Dhanansayan (Dhanu) Shanmuganayagam, PhD

Dhanu Shanmuganayagam, PhD

Biography

Dr. Shanmuganayagam is currently the Director of Research of the Reed Research Group at the University of Wisconsin – Madison.  He has a diverse research background than spans the fields of cardiovascular disease, aging, immune dysfunction and nutrition. His research has included the exploration of how polyphenolic compounds in fruits regulate various physiological processes that impact the development of diseases in animals and humans.

Abstract

Polyphenolics and the gastrointestinal immune system

A significant portion of the body’s immune system is concentrated in the gastrointestinal (GI) tract,1 and thus the modulation of the GI immune system by dietary and environmental factors can influence systemic processes. The innate and acquired immune components of the GI immune system is highly regulated to preserve the integrity of the mucosal barrier that is critical for maintaining the physical and chemical barrier against food and environmental antigens, including microbes.

Enteral nutrition or enteral formulas (e.g., elemental enteral nutrition (EEN) solutions) are widely used to treat gastrointestinal disorders (e.g., Crohn’s disease), inflammatory bowel disease and to maintain appropriate nutrition in the patients with acute (e.g., trauma, burns) and chronic illnesses.2 However, the absence of normal solid food consumption suppresses the intestinal immune system and dramatically increases the risk of infections, related complications and mortality.3-6 For example, risk of complications (e.g., pneumonia and abscess) have been shown to increase 20-40% in hospitalized patients when they are not on oral solid food consumption, resulting in tremendous emotional, medical and economic burden.

In a series of studies in a mouse model of EEN-induced mucosal immune dysfunction, we explored whether the addition of cranberry proanthocyanidins (PACs), which are unabsorbed and have complex interactions with biological components, to EEN solution would stimulate the mucosal immune system and preserve the integrity of the mucosal barrier.

The addition of PACs to EEN solution significantly protected against the impairment of intestinal barrier function following EEN by stimulating lamina propria Th2 cytokines, interleukin (IL)-4 and IL-13 that in turn induced goblet cell (GC) proliferation and mucin-2 (MUC2) production.7 The PACs stimulated Th2 cytokines without any significant effect on Th1 cytokines IL-1β, IL-6, and TNF-α.

Furthermore, the addition of PACs to EEN solution also preserved gut-associated lymphoid tissue (GALT) function by maintaining the Peyer Patch lymphocyte population and the secretion of luminal secretory immunoglobulin A (sIgA).8 We believe that the preservation of luminal sIgA was in part due to the observed preservation of the expression of polymeric immunoglobulin receptor (pIgR) on the GI epithelium that is required for the transport of sIgA into the lumen. Our studies suggest that the preservation of ileal IL-4 by PACs is involved in the maintained modulation of pIgR expression. This notion is supported by the observation that phosphorylation of nuclear factor STAT-6 (a member of the JAK/STAT signaling) at phosphorylation sites Tyrosine 641 (Tyr641) and Threonine 645 (Thr645), a process which modulates pIgR expression, is preserved by the addition of PACs to EEN.

In conclusion, our work suggests that the absence of normal solid food consumption, for example during the administration of EEN solutions, suppresses the intestinal immune system, and that the addition of cranberry PACs to such diets counteracts the observed dysfunction. We believe that a formulation of EEN solutions that includes cranberry PACs has great potential for use as prevention or therapy to preserve or improve intestinal immune function in hospital and home-care settings.

Keywords: enteral nutrition; cranberry; proanthocyanidins; gut-associated lymphoid tissue; goblet cells; mucin; cytokines, secretory IgA; JAK-STAT; polymeric immunoglobulin receptor

References:
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2. Isaacs KL, Lewis JD, Sandborn WJ, Sands BE, Targan SR. State of the art: Ibd therapy and clinical trials in ibd. Inflammatory bowel diseases. 2005;11 Suppl 1:S3-12
3. Li J, Kudsk KA, Gocinski B, Dent D, Glezer J, Langkamp-Henken B. Effects of parenteral and enteral nutrition on gut-associated lymphoid tissue. The Journal of trauma. 1995;39:44-51; discussion 51-42
4. Wu Y, Kudsk KA, DeWitt RC, Tolley EA, Li J. Route and type of nutrition influence iga-mediating intestinal cytokines. Annals of surgery. 1999;229:662-667; discussion 667-668
5. King BK, Li J, Kudsk KA. A temporal study of tpn-induced changes in gut-associated lymphoid tissue and mucosal immunity. Archives of surgery. 1997;132:1303-1309
6. Mosenthal AC, Xu D, Deitch EA. Elemental and intravenous total parenteral nutrition diet-induced gut barrier failure is intestinal site specific and can be prevented by feeding nonfermentable fiber. Critical care medicine. 2002;30:396-402
7. Pierre JF, Heneghan AF, Feliciano RP, Shanmuganayagam D, Roenneburg DA, Krueger CG, Reed JD, Kudsk KA. Cranberry proanthocyanidins improve the gut mucous layer morphology and function in mice receiving elemental enteral nutrition. JPEN. Journal of parenteral and enteral nutrition. 2012
8. Pierre JF, Heneghan AF, Feliciano RP, Shanmuganayagam D, Krueger CG, Reed JD, Kudsk KA. Cranberry proanthocyanidins improve intestinal siga during elemental enteral nutrition. JPEN. Journal of parenteral and enteral nutrition. 2013