In Japan, the intake of milk, animal meat, and vegetable oil began to increase from the 1960s onward, whereas the intake of fish products and cereals has decreased since the 1990s. As a result, the Western diet has become more mainstream among the current Japanese population, particularly young people [1] [2] , despite traditional Japanese cuisine being added to the UNESCO List of Intangible Cultural Heritage in 2013. With this sudden change in dietary habits, the incidence of inflammatory bowel disease (IBD) [3] has rapidly increased in Japan. Consequently, the number of patients with IBD in Japan has been increasing since the 1980s, and an excess of 200,000 patients (ulcerative colitis, UC: approximately 160,000 patients; Crohn’s disease, CD: approximately 40,000 patients) currently suffer from the condition. The role of excessive intake of fat in the Western diet is emphasized in IBD, particularly the excessive consumption of n-6 polyunsaturated fatty acids (PUFA), including linoleic acid (LA), an essential fatty acid contained in large amounts in vegetable oil. These n-6 PUFA increase the release of arachidonic acid (AA)-derived inflammatory mediators such as prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄), which exacerbate IBD.

With respect to n-3 PUFA, alpha-linolenic acid (ALA) is metabolized to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). N-3 PUFA are essential fatty acids present in large amounts in perilla oil and fish oils and inhibit the metabolism of n-6 PUFA by competitively antagonizing metabolic enzymes, such as delta 6- and delta 5-desaturases, cyclooxygenase (COX) and 5 lipoxygenase (LOX), thereby producing anti-inflammatory actions by inhibiting the synthesis of AA-derived inflammatory mediators and thromboxane A₂ (TXA₂). Therefore, it is thought that the regulation of the n-3/n-6 ratio with a therapeutic diet may be important for reducing disease activity in patients with IBD. We previously reported that the n-3/n-6 ratio of vital cell membrane phospholipids influenced the disease activities in IBD patients receiving dietary therapy that aimed to reduce the intake of n-6 PUFA and increase that of n-3 PUFA [4] , i.e., the n-3 diet. However, the influence of the actual intake of PUFA and the dietary n-3/n-6 ratio on disease activity remains to be clarified. Therefore, we conducted a survey on the efficacy of and adherence to the n-3 diet.

In Japan, the consumption of a Western diet is considered an etiological environmental factor related to the recent increase in the incidence of IBD [3] . In particular, the role of excessive fat intake has been emphasized in this disease. In the EPIC study of IBD, Tjonneland et al. [10] reported that a large intake of LA and n-6 PUFA was associated with an increased risk of UC. Excessive consumption of the n-6 PUFA contained in vegetable oils may increase the release of inflammatory mediators such as PGE2 and LTB4, which can exacerbate various allergic diseases as well as IBD. In our previous report, we showed that the activity of delta 6 desaturase, which metabolizes LA to gamma linolenic acid, was significantly higher in CD patients than that in healthy subjects. In addition, the percentage weight of AA in vital cell membranes was significantly higher in patients with CD than in healthy subjects and in patients with UC [11] . Therefore, LA may be efficiently metabolized to AA in patients with CD. Other previous

studies have confirmed an increase in LTB4 production in the intestinal mucosa of patients with UC and CD [12] . On the other hand, n-3 PUFA may inhibit the production of inflammatory mediators by antagonizing the metabolism of LA, thereby causing immunosuppressive effects [13] [14] [15] . Therefore, it is desirable to reduce the percentage weights of AA in vital cell membranes to control the disease activity of IBD through the proactive consumption of n-3 PUFA. Belluzzi et al. [16] reported that fish oil incorporated into phospholipids and reduced the percentage weights of AA both in plasma and in the membranes of red blood cells. Furthermore, Lands et al. [17] reported that the restricted intake of LA and a high consumption of n-3 PUFA efficiently decreased the percentage weights of AA and DGLA in phospholipids. Thus, as dietary therapy, both intake restriction of n-6 PUFA and proactive ingestion of n-3 PUFA may be desirable to reduce the disease activity of IBD. In our previous report, we showed that dietary fatty acid content reflected the fatty acid composition of the cellular membranes and that the n-3 diet significantly increased the n-3/n-6 ratio of the cell membranes of erythrocytes and was effective at maintaining IBD remission [4] . Similarly, another previous report revealed that a novel enteric-coated fish oil preparation was effective at reducing the rate of relapse in patients with CD in remission [18] . Currently, Scaioli E [19] , et al. reported that highly purified EPA capsules reduced fecal calprotectin levels and prevents clinical relapse in UC patients. Thus, these previous reports suggest that dietary fatty acid intake is strongly linked with the disease activity characteristics of IBD and that adjustment of dietary PUFA is important. However, whether IBD patients could adhere to the n-3 diet regimen remained unclear, and the relationship between the actual PUFA intake and the remission maintenance rate of IBD was not reported. Therefore, in the present study, we conducted a questionnaire on patient adherence to the n-3 diet therapy using an original questionnaire and evaluated the efficacy of the therapeutic diet for the maintenance of remission in IBD patients.

We found that the mean intakes of n-6 PUFA and n-3 PUFA were 9146 ± 5217 and 1673 ± 1651 mg/day before hospitalization, respectively. Compared with the results of the national survey mentioned above, the mean intake of n-3 PUFA before hospitalization was significantly lower (one-sample t-test; p < 0.01), while there was no significant difference for that of n-6 PUFA (one sample t-test; p = 0.144). After education, the mean intakes of n-6 and n-3 PUFA were 5.22 ± 1.97 and 3.67 ± 1.68 g/day, respectively. In the n-3 diet regimen, the intake of n-6 PUFA was restricted to 50% of the mean intake, i.e., approximately 5.5 g/day, and n-3 PUFA intake was increased approximately 2-fold compared to the mean intake found in the national survey, i.e., 5.1 g (3 units) a day. According to these results, adherence to the intake restriction of n-6 PUFA was sufficient. Although the intake of n-3 PUFA after education was increased significantly over the level before hospitalization (p < 0.001), it did not reach the target intake level. The average n-3 PUFA intake at Q2 tended to be lower in relapsed patients than that in patients in remission (p = 0.068). It is thought that low adherence to n-3 PUFA intake affect relapse. However, the dietary n-3/n-6 ratio was significantly increased, and 17 of 24 participants (70.8%) achieved the 0.432 ratio, derived by ROC curve analysis. Additionally, 14 of 17 patients (82.4%) who maintained a dietary n-3/n-6 ratio of 0.432 or higher maintained remission (p < 0.03). Interestingly, a positive correlation was found between the intake of n-6 PUFA before hospitalization (Q1) and the UCDAI score in Q2 in UC patients (y = 0.0006x − 3.7309, R² = 0.485, p < 0.01, ρ = 0.798). Therefore, UC patients with high n-6 PUFA intake before remission may relapse easily. This result suggests that IBD patients, especially UC patients, should refrain from the ingestion of n-6 PUFA on a long-term basis. Although the intake of fat has increased with the spread of the Western style diet in Japan, the absolute intake of n-6 PUFA in the Japanese population may be less compared with that of Westerners, and for Japanese IBD patients, the acceptance of traditional Japanese cuisine such as marine products, including those foods rich in n-3 PUFA, may be higher compared to those in the diets of Westerners. In this study, all subject-patients were from a single nation, i.e., Japan. Therefore, the possibility that these effects of the n-3 diet and these results are limited to Japanese subjects cannot be excluded. Moreover, in this study, adherence to medications was not investigated, and a correlation between adherence to the therapeutic diet and adherence to medication regimens cannot be excluded and may have affected our results. Moreover, the number of patients in this study was small, so we must consider the possibility that these factors affected the results of this study. The results will be more convinced if the sample size is larger. In the future, we intend to enroll a larger number of IBD patients for further assessment with multiple regression analysis for the related factors.

These results suggest that adherence to the n-3 diet and its impact on the maintenance of remission may be achieved by understanding the importance of adjustments to dietary PUFA.

The authors declare no conflicts of interest.

Uchiyama, K., Aiki, H., Matsumura, A., Saruta, K., Yuasa, A., Ito, Z., Takami, S., Saito, K., Ohtaki, Y., Suzuki, S., Hayashi, S., Koido, S., Yoshida, H., Ohkusa, T. and Saruta, M. (2018) The Efficacy of the Consumption of n-3 Polyunsaturated Fatty Acids for the Maintenance of Remission in Patients with Inflammatory Bowel Disease. Food and Nutrition Sciences, 9, 105-118. https://doi.org/10.4236/fns.2018.92009