Common Mucosal Immunity: A Novel Hypothesis

Over the past 15 years, considerable research effort has been directed at elucidating the role of the gut in the pathogenesis of nosocomial infections. The following figure integrates this information into our current paradigm of postinjury multiple organ failure (MOF). ¹

Briefly, trauma patients are resuscitated into the systemic inflammatory response system (SIRS) and when severe, it causes early MOF. As time goes on, certain aspects of SIRS are down-regulated to prevent ongoing “auto-destructive” inflammation, which results in delayed immunosuppression and when severe, contributes to the nosocomial infections that cause late MOF. With regard to the gut’s potential involvement, shock (via ischemia/reperfusion injury and inhibitory neuroendocrine reflexes) and emergency laparotomy (via anesthesia and bowel manipulation) cause an early ileus. Disuse (parenteral instead of enteral nutrition) and intensive care unit therapies (e.g., H₂-antagonists, narcotics, broad-spectrum antibiotics) promote further gut dysfunction, characterized by progressive ileus, colonization of the upper gut, increased permeability, and decreased gut-associated lymphoid tissue (GALT) function. Consequently, the upper gut becomes a reservoir for pathogens, and local and systemic defense mechanisms that prevent the spread of these organisms become impaired; the primary route of dissemination (i.e., aspiration vs. translocation) is not clear. Although there is good epidemiologic evidence for this sequence of events, prospective randomized controlled trials of gut-specific therapies (e.g., selective gut decontamination, early enteral nutrition, and most recently immune-enhancing enteral formulas) that have consistently demonstrated a reduction in postinjury nosocomial infections (principally pneumonia) are the most convincing evidence.

How nutrition modulates this complex clinical scenario has been an area of great interest. In the 1980s, early nutrition was provided to prevent the acute protein malnutrition induced by SIRS. ^2,3 This presumably maintained vital organ function and blunted immunosuppression. Prospective randomized controlled trials in the late 1980s demonstrated that early enteral nutrition, compared to total parenteral nutrition (TPN), reduced postinjury infections. ^4,5 The exact mechanisms responsible for this difference in septic morbidity has been an enigma. Multiple factors are likely involved. ⁶ First, lack of enteral nutrition or lack of specific nutrients (e.g., glutamine, SCFA, fiber) may promote bacterial translocation. While bacterial translocation has been a popular endpoint in laboratory models, clinical studies have had a difficult time demonstrating that bacterial translocation is a common pathogenic event in critically injured patients. Second, excessive administration of glucose or lipids with TPN may worsen immunosuppression. This has been demonstrated in laboratory models, and three recent prospective randomized controlled trials of perioperative TPN have demonstrated that the TPN-fed patients, compared to controls who received no nutritional supplementation, have higher postoperative septic morbidity. Third, specific nutrients (e.g., glutamine, arginine, omega-3 fatty acids, and nucleotides) enhance immune effector cell function independent of preventing SIRS-induced acute protein malnutrition. “Immune-enhancing” enteral formulas supplemented with one or more of the aforementioned nutrients have been tested in at least 13 published prospective randomized controlled trials. Of those, 11 trials have demonstrated that patients who received the immune-enhancing diets, compared to standard enteral diets, had improved outcomes (principally reduced infectious morbidity).

Kudsk and colleagues, in this issue of Annals of Surgery, ⁷ offer a fourth compelling explanation. Stimulation of the enteric nervous system (by enteral feeding or parenteral bombesin) enhances both local GALT and systemic mucosa-associated lymphoid tissue (MALT) function, which decreases the risk of nosocomial pneumonia. Specifically, they demonstrate that 5 days of TPN, compared to chow feeding, results in decreased GALT mass, decreased IgA levels in the gut and lung, and increased mortality to a clinically relevant septic challenge. Of note, these differences can be reversed by treating the TPN-fed animals with 3 days of the neuropeptide bombesin. While these consistent and logical associations do indicate a cause-and-effect relationship, it is important to emphasize that the authors’ studies have focused on specific immunologic parameters that they believe are important. However, the pulmonary immune response to a bacteria challenge involves a variety of other effector pathways that may have been directly or indirectly enhanced by intravenous bombesin therapy.

In summary, this is another in a series of thought-provoking experimental models by Dr. Kudsk and his colleagues. It emphasizes that the gut is an important immunologic organ that can be modulated to favorably affect systemic immunity. The common mucosal immune system hypothesis is an exciting area of research, and their observations provide an alternative plausible explanation of how early enteral nutrition decreases postinjury infections, and provide new insight into the role of the gut in postinjury MOF and other critical illnesses. Ultimately, this research may lead to novel therapeutic interventions that will benefit patients who can only be fed by the parenteral route. I look forward to the authors’ next round of experiments.