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Effects of Route and Type of Nutrition on Mucosal Defense Mechanisms

Funding:

Department of Veteran’s Affairs, Merit Review

Principal Investigator:

Kenneth A. Kudsk, MD

Project Summary:

Ventilator-dependent and hospital-acquired pneumonia occurs in many critically ill or injured trauma patients, costing the U.S. health system approximately $2 billion per year. Enteral (ENT) feeding reduces pneumonia in critically injured trauma and general surgical patients compared with parenteral nutrition (PN) or with starvation.

Our experimental and clinical work provides evidence of altered mucosal immunity. IgA levels increase initially after injury and then drop in non-ENT-fed patients following physical trauma or during illness. Similar results occur in mice as defenses to bacteria drop as the IgA levels drop in PN-fed mice. Defenses improve with increased complexity of ENT diets. Experimentally, glutamine (GLN) and the neuropeptide, bombesin (BBS), maintain mucosal defenses in PN-fed mice. Understanding control mechanisms for IgA production and the effects of supplements to PN such as GLN and BBS can provide a tool to increase IgA levels and minimize pneumonia, sepsis, and subsequent multiple organ failure. ENT feeding maintains normal mucosal immune cell populations and Th-2 IgA-stimulating cytokines in mice. Lack of ENT depresses respiratory IgA levels, resulting in loss of established antibacterial and antiviral respiratory defenses. These immune alterations recover with ENT refeeding. We identified significant decreases in transport of IgA in non-ENT-fed animals associated with decreased mucosal polymeric immunoglobulin receptor (pIgR) expression. pIgR transports IgA to mucosal surfaces after plasma cell production. Each molecule of IgA requires one molecule of pIgR. Basal pIgR levels are controlled by the Th-2 cytokine, IL-4, via the JAK-STAT signaling pathway. Our new data show that pIgR protein drops with PN. Physical trauma in mice increases respiratory IgA levels after 8 hr in association with elevated stress cytokines and increases in pIgR. We confirmed this IgA increase in trauma patients, noting dramatic increase in respiratory IgA 24 hr after injury, with rapid decrease (by 90-95%) within 48 hr in non-ENT-fed patients. Acute increases are stimulated by the stress cytokine, TNF-alpha, via the NFkB signaling pathway.

 

We will study effects of route and type of nutrition (and GLN and BBS) on this immunity, hypothesizing:

  1. that PN reduces intestinal and respiratory SIgA levels by reducing pIgR expression due to lack of ENT stimulation.
  2. that the mechanism of basal-reduced pIgR is through down-regulation of IL-4 signaling.
  3. that the down-regulated IL-4 results in attenuated pIgR production via reduced JAK-STAT signaling in the intestine and respiratory tracts.
  4. that PN impairs the innate mucosal IgA response to injury by reducing the pIgR through reduced NFkB pathway stimulation.
  5. that GLN and BBS maintain IgA levels by reversing the negative IV-TPN effects on the pathways.

 

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