Date Published: February 28, 2019
Publisher: Public Library of Science
Author(s): Eun-Ju Choi, Hyuek Jong Lee, Wan-Jae Kim, Kwon-Il Han, Masahiro Iwasa, Kazumasa Kobayashi, Trishna Debnath, Yujiao Tang, Yi-Sub Kwak, Jin-Hwan Yoon, Eun-Kyung Kim, Hiroyasu Nakano.
Recent studies have demonstrated the immunomodulatory effects of heat-killed lactic acid bacteria. The aim of this study was to evaluate the protective effect of heat-killed Enterococcus faecalis EF-2001 (EF-2001) on a model of inflammatory bowel disease (IBD). A total of 28 female NC/Nga mice were divided into 4 treatment groups. Controls were fed a normal commercial diet. In the experimental groups, colitis was induced by rectal administration of dinitrobenzene sulfonic acid. Two groups were orally administered 2 and 17 mg/kg EF-2001, respectively. EF-2001 treatment decreased the expression of several cytokines, including cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, interleukin (IL)-1β, and IL-6 in inflamed colon compared to the DNBS alone group. In addition, EF-2001 suppressed DNBS-induced colonic tissue destruction. Therefore, this study strongly suggests that EF-2001 could alleviate the inflammation associated with mouse IBD.
Several probiotic bacteria have been reported as favorable candidates for the treatment and prevention of disease through the regulation of the host immune system [1,2]. Consuming probiotic foods, such as yogurt, has been reported to improve abnormal immune function [3,4]. In addition to live lactic acid bacteria, heat-killed cells also display immunomodulatory functions [5,6]. Inflammatory bowel disease (IBD) is a group of inflammatory disorders of the digestive tract that includes Crohn’s disease (CD) and ulcerative colitis (UC). UC occurs in the innermost lining of the colon and rectum, whereas CD occurs throughout the digestive tract, with inflammation that frequently spreads deep into affected tissues. Clinically, the key symptoms of IBD involve severe diarrhea, pain, fatigue, weight loss and enlargement of lymph nodes . In addition, IBD increases the risk of colon cancer. There is a wealth of evidence that the immune system plays an important role in the development and progression of CD and UC [8,9]. A useful approach to study the pathogenesis and complexity of human IBD is to induce IBD in animals. Widely used models include chemical-induced colitis models such as dinitrobenzene sulfonic acid (DNBS)-induced colitis . DNBS provokes cell-mediated immune responses and prompts transmural inflammation in the gut with morphological and histopathological features similar to human IBD .
In recent years, major progress has been made in both the diagnosis and treatment of IBD, resulting in a better quality of life for individuals affected by CD and ulcerative colitis. The probiotics—microorganisms with preventive and/or therapeutic potential may be reduced the duration of active disease [22, 23]. Recently, probiotics such as Streptococcus thermophilus NCIMB 41856, Lactobacillus plantarum CGMCC1258, and Lactobacillus delbrueckii TUA4408L showed beneficial anti-inflammatory effects in inflammatory bowel disease [24,25]. However, when the microorganism makes a change from commensal to pathogenic, and migrate from the gastrointestinal tract to the bloodstream potentially, it can lead to life-threatening infections, such as sepsis or bacterial endocarditis [26,27]. Although the treatment benefits of probiotics have been reported for more than 100 years ago, the safety issues have not yet been clearly identified. There are case reports of complications from certain bacteria treatments that means that the probiotic safety should be reconsidered [27–29]. In individuals with severe immunodeficiency or a pre-existing structural heart disease, lactic acid bacteria can shift and cause serious infection [30–32]. In contrast, non-viable microbial or microorganisms cell extracts have no shelf-life problems and can reduce the risks of microbial translocation and infection associated with live probiotics. In particular, non-viable or heat-sterilized lactobacilli provide biological activities as well as advantages of extended product shelf life, convenient transportation and easier storage . However, the health benefits of non-viable probiotics for IBD are not well known. Therefore, in this context, we have used heat-killed E. faecalis to treat colonic injury in mice induced by rectal supplementation with DNBS. DNBS-induced colitis is a widely used model that is phenotypically similar to colitis in humans, including loss of body weight, mucosal ulceration, and colonic shortening . We monitored body weight, rectal prolapse, and colon and mesenteric lymph node size. EF-2001 did not affect body or colon weight, or mesenteric lymph node length; however, it affected rectal prolapse, colon length, and mesenteric lymph node weight.
The present study demonstrates the ability of EF-2001 to protect from DNBS-induced colitis. EF-2001 attenuated IBD symptoms, suppressing the pathogenic shortening of colon length, reducing mesenteric lymph node weight, and downregulating proinflammatory cytokine expression in the colon, thereby improving DNBS-induced colonic tissue destruction. These results clearly demonstrate that therapeutic use of EF-2001 may reduce inflammation associated with colitis. However, in this study there were no groups for heat killed or live EF-2001 without administration of DNBS, and live EF-2001 with administration of DNBS. Therefore further study is strongly suggested to demonstrate the difference of the heat killed and live EF-2001 on IBD.