mucosal affects, these alternations in cytokines (decreases in interleukin-4 and interleukin-10) also appear to influence the vascular endothelium of the GI tract. DATA SOURCES: This review examines the laboratory data regarding cytokine profile within the gut, endothelial adhesion molecule expression within the intestinal and extraintestinal organs, and the effect of these alterations on neutrophil accumulation and organ responses to gut ischemia/reperfusion. It also describes the effect of a specific nutrient, glutamine, on the starved gut. CONCLUSIONS: Changes induced by failure to feed the GI tract affects GI vascularity increasing expression of proinflammatory adhesion molecules. These adhesion molecules attract neutrophils and prime them for subsequent ischemic events. Lack of feeding the gastrointestinal tract acts as a "first hit" and increases the inflammatory response to a secondary insult in the lungs, liver, and GI tract. The addition of the specific nutrient, glutamine, reverses many of these defects and favorably influences the proinflammatory effects of gut starvation.     

Splanchnic ischaemia and multiple organ failure in the critically ill.

The development of a safe and simple tonometric method of monitoring the adequacy of gastrointestinal mucosal perfusion has provided a new perspective of splanchnic ischaemia in the critically ill. It would appear that splanchnic hypoxia, identified by the presence of intramucosal acidosis in the gut, may be one of the most consistent and earliest indications of impaired tissue perfusion in the critically ill and be causally related to the development of sepsis and multiple organ failure.     

Bacterial translocation: what it is and what it is not

The reasons our critically ill patients die have been a matter of great interest for many decades, with the hope that if we can identify the mechanisms responsible for death, we might be able to intervene and improve outcome. Over the last 1 to 2 decades, the concept of bacterial translocation-the movement of gut origin microbes across the intact gastrointestinal tract into normally sterile tissues where the organisms may then directly cause infection or incite an inflammatory response that causes tissue injury, organ failure, and death-has grown to the point where it is virtually impossible to make rounds in any intensive care setting without a resident or student blaming some complication or another on bacterial translocation. We will attempt to review the clinically relevant information that supports and refutes the concept of bacterial translocation as a cause of our critically ill patients to exhibit the symptoms and signs of sepsis, develop organ failure, and ultimately die.     

The role of the gastrointestinal tract in postinjury multiple organ failure

Despite intensive investigation, the pathogenesis of postinjury multiple organ failure (MOF) remains elusive. Laboratory and clinical research strongly implicate that the gastrointestinal tract plays a pivotal role. Shock with resulting gut hypoperfusion appears to be one important inciting event. While early studies persuasively focused attention on bacterial translocation as a unifying mechanism to explain early and late sepsis syndromes that characterize postinjury MOF, subsequent studies suggest that other gut-specific mechanisms are operational. Based on our Trauma Research Center observations and those of others, we conclude that: 1) bacterial translocation may contribute to early refractory shock; 2) for patients who survive shock, the reperfused gut appears to be a source of proinflammatory mediators that may amplify the early systemic inflammatory response syndrome; and 3) early gut hypoperfusion sets the stage for progressive gut dysfunction such that the gut becomes a reservoir for pathogens and toxins that contribute to late MOF.     

Enteral nutrition and mucosal immunity: implications for feeding strategies in surgery and trauma.

Systemic inflammatory responses to severe trauma and surgical illnesses may be partly responsible for numerous complications, including sepsis, multiple organ failure and unregulated hypermetabolism leading to protein-calorie malnutrition. The integrity of the gastrointestinal tract appears to be an important factor in the pathogenesis of the systemic inflammatory response and sepsis. Resuscitation and nutrition support strategies for preserving gut mucosal integrity have therefore been strongly promoted. This review summarizes the scientific rationale for emphasizing enteral nutritional support of surgical patients, discusses some important limitations of enteral feeding and argues for a flexible approach to nutrition support for these complex patients.     

Gastrointestinal dysfunction in the intensive care unit

Critical illness can disrupt the many functions of the gastrointestinal (GI) system and signs of gut failure are a clear marker of critical illness severity. Prevention and management of GI dysfunction aims to improve outcomes for the critically ill patient. Early enteral nutrition is protective on the gut and encourages GI motility. A careful balance must be struck to deliver sufficient calories and protein while avoiding overfeeding with its associated complications. Gut dysmotility at any level of the GI tract is a common barrier to nutrient delivery in the critically ill. The microbiome is central to gut health and critical illness has an invariably harmful effect on its composition and function. Gut-derived sepsis is one possible consequence that carries high mortality. GI bleeding, intra-abdominal hypertension and bowel ischaemia represent severe manifestations of gut dysfunction. Management of all these complications in the ICU should involve prevention strategies, detection through regular and thorough assessment, and systematic approach to treatment.     

The role of microvascular thrombosis in sepsis

The acute inflammatory response to sepsis gives rise to significant morbidity and mortality. The mechanisms underlying this form of tissue injury are poorly understood. This review examines the evidence that tissue ischaemia due, to generalized microvascular thrombosis may play an important role. Microvascular thrombosis is probably an adaptive response that prevents bacteria in the tissues reaching the systemic circulation via the capillaries. In time, a definitive response by leucocytes removes the bacteria and repairs the damaged tissues. There is however evidence that if microvascular thrombosis becomes generalized, then extensive tissue ischaemia may precipitate organ failure and death. Post-mortem studies of patients with sepsis demonstrate microvascular thrombi in many organs including the kidney, liver, lung, gut, adrenals and brain, and the degree of organ injury is related to the quantity of thrombi. Furthermore studies in human and animal models of sepsis demonstrate therapies that inhibit coagulation or promote fibrinolysis reduce organ failure and mortality. In view of the personal and economic burdens that tissue injury associated with the acute inflammatory response places on the community, further studies to establish the role of microvascular thrombosis are clearly required. Such studies may lead to new therapies to limit or prevent this form of injury.     

Immunonutrition with Long-Chain Fatty Acids Prevents Activation of Macrophages in the Gut Wall

Background  

Immune cells and inflammatory mediators are released from the gastrointestinal tract into the mesenteric lymph during sepsis causing distant organ dysfunction. Recently, it was demonstrated that macrophages in the gut wall are controlled by the vagus nerve, the so-called cholinergic anti-inflammatory pathway.     

肠道细菌移位的研究现状

目的 探讨肠道细菌移位研究的进展。方法 复习2000年至2005年6月关于肠道通透性的改变、肠道菌群失调和全身炎症反应综合征（SIRS）的文献。结果 随着对SIRS和MODS的深入研究，越来越多的证据显示，肠道不仅是MODs的靶器官，更是始动器官。只有保证了肠道黏膜屏障的完整性，才能有效的预防肠道细菌移位。去除原发病，保证肠道的血供和氧供是最基本的治疗方法。早期启动肠道、建立肠内营养以及选择性的肠道去污染也是有效的治疗手段。结论 随着对肠道细菌移位认识的深入，我们的治疗手段不断丰富，可以更有效预防肠道细菌移位的发生，并阻止向SIRS和MODS进一步发展。     

The role of intestinal barrier failure and bacterial translocation in the development of systemic infection and multiple organ failure

Traditionally, evaluation of intestinal function has been limited largely to monitoring gastric pH and intestinal motility. This clinical approach has led clinicians to equate normal intestinal motility with normal intestinal function and to assume that if stress-induced gastric bleeding can be prevented, all will be well. However, it is becoming increasingly clear that the gastrointestinal tract is not a passive organ and that intestinal dysfunction is not limited to ileus and upper gastrointestinal bleeding. Instead, the gastrointestinal tract is recognized as having important endocrine, metabolic, immunologic, and barrier functions, as well as its traditional role in nutrient absorption. Over the last 5 years, there has been a resurgence of interest in the role of intestinal barrier failure in the development of systemic infection and multiple organ failure in the critically ill or injured patient.     

A new perspective on stress ulcer prophylaxis.

Gastric acid suppression by use of either antacids or histamine H2-receptor antagonist therapy is the mainstay of stress ulcer prophylaxis. Available evidence indicating an antimicrobial role for gastric acid calls for the reevaluation of gastric acid suppression. A pH of greater than 4.0 leads to bacterial overgrowth and colonization of the upper gastrointestinal tract which has been associated with nosocomial pneumonia, bacterial translocation from the gut, systemic sepsis, and multiple-organ failure. The availability of alternative therapy should discourage the routine use of acid-suppression therapy in the critically ill patient.     

Ileostomy and colostomy

The formation of intestinal stomas, mainly ileostomy and colostomy, has become an integral approach to the surgical management of several pathologies of the gastrointestinal tract – in both the emergency and elective patient. The basic underlying principle is that faecal flow is diverted away from the site of the pathology, by bringing an end or a loop of bowel, through the anterior abdominal wall. Either in a temporary capacity or permanent role stomas can reduce morbidity and mortality associated with several conditions of the gastrointestinal tract such as perforated colon, inflammatory bowel disease, bowel obstruction and elective cancer operations, for example a low anastomosis in an anterior resection of rectum. It has to be appreciated though that stomas are not without their own set of complications, both in the early and late phases. Initial concerns can be due to ischaemia of the bowel forming the stoma, stomal retraction and obstruction through to later complications such as parastomal hernia formation, stomal prolapse and peristomal skin changes.     

Hydrogen Inhalation Ameliorates Oxidative Stress in Transplantation Induced Intestinal Graft Injury

Ischemia/reperfusion (I/R) injury during small intestinal transplantation (SITx) frequently causes complications including dysmotility, inflammation and organ failure. Recent evidence indicates hydrogen inhalation eliminates toxic hydroxyl radicals. Syngeneic, orthotopic SITx was performed in Lewis rats with 3 h of cold ischemic time. Both donor and recipient received perioperative air or 2% hydrogen inhalation. SITx caused a delay in gastrointestinal transit and decreased jejunal circular muscle contractile activity 24 h after surgery. Hydrogen treatment resulted in significantly improved gastrointestinal transit, as well as jejunal smooth muscle contractility in response to bethanechol. The transplant induced upregulation in the inflammatory mediators CCL2, IL‐1β, IL‐6 and TNF‐α were mitigated by hydrogen. Hydrogen significantly diminished lipid peroxidation compared to elevated tissue malondialdehyde levels in air‐treated grafts demonstrating an antioxidant effect. Histopathological mucosal erosion and increased gut permeability indicated a breakdown in posttransplant mucosal barrier function which was significantly attenuated by hydrogen treatment. In recipient lung, hydrogen treatment also resulted in a significant abatement in inflammatory mRNA induction and reduced neutrophil recruitment. Hydrogen inhalation significantly ameliorates intestinal transplant injury and prevents remote organ inflammation via its antioxidant effects. Administration of perioperative hydrogen gas may be a potent and clinically applicable therapeutic strategy for intestinal I/R injury.     

Strategies to prevent organ failure

The gastrointestinal tract and the generalized inflammatory response initiated by severe injury or infection have been implicated in the pathophysiology of multiple-organ system failure. Once multiple-organ system failure has occurred, treatment focuses on supporting end-organ function. Recent studies have shown, however, that it may be possible to reduce the incidence and prevalence of multiple-organ system failure by controlling the reperfusion injury cascade, normalizing gastrointestinal blood flow and preserving the integrity of the gastrointestinal immune barrier.     

Does selective decontamination of the gastrointestinal tract prevent multiple organ failure? An experimental study

Gut bacteria have been incriminated as causing or contributing to generalized sepsis with multiple organ failure in severely ill patients, and selective decontamination of the gastrointestinal tract of Enterobacteriaceae has been claimed to decrease septic complications in these patients. We studied the effects of selective decontamination of the gastrointestinal tract on survival and organ function in an experimental model of sepsis with multiple organ failure. Wistar rats were inoculated intraperitoneally with zymosan and randomized into control or treatment groups (trimethoprim or streptomycin sulfate). Selective decontamination effectively prevented bacterial translocation of Enterobacteriaceae. However, only early mortality was decreased, and only so in the streptomycin-treated rats. Selective decontamination did not result in a significantly better condition of the surviving animals on day 12.     

Nutrition and metabolism in sepsis and multisystem organ failure

Sepsis and organ failure produce profound metabolic changes that contribute to hepatic and musculoskeletal failure. When multiple organ failure develops, the mortality rate is high, and therapy is unlikely to be effective unless the causative process (e.g., infection, low cardiac output) can be eliminated. Thus, the prevention of multiple organ failure and the prevention or early treatment of infection are paramount. Organ and nutritional support to prevent complications is necessary. The gastrointestinal tract should be used for nutrition whenever possible with a blenderized regular diet with fiber, glutamine, and short-chain fatty acids to protect and preserve the gut. If parenteral nutrition is necessary, special solutions may be necessary for the liver, kidneys, or lungs. If not, protein with 45% branched-chain amino acid, medium- and short-chain triglycerides, glutamine supplementation, and carbohydrates seem best. Other substances are being evaluated that may be helpful in nutrition and organ support, including arginine, xylitol, growth hormone, and anabolic steroids. Multiple organ failure should be prevented, if at all possible, by stopping or controlling the injury, removing as much necrotic tissue as possible, improving blood flow and oxygen consumption, supporting metabolism, and preventing infection or treating it early and adequately. Nutritional support plays a key role in preventing metabolic failure.     

Presidential address: imagination trumps knowledge

Multiple organ failure (MOF) emerged 30 years ago and became our research focus. Over the years, we have proposed a series of cartoons that rallied multidisciplinary translational research teams around common themes to generate “win-win” hypotheses that when tested (right or wrong) have advanced our understanding of MOF. MOF has a bimodal trajectory, and the gut plays a role in both trajectories. Early MOF occurs because of excessive proinflammation (ie, systemic inflammatory response syndrome [SIRS]), and early gut ischemia-reperfusion can amplify SIRS and contribute to the early fulminant SIRS-MOF trajectory. Fortunately, most patients survive early SIRS, but some develop excessive anti-inflammation (ie, compensatory anti-inflammatory response syndrome). The gut also plays a role in this late indolent compensatory anti-inflammatory response syndrome–MOF trajectory. Multiple factors cause progressive gut dysfunction such that the gut (an important immunologic organ) worsens compensatory anti-inflammatory response syndrome and becomes the reservoir for pathogens and toxins that cause late sepsis.     

Postoperative alterations in interorgan glutamine exchange in enterectomized dogs

The effect of enterectomy on postoperative visceral organ glutamine exchange was studied in order to gain further understanding of the role of the intestinal tract in the altered glutamine metabolism that occurs following catabolic illness. In addition to studying glutamine, which transports 1/3 of whole blood amino acid nitrogen, we determined the fluxes of glutamate and alanine across the gastrointestinal tract, liver, and kidneys in 18 postoperative dogs. Arterial glutamine and glutamate were significantly higher in enterectomized animals than in controls. With enterectomy the gut became an organ of glutamine balance while in control dogs the GI tract consumed glutamine (0.11 +/- 0.04 vs 1.67 +/- 0.14 mumole/kg X min, P less than 0.001). The gut switched from an organ of glutamate release to one of net glutamate uptake following enterectomy and intestinal alanine release simultaneously fell by 50%. Simultaneously, the liver reduced its uptake of alanine and became an organ of glutamine release. Renal glutamine consumption was also diminished in enterectomy animals. The interorgan exchange of glutamine and other amino acids is altered by enterectomy. The increase in circulating glutamine levels in enterectomized animals suggests that the accelerated intestinal glutamine consumption that characterizes catabolic illnesses contributes to the low glutamine levels in these stress states. In addition, it becomes apparent that the gut is an important supplier of alanine to the liver, which supports gluconeogenesis. Metabolic adaptation and cooperation between organs is essential during organ absence or dysfunction if the organism is to survive critical illness.     

IgG4-related Disorders of the Gastrointestinal Tract

IgG4-related disease, a newly established multisystemic disease can affect virtually every organ. Histologically, it is characterized by the presence of a dense lymphoplasmacytic infiltrate, storiform-type fibrosis, and obliterative phlebitis. The disease shows elevated serum and tissue IgG4. The pancreas and hepatobiliary tract are involved far more commonly than the tubular gut. This review summarizes the clinical and pathologic features of the gastrointestinal manifestations of IgG4-related disease and discusses the wide spectrum of diseases that this entity may mimic.