Gastroenterology

Gastroenterology

Volume 136, Issue 2, February 2009, Pages 564-574.e2
Gastroenterology

Basic—Alimentary Tract
Dietary Histidine Ameliorates Murine Colitis by Inhibition of Proinflammatory Cytokine Production From Macrophages

https://doi.org/10.1053/j.gastro.2008.09.062Get rights and content

Background & Aims

Elemental diet (ED) is effective for human Crohn's disease (CD). Although some of this effectiveness may be due to its low antigenic load and low fat content, the mechanisms remain unclear. We sought to assess the role of histidine, one of the constituent amino acids of ED, in controlling colitis.

Methods

The interleukin (IL)-10-deficient (IL-10−/−) cell transfer model of colitis was used. SCID mice with colitis induced by transfer of IL-10−/− cells were maintained on experimented diets containing either single amino acids or a mixture. The severity of colitis was assessed by wet colon weight. Colonic tumor necrosis factor (TNF)-α messenger RNA (mRNA) expression was detected by quantitative reverse-transcription polymerase chain reaction. Mouse peritoneal macrophages were stimulated by lipopolysaccharides (LPS), with or without amino acids. The concentration of cytokines in the supernatant was determined by enzyme-linked immunosorbent assay. Inhibitor of nuclear factor (NF)-κB-α and nuclear p65 were confirmed by immunoblotting.

Results

In the IL-10−/− transfer model, dietary histidine, but not alanine, reduced histologic damage and colon weight and TNF-α mRNA expression. Histidine inhibited LPS-induced TNF-α and IL-6 production by mouse macrophages in a concentration-dependent manner, whereas alanine or histidine-related metabolites had no such effect. Histidine inhibited LPS-induced NF-κB in macrophages.

Conclusions

These results showed that histidine could be a novel therapeutic agent for CD by inhibition of NF-κB activation, following down-regulation of proinflammatory cytokine production by macrophages. Thus, our studies provided new insights into the roles of amino acid metabolism in the pathophysiology of CD and for therapeutic strategies.

Section snippets

Reagents

Amino acids used were as follows: l-histidine, carnosine (Sigma–Aldrich, St. Louis, MO) and d-histidine (Wako, Japan). Lipopolysaccharide (LPS) from Escherichia coli 0111:B4 was also purchased from Sigma–Aldrich. Polyclonal antibodies against inhibitor of NF-κB (IκB)-α and p65 were purchased from Cell Signaling technology (Danvers, MA) and Santa Cruz Biotechnology (Santa Cruz, CA), respectively.

Animals

IL-10−/− mice from a C57BL/6 background were purchased from Jackson Laboratory (Bar Harbor, ME). Mice

ED Amino Acids Ameliorate Murine IL-10−/− Cell Transfer Colitis Models

We previously reported that ED reduces colonic inflammation in murine IL-10−/− cell transfer colitis models.23 ED was composed of 17.6% amino acids, 79.3% dextrin, 0.6% soybean oil, 0.5% vitamins, and 2.0% minerals (Table 1). We first analyzed the efficacy of a premixture of EDAAs on IL-10−/− cell transfer colitis models. EDAAs mixed in the standard formula improved colonic weight in a dose-dependent manner (Figure 1A). TNF-α has been well characterized as an important inflammatory cytokine

Discussion

We demonstrated that orally administered histidine ameliorated intestinal inflammation in an IL-10−/− cell transfer colitis model. It has been reported that IL-10−/− cell transfer colitis models exhibit features similar to IBD, both pathophysiologically and pharmacologically.18 Consistent with previous reports that show the efficacy of ED for CD,10, 11, 12, 13 we found that ED was effective in this colitis model. ED was composed of 17 amino acids, dextrin, bean oil, vitamins, and minerals (

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    The authors disclose the following: Supported in part by grants-in-aid from the Japanese Ministry of Education, Culture and Science; the Japanese Ministry of Health, Labor and Welfare; Keio University; and Keio Medical Foundation, Tokyo, Japan.

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