Research PaperFermented rice bran supplementation attenuates chronic colitis-associated extraintestinal manifestations in female C57BL/6N mice
Graphical abstract
Introduction
Inflammatory bowel disease (IBD), a term used for the conditions Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic, relapsing inflammation of the gastrointestinal (GI) tract [1]. The pathogenesis of IBD is multifactorial; however, microbial dysbiosis, altered immune function, genetics, and environmental factors are considered to be the major risk factors [2]. IBD mainly affects the GI tract, and about 25–50% of IBD patients also develop extraintestinal manifestations (EIM) in the musculoskeletal, dermatologic, hepatopancreatobiliary, ocular, renal, and pulmonary systems. IBD can also cause cognitive impairment [3,4]. IBD-induced EIM can detrimentally impact the patient's quality of life and increase morbidity and disability rates. Clinical and epidemiologic studies have revealed that EIM may affect many organs, and multiple EIM may occur concurrently [5,6]. Patients with EIM may require specific treatment or drugs depending on the affected organ(s) [6]. The current maintenance therapies in IBD include drugs like 5-aminosalicylic acid (5-ASA) or corticosteroids, which are inefficient and associated with adverse health effects (i.e., hepatitis, pancreatitis, and pulmonary dysfunction), and in some cases, these agents can even increase the IBD and EIM severity [7]. Thus, it is essential to find alternative strategies to manage colitis-induced EIM.
There are numerous studies being conducted on the prevention of IBD, but only a few studies have focused on the prevention of IBD-induced EIM using food supplements. In recent years, dietary supplements or functional foods have gained attention owing to their nutritional and therapeutic values and lower side effects, even after long term usage [8]. Previously, we reported that fermented rice bran (FRB) effectively prevented dextran sulfate sodium (DSS)-induced acute colitis in a mice model [9]. FRB is a novel nutritional food adjunct, generated from rice bran (RB) by a dual fermentation process using Aspergillus kawachii and Lactobacillus sp [10]. RB is an abundant and underutilized by-product of rice milling, and RB itself is a functional food [11]. However, the stability of RB is very low, and it is rancidified easily [12]. There is a growing consensus that functional foods and nutraceuticals can be used in IBD management.
Although the mechanism of IBD-mediated EIM occurrence is still unclear, EIMs are thought to be the outcome of an antigen-specific immune response from the intestine to an extraintestinal site or an independent inflammatory response that is originated from genetic or environmental risk factors in the host, or from IBD [13]. However, it is very challenging to simultaneously induce appropriate EIM characteristics such as sarcopenia, liver disorders, and neuroinflammation in experimental animal models of colitis. Several studies have been conducted by exposing mice repeatedly to DSS for a long period to induce relapsing chronic colitis similar to that in humans [2,[14], [15], [16]. DSS is a sulfated polysaccharide that decreases the thickness of the mucus layer and is responsible for compromised gut permeability, allowing bacteria to penetrate into the lamina propria, which may augment the uncontrolled intestinal immune response coupled with excessive oxidative stress, and enhanced proinflammatory cytokine and chemokine signaling [15], [16], [17]. Cytokines and chemokines are proteins that modulate immune responses such as growth, survival, and differentiation [17]. However, aberrantly expressed proinflammatory cytokines and chemokines are involved in overactivated effector T cells trafficking to extraintestinal sites, which may facilitate EIM occurrence [1].
Myeloperoxidase (MPO), a neutrophilic enzyme responsible for potent reactive oxygen species production in IBD patients and murine model of experimental colitis, can be used as a marker for colitis diagnosis [17]. Thus, depending on the chronic or acute colonic inflammatory response occurred in the DSS model, IBD may be strongly linked to EIM occurrence. Here, we hypothesized that in this chronic colitis model, aberrant immune responses occurred due to mucosal injury by DSS, and is responsible for colitis as well as EIM pathophysiology. Further, FRB, whose bioactive compounds exhibit anti–colitis activity and metabolic syndrome prevention capability [9,10], has been considered as a novel functional food candidate for EIM prevention. FRB supplementation may ensure short chain fatty acids (SCFAs) and tryptophan metabolites availability. SCFAs, especially butyrate, are well-known compounds in colonic inflammation prevention [18]. Tryptophan metabolites, including indole, indole acetic acid, and tryptamine, act as ligands for aryl hydrocarbon receptor (AHR). Recently, it has been shown that ligand-mediated AHR activation regulates intestinal immunity, homeostasis, rapid recovery, and host defense through interleukin (IL)-22 production by innate lymphoid cells (ILCs) [19, 20].
In this study, we performed repeated DSS administration in a mouse model to observe EIMs, such as liver disorder, sarcopenia, and neuroinflammation, and simultaneously investigated the impact of FRB supplementation on EIM prevention.
Section snippets
Materials
Components of the AIN-93M standard diet were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan) and Oriental Yeast Co., Ltd. (Tokyo, Japan). We purchased DSS salt (MW <50 kD) from MP Biomedicals (Santa Ana, CA, USA) and myeloperoxidase (MPO) assay kit from Biovision (Milpitas, CA, USA). The amounts of Tnf-α (Cat no#. 860.040.096) and Il-6 (Cat no#. M6000B) in mouse serum were determined using commercially available mouse ELISA kits from Diaclone SAS (Besancon Cedex, France) and
FRB improved the clinical features of colonic inflammation
Administration of 1.5% DSS for 4 d initiated the clinical symptoms of colitis in mice, such as body weight loss, gross rectal bleeding, and diarrhea. In comparison with the control and RB groups, FRB diet-supplemented mice had higher body weight gain from day 20 onwards (Fig. 2A). However, significant differences were found on days 20, 24, 28, 32, 36, 60, and 64 (Fig. 2A). Under these conditions, FRB effectively prevented body weight loss and showed early tendency to return to the baseline
Discussion
Diets and functional foods have emerged as promising alternatives for the prevention and management of IBD owing to their anti–inflammatory functions [8]. In this study, we investigated the role of FRB in the prevention, and amelioration of EIM in a chronic colitis model using female mice.
As RB type and the microbiota used for fermentation can influence production of the end product, FRB was produced from RB by a dual fermentation process in this study, which enriched the number of bioactive
Author contributions
JI, MK, and HS conceived and designed the experiments. JI and HS analyzed the data and wrote the manuscript. JI, AZA, KW, TN, HA, YO, and TK performed the experiments. All authors have read and approved the final version of the manuscript.
Declaration of competing interests
The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
Funding
This work was partially supported by grants from the JSPS Core-to-Core Program A (Advanced Research Networks) entitled: “Establishment of international agricultural immunology research-core for quantum improvement in food safety,” the Kobayashi Foundation, the Tojuro Iijima Foundation for Food Science and Technology, and the Joint Projects of Rice Bran of Sunstar Inc.
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