Newsletter

[ Vol. 13 No. 3 ] (September - December 2012 )
How can we restore gut starvation-induced impairment of gut immunity?

Kazuhiko Fukatsu
Surgical Center, The University of Tokyo (Japan)

Background and Aim
Gut associated lymphoid tissue (GALT) is a center of systemic mucosal immunity. Naïve lymphocytes are sensitized in Peyer patches (PPs), migrate to mesenteric lymph nodes, enter the systemic circulation via the thoracic duct, and home to intestinal and extra-intestinal mucosal sites. Clinically and experimentally, gut starvation diminishes GALT mass and function, thereby rendering the host susceptible to infectious complications. The best way to keep the gut immune system healthy is to use the gut. However, there are some patient populations who cannot receive or tolerate enteral nutrition. This presentation focuses mainly on our recent work and proposes new methods of reversing gut starvation induced impairments of gut immunity.

Methods and Results
Gut starvation effects on GALT
Murine feeding models have revealed that absence of enteral delivery of nutrients markedly reduces GALT lymphocyte numbers and functions, resulting in poor outcomes in a gut derived-sepsis model and respiratory tract infection models, even when adequate amounts of nutrients are given parenterally. This phenomenon was also verified in humans by immunohistochemical staining of terminal ileum specimens from colon cancer patients.

Use of pharmaconutrients
Because specific nutrients have been demonstrated to enhance and/or modulate host immunity, influences of supplementation of these nutrients via parenteral nutrition (PN) on gut immunity have been tested in murine models.

Glutamine: Glutamine addition to PN moderately restored GALT with PN-induced atrophy and reversed mucosal lgA level reductions, improving survival in a bacterial pneumonia model. PN containing a mixture of three glutamine-dipeptides (Ala-Gln, Gly-Gln and Arg-Gln) can also restore gut lgA levels with well balanced plasma amino acid levels.

Arginine: Arginine reportedly increases lymphocyte proliferation and enhances its function. However, arginine-enriched PN (1%) failed to reverse PN-induced GALT changes in mice.

ω-3 PUFAs: Adding fish oil as an ω-3 PUFA source to PN did not normalize gut immunity. However, an optimal ratio of ω-3 to ω-6 PUFAs may exist for maintenance of GALT and should be explored in future studies.

Butyric acid: Beneficial effects of enteral supplementation of butyric acid have been demonstrated. Our research group is now examining effects of butyric acid-supplemented PN on gut immunity and has found moderate but significant recovery of GALT with normalization of the gut cytokine milieu.

Use of neuropeptides and cytokines
IV administration of bombesin, CCK or gastrin maintained GALT size and function thereby preserving immunity to bacterial pneumonia in PN-fed mice.

IL-7 known as a stimulant of lymphocyte proliferation is produced by gut epithelial cells. Its production is inhibited during PN. Exogenous administration of IL-7 maintained GALT mass and resistance to gut derived sepsis and bacterial pneumonia.

Use of small amounts of enteral nutrition
When mice were fed both EN and PN at various ratios, GALT cell numbers and gut lgA levels were increased EN-dose dependently, suggesting beneficial but limited effects of small amounts of EN on gut immunity.

Conclusions
Surrogated of EN in terms of maintenance of gut immunity have been explored. Glutamine, butyric acid, neuropeptides and IL-7 are promising candidates for clinical trials.

From  
The 14^th Congress of Parenteral and Enteral Nutrition Society of Asia
“From Nutrition Support to Nutrition Therapy”
October 14-16, 2011, Taipei, Taiwan 
Page: 21-22