Research Paper
Fermented rice bran supplementation attenuates chronic colitis-associated extraintestinal manifestations in female C57BL/6N mice

https://doi.org/10.1016/j.jnutbio.2021.108855Get rights and content

Abstract

Patients with inflammatory bowel disease (IBD) have higher incidence of extraintestinal manifestations (EIM), including liver disorders, sarcopenia, and neuroinflammation. Fermented rice bran (FRB), generated from rice bran (RB), is rich in bioactive compounds, and exhibits anti–colitis activity. However, its role in EIM prevention is still unclear. Here, for the first time, we investigated whether EIM in female C57Bl/6N mice is attenuated by FRB supplementation. EIM was induced by repeated administration of 1.5% dextran sulfate sodium (DSS) in drinking water (4 d) followed by drinking water (12 d). Mice were divided into 3 groups—control (AIN93M), 10% RB, and 10% FRB. FRB ameliorated relapsing colitis and inflammation in muscle by significantly lowering proinflammatory cytokines Tnf-α and Il-6 in serum and advanced glycation end product-specific receptor (Ager) in serum and muscle when compared with the RB and control groups. As FRB reduced aspartate aminotransferase levels and oxidative stress, it might prevent liver disorders. FRB downregulated proinflammatory cytokine and chemokine transcripts responsible for neuroinflammation in the hippocampus and upregulated mRNA expression of G protein coupled receptors (GPRs), Gpr41 and Gpr43, in small and large intestines, which may explain the FRB-mediated protective mechanism. Hence, FRB can be used as a supplement to prevent IBD-associated EIM.

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.

References (72)

  • VO Palmieri et al.

    Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome

    J Nutr

    (2006)
  • Y Yilmaz et al.

    Serum levels of soluble receptor for advanced glycation end products (sRAGE) are higher in ulcerative colitis and correlate with disease activity

    J Crohns Colitis

    (2011)
  • BL Bonaz et al.

    Brain-gut interactions in inflammatory bowel disease

    Gastroenterology

    (2013)
  • AM Hein et al.

    Sustained hippocampal IL-1β overexpression impairs contextual and spatial memory in transgenic mice

    Brain Behav Immun

    (2010)
  • EY Hsiao et al.

    Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders

    Cell

    (2013)
  • A Agus et al.

    Gut microbiota regulation of tryptophan metabolism in health and disease

    Cell host & microbe

    (2018)
  • L Peng et al.

    Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers

    J Nutr

    (2009)
  • MF Neurath

    Targeting immune cell circuits and trafficking in inflammatory bowel disease

    Nat Immunol

    (2019)
  • KE Lee et al.

    The efficacy of conditioned medium released by tonsil-derived mesenchymal stem cells in a chronic murine colitis model

    PLoS ONE

    (2019)
  • JS Levine et al.

    Extraintestinal manifestations of inflammatory bowel disease

    Gastroenterol Hepatol (N Y)

    (2011)
  • SR Vavricka et al.

    Frequency and risk factors for extraintestinal manifestations in the Swiss inflammatory bowel disease cohort

    Am J Gastroenterol

    (2011)
  • F Reichmann et al.

    Dextran sulfate sodium-induced colitis alters stress-associated behaviour and neuropeptide gene expression in the amygdala-hippocampus network of mice

    Sci Rep

    (2015)
  • SR Vavricka et al.

    Extraintestinal manifestations of inflammatory bowel disease

    Inflamm Bowel Dis

    (2015)
  • AA Chumanevich et al.

    Looking for the best anti-colitis medicine: A comparative analysis of current and prospective compounds

    Oncotarget

    (2017)
  • M Al Mijan et al.

    Diets, functional foods, and nutraceuticals as alternative therapies for inflammatory bowel disease: Present status and future trends

    World J Gastroenterol

    (2018)
  • J Islam et al.

    Dietary supplementation of fermented rice bran effectively alleviates dextran sodium sulfate-induced colitis in mice

    Nutrients

    (2017)
  • M Alauddin et al.

    Fermented rice bran supplementation mitigates metabolic syndrome in stroke-prone spontaneously hypertensive rats

    BMC Complement Altern Med

    (2016)
  • N Saji et al.

    Rice bran derived bioactive compounds modulate risk factors of cardiovascular disease and type 2 diabetes mellitus: An updated review

    Nutrients

    (2019)
  • JM Kim et al.

    Pathogenesis and clinical perspectives of extraintestinal manifestations in inflammatory bowel diseases

    Intest Res

    (2020)
  • KJ Kim et al.

    Oligonol prevented the relapse of dextran sulfate sodium-ulcerative colitis through enhancing NRF2-mediated antioxidative defense mechanism

    J Physiol Pharmacol

    (2018)
  • JM Royal et al.

    Repeated oral administration of a KDEL-tagged recombinant Cholera toxin B subunit effectively mitigates DSS colitis despite a robust immunogenic response

    Toxins (Basel)

    (2019)
  • I Masoodi et al.

    Biomarkers in the management of ulcerative colitis: a brief review

    GMS Ger Medical Sci

    (2011)
  • X Tang et al.

    Butyric acid increases the therapeutic effect of EHLJ7 on ulcerative colitis by inhibiting JAK2/STAT3/SOCS1 signaling pathway

    Front Pharmacol

    (2020)
  • B Lamas et al.

    CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands

    Nature medicine

    (2016)
  • A. Rannug

    How the AHR became important in intestinal homeostasis—A Diurnal FICZ/AHR/CYP1A1 feedback controls both immunity and immunopathology

    Int J Mol Sci

    (2020)
  • Y Nishiyama et al.

    Suppression of dextran sulfate sodium-induced colitis in mice by radon inhalation

    Mediators Inflamm

    (2012)
  • Cited by (10)

    • Cereal grains and vegetables

      2023, Natural Plant Products in Inflammatory Bowel Diseases: Preventive and Therapeutic Potential
    • Food industry by-products

      2023, Natural Plant Products in Inflammatory Bowel Diseases: Preventive and Therapeutic Potential
    View all citing articles on Scopus
    View full text