Rodney D. Berg

The indigenous gastrointestinal microflora

The indigenous gastrointestinal (GI) tract microflora has profound effects on the anatomical, physiological and immunological development of the host. The indigenous microflora stimulates the host immune system to respond more quickly to pathogen challenge and, through bacterial antagonism, inhibits colonization of the GI tract by overt exogenous pathogens. Indigenous GI bacteria are also opportunistic pathogens and can translocate across the mucosal barrier to cause systemic infection in debilitated hosts.

The gut as a portal of entry for bacteremia. Role of protein malnutrition.

The current studies were performed to determine the influence of malnutrition alone or in combination with endotoxemia in promoting bacterial translocation from the gastrointestinal tract. Bacterial translocation did not occur in control, starved (up to 72 hours), or protein-malnourished (up to 21 days) mice not receiving endotoxin. Bacterial translocation to the mesenteric lymph nodes (MLNs) occurred in 80% of control mice 24 hours after receiving endotoxin (p less than 0.01). However, the combination of malnutrition plus endotoxin was associated with a higher incidence of translocation to the systemic organs (p less than 0.01), and higher numbers of bacteria per organ (p less than 0.01), than was seen in normally nourished mice receiving endotoxin. Additionally, mice that were protein malnourished were more susceptible to the lethal effects of endotoxin than were control animals, and the mortality rate was directly related to the degree of malnutrition (R2 = 0.93) (p less than 0.05). Histologically, endotoxin in combination with protein malnutrition resulted in mechanical damage to the gut mucosal barrier to bacteria. Thus, in the mice that were protein malnourished the spread of bacteria from the gut could not be controlled nor could translocated bacteria be cleared as well as normally nourished mice receiving endotoxin. These results support the concept that under certain circumstances the gut may serve as a clinically important portal of entry for bacteria.

Hemorrhagic shock induces bacterial translocation from the gut.

Sepsis and multiple organ failure are common after hemorrhagic shock. The goal of the current experiments was to determine whether hemorrhagic shock would promote the translocation of bacteria from the gut to visceral organs. Twenty-four hours after being subjected to sham shock, or 30, 60, or 90 minutes of shock (30 mm Hg), rats were sacrificed and their organs quantitatively cultured for translocating bacteria. There was a direct relationship between the duration of hemorrhagic shock and the 24-hour mortality rate (p = 0.02). Bacteria did not translocate from the gut in the sham-shock rats, but did translocate to the mesenteric lymph nodes, livers, and spleens of the rats subjected to hemorrhagic shock (p less than 0.01). Rats subjected to 90 minutes of shock shock exhibited a greater degree of bacterial translocation than rats receiving 30 or 60 minutes of shock (p less than 0.05). The most common translocating bacteria were Escherichia coli and Enterococcus. Hemorrhagic shock injured the gut mucosa and caused subepithelial edema and focal areas of necrosis. Thus hemorrhagic shock followed by reinfusion of shed blood disrupts the gut barrier and allows indigenous bacteria normally contained within the gut to cause systemic infections.

Bacterial translocation from the gastrointestinal tract

Bacterial translocation is defined as the passage of viable indigenous bacteria from the gastrointestinal tract to extraintestinal sites, such as the mesenteric-lymph-node complex, liver, spleen and bloodstream. Three major mechanisms promote bacterial translocation: intestinal bacterial overgrowth, deficiencies in host immune defenses and increased permeability or damage to the intestinal mucosal barrier.

Bacterial translocation from the gastrointestinal tract.

Bacterial translocation is defined as the passage of viable bacteria from the gastrointestinal tract to extraintestinal sites, such as the mesenteric lymph node complex, liver, spleen, kidney, and blood. The major mechanisms promoting bacterial translocation in animal models are: (a) disruption of the ecologic equilibrium to allow intestinal bacterial overgrowth, (b) deficiencies in host immune defenses, and (c) increased permeability of the intestinal mucosal barrier. These mechanisms can act in concert to promote synergistically the systemic spread of indigenous translocating bacteria to cause lethal sepsis. Studies are presented of attempts to delineate the mechanisms promoting bacterial translocation utilizing animal models of intestinal bacterial overgrowth, immunosuppression, T-cell deficiencies, solid tumors, leukemia, diabetes, endotoxemia, hemorrhagic shock, thermal injury, bowel obstruction, bile duct ligation, protein malnutrition and parenteral nutrition. Also described are the use of selective antibiotic decontamination or nonspecific macrophage immunomodulators in attempts to reduce bacterial translocation from the gastrointestinal tract.

Obstructive jaundice promotes bacterial translocation from the gut

Experiments were performed to determine if obstructive jaundice promotes the translocation of bacteria from the gastrointestinal tract to visceral organs. Three groups of mice were studied: control (n = 20), sham ligated (n = 28), and bile duct ligated (n = 33). The sham-ligated group underwent laparotomy and manipulation of the portal region, whereas the ligated group had their common bile ducts ligated. Seven days later, the mice were killed, their organs cultured, and the gastrointestinal tract examined histologically. The bilirubin levels of the ligated group (18.7 mg/dL) were elevated compared with the other groups (0.5 mg/dL) (p less than 0.05). The incidence of bacterial translocation was higher in the ligated (33%) than in the control (5%) or sham-ligated (7%) groups (p less than 0.05). Since bile is important in binding endotoxin and maintaining a normal intestinal microflora, cecal bacterial populations were quantitated. The cecal levels of gram-negative, enteric bacilli were 100-fold higher in the bile duct-ligated mice in which bacterial translocation occurred (p less than 0.05), indicating that intestinal bacterial overgrowth was a major factor responsible for bacterial translocation. The mucosal appearance of the intestines from the control and sham-ligated groups was normal. In contrast, subepithelial edema involving the ileal villi was present in the ligated group. In conclusion, the absence of bile within the gastrointestinal tract allows intestinal overgrowth with enteric bacilli and the combination of bacterial overgrowth and mucosal injury appears to promote bacterial translocation.

Effect of oral antibiotics and bacterial overgrowth on the translocation of the GI tract microflora in burned rats.

Infections in burned patients have generally been considered to arise from exogenous organisms. Consequently, the therapy of burned patients has emphasized the use of infection control policies and topical antimicrobial agents to reduce bacterial colonization. Even though enteric bacteria are frequently found in the burn wound little attention has been paid to the patients own GI tract microflora as a potential source of organisms colonizing the burn wound. The current experiments were carried out to determine if the bacteria present in the GI tract of healthy animals would penetrate (translocate) through the GI mucosa and spread to visceral organs after a moderate or major thermal injury. The results of these experiments indicated that bacteria can translocate across the wall of the GI tract and survive in the mesenteric lymph nodes in healthy rats. Furthermore, when the GI tract microflora is altered, either due to bacterial overgrowth or under the influence of oral antibiotic therapy, not only will bacteria translocate to the mesenteric lymph nodes but bacteria will also spread to other visceral organs. The results of these experiments support the hypothesis that the GI tract can serve as a reservoir for nosocomial infections in the burned patient, since bacteria can translocate across the mucosal barrier of the GI tract after thermal injury and survive in visceral organs before colonization of the burn wound occurs.

Effect of hemorrhagic shock on bacterial translocation, intestinal morphology, and intestinal permeability in conventional and antibiotic-decontaminated rats.

Bacterial translocation and ileal and cecal injury have been shown to occur 24 h after limited periods of hemorrhagic shock. The present studies were performed to determine the temporal sequence of mucosal injury, permeability, and bacterial translocation after hemorrhagic shock. The results indicated that bacterial translocation and mucosal injury have occurred by 2 h after a 30-min episode of shock (mean arterial pressure 30 mm Hg). Although the histologic extent of the intestinal mucosal injury was less at 2 h postshock than at 24 h postshock, at both times intestinal barrier function was lost as measured by permeability to horseradish peroxidase. Since the role of translocating bacteria in potentiating the loss of intestinal barrier function after shock is unclear, the second goal was to determine whether the extent of shock-induced mucosal injury and permeability could be reduced or abrogated by antibiotic decontamination of the gut. The extent of shock-induced mucosal injury and intestinal permeability was similar between rats with a normal gut flora (greater than 10(6) bacteria/g cecum) and antibiotic-decontaminated rats (less than 10(3) bacteria/g cecum) 2 h postshock, although the incidences of bacterial translocation were 67% and 0, respectively. Thus, shock-induced mucosal permeability and injury appear not to be directly related to the presence of translocating bacteria.

Bacterial translocation from the gut: a mechanism of infection.

Bacterial infection is a common and serious problem in burn victims who survive the shock phase of thermal injury. Our experimental work, plus the clinical studies of others, suggests that the gut can serve as a reservoir for systemic infections caused by bacteria that cross (translocate) the gastrointestinal (GI) epithelium. Bacterial translocation from the GI tract does not normally occur in the healthy animal owing to (1) the presence of an indigenous GI microflora preventing bacterial overgrowth, (2) an intact intestinal epithelial barrier, and (3) normal host immune defenses. However, a thermal injury, as well as other stressors, can result in the disruption or impairment of any of these protective mechanisms, potentially leading to lethal systemic infections with bacteria colonizing the gut.

Endotoxin-induced bacterial translocation and mucosal permeability: role of xanthine oxidase, complement activation, and macrophage products.

Background and MethodsPreviously, we documented that nonlethal doses of endotoxin injure the intestinal mucosal barrier and promote bacterial translocation from the gut to systemic organs. The current study was performed to determine the role of cytokines and complement activation in the pathogenesis of endotoxin-induced mucosal injury and bacterial translocation, as well as to quantify the magnitude of endotoxin-induced intestinal mucosal permeability. ResultsThe frequency of endotoxin-induced bacterial translocation was similar between normal outbred (88%), complement deficient (67%), and macrophage-hyporesponsive (55%) mice, indicating that neither complement nor macrophage activation is necessary for endotoxin-induced bacterial translocation to occur. As early as 2 hrs after endotoxin challenge, there was evidence of a greater than two-fold increase in ileal (p = .008) but not jejunal (p = .11) permeability as measured by the clearance of 51Cr EDTA. Both the increase in endotoxin-induced ileal permeability and the occurrence of bacterial translocation were largely prevented by pretreatment with allopurinol, a competitive inhibitor of xanthine oxidase. ConclusionsThese results suggest that endotoxin-induced bacterial translocation, mucosal injury, and ileal permeability are mediated via activation of xanthine oxidase, and not through complement activation or the liberation of macrophage products.