Rice Bran Usage in Diarrhea

Chapter 21

Rice Bran Usage in Diarrhea Shaohua Lei, Lijuan Yuan Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States

1. OVERALL HEALTH BENEFITS OF RICE BRAN DIETARY SUPPLEMENT Rice (Oryza sativa L.) is grown in over 100 countries and served as the staple food for around 3.5 billion people all over the world.1 While the milled and polished rice grain widely counts for human consumption, the outer covering layer, rice bran, is usually considered as a type of livestock feed, mainly because of traditional perceptions and the rapid development of hydrolytic rancidity in the bran during storage.2,3 Therefore, rice bran is known as an underutilized by-product of rice milling. To overcome the storage issue, heat stabilization is applied to inactivate rancidity-inducing lipoxygenases and lipases in rice bran; the increased shelf life and retained bioactivity have expanded the usage of rice bran for human health and nutrition.4 Rice bran is a natural mixture of a large variety of bioactive compounds. Rice bran metabolite profiling revealed a suite of 65 biochemical molecules with health properties, including amino acids, vitamins and cofactors, and secondary metabolites.5 The multifaceted health benefits of rice bran have been illuminated using whole rice bran and extracts such as rice bran oil, polysaccharides, proteins/peptides, and minerals.6 As a result, there is an increasing interest in dietary rice bran supplementation in animals and humans for the medicinal and nutritional properties. In mice, consumption of rice bran induced an increase in fecal and serum immunoglobulin A (IgA), as well as increased antigen-presenting cells in mesenteric lymph nodes and lamina propria.7 Another study showed that rice bran glycoprotein was able to help cyclophosphamide-treated mice recover from immunosuppression by promoting the proliferation of splenic lymphocytes.8 These reports indicate the immunomodulatory effects of rice bran in enhancing mucosal and systemic immunity. In gnotobiotic (Gn) pigs, rice bran intake exhibited high protective efficacy against diarrhea induced by human rotavirus (HRV) and norovirus,9,10 the two most prevalent viral pathogens causing gastroenteritis. In human clinical trials, dietary rice bran ameliorated type 2 diabetes by lowering lipid and glycemic levels,11,12 and arabinoxylan rice bran has been evaluated with promising therapeutic effects on irritable bowel syndrome (IBS) and chronic hepatitis C virus infection.13,14 In addition, emerging scientific evidence indicates that dietary rice bran represents chemopreventive potential against several types of cancer such as liver, lung, breast, and colon cancer.15 Overall, rice bran is being recognized as an economical, natural, novel, and safe dietary supplement with broad beneficial effects on animal and human health, including treating gastrointestinal diseases.

2. DIETARY RICE BRAN SUPPLEMENTATION IN REDUCING DIARRHEA It is well known that rice bran has been a traditional home remedy for patients with acute or chronic gastrointestinal illnesses in Asian countries such as China and India, especially in the rural areas because of its easy accessibility and low cost. Diarrhea is a manifestation of gastrointestinal malfunction, and we highlighted several animal and clinical studies to demonstrate the antidiarrheal effect of rice bran.

2.1 Diarrhea in Irritable Bowel Syndrome IBS is a chronic functional bowel disorder in which recurrent abdominal pain is related to defecation or a change of stool frequency or pattern, including diarrhea, constipation, or mixed type.16 IBS is diagnosed on the basis of at least 6 months of recurrent symptoms, with average occurrence of at least once per week in the last 3 months.17 IBS has a significant negative impact on work productivity and quality of life, and patients would sacrifice 10–15 years of life expectancy for a permanent and immediate cure of the disease, although it has no attributable mortality.18 It is estimated that the prevalence of IBS is 11% worldwide and 7%–16% in the United States, women and young people are at a slightly higher risk,19 and the direct costs associated with IBS in the United States is over $1 billion.20 Thus, developing novel and effective treatment plays an important role in reducing the economic and societal effects caused by IBS. Dietary Interventions in Gastrointestinal Diseases. https://doi.org/10.1016/B978-0-12-814468-8.00021-1 Copyright © 2019 Elsevier Inc. All rights reserved.

257

258  SECTION | V  Foods and Macro Dietary Materials in GI Function

TABLE 21.1  Summary of the Rice Bran Studies on Diarrhea-Reducing Effects Syndrome or Pathogen

Host

Treatment Group

Sample Size

Diarrhea Score, Occurrence, and/ or Duration (SEM) standard

Diarrhea in irritable bowel syndrome13

Human adults

Placebo

20

4.39 (0.36) vs. 3.95 (0.31)a

Biobran

19

4.88 (0.45) vs. 3.51 (0.46)a

Any diarrheab

Human infants

Control

24

79%

Rice bran

24

33%

Human rotavirus (HRV)9,30

Human norovirus (HuNoV)10

Gnotobiotic pigs

Gnotobiotic pigs

Control

9

100%, 5.6 (0.3) days

Rice bran

5

20%, 0.2 (0.2) days

LGG + EcN

6

50%, 0.7 (0.3) days

Rice bran + HRV vaccine

6

0%, 0 (0) days

Rice bran + LGG + EcN

6

0%, 0 (0) days

Control

9

89%, 2.2 (0.4) days

Rice bran

4

75%, 1.3 (0.5) days

LGG + EcN

5

60%, 1.8 (1.1) days

Rice bran + LGG + EcN

5

20%, 0.2 (0.2) days

EcN, Escherichia coli Nissle 1917; LGG, Lactobacillus rhamnosus GG; SEM, standard error of the mean. aDiarrhea scores of baseline versus treatment. bPersonal communication (from a pilot randomized controlled clinical trial with Malian infants NCT02557373).

As many patients recognize specific dietary contributors for their IBS symptoms, the traditional first recommended treatment is to increase the dietary fiber intake. Notably, fiber is classified as “soluble” or “insoluble;” psyllium is a typical soluble fiber, and psyllium husk, the outer cover of the psyllium seed, has been identified with beneficial effects to alleviate IBS,21 but insoluble fiber can exacerbate IBS symptoms such as abdominal pain.17 Crude rice bran is unsuitable for the management of IBS as it is insoluble, but the modified arabinoxylan rice bran (also known as MGN-3 or Biobran) is highly water soluble and a potential dietary intervention as shown in a randomized clinical trail.13 In this study, 20 patients in the placebo group and 19 patients in the Biobran group all suffered from diarrhea, either IBS with diarrhea or mixed type IBS with both diarrhea and constipation. After 4 weeks of treatment with 2 g of Biobran powder per day, the global assessment indicated that 30% of the placebo and 63.2% of the Biobran group had symptom relief in IBS. The Biobran group had significant improvement compared with placebo. More importantly, significantly lower diarrhea scores over the baseline, but not constipation scores, were observed after Biobran treatment (Table 21.1), indicating the therapeutic effects of dietary Biobran in reducing diarrhea in IBS.13

2.2 Human Rotavirus–Induced Diarrhea HRV is a nonenveloped, segmented, double-stranded RNA virus that belongs to the family Reoviridae. As a leading cause of acute gastroenteritis in children under 5 years old, HRV claims approximately 500,000 lives each year before the two vaccines (RotaTeq in 2006 and Rotarix in 2008) become commercially available and accounts for an estimated €400 million in Europe and $1 billion in the United States in health care costs.22,23 Because of the low efficacy of vaccines in low middle income countries, HRV infections are still responsible for over 200,000 deaths annually.24 HRV gastroenteritis consists of vomiting, diarrhea, and dehydration. HRV-associated diarrhea results from the viral destruction of absorptive enterocytes, villus ischemia, intestinal secretion induced by viral nonstructural protein 4, and activation of the enteric nervous system.24,25 Gn pigs have been extensively used to study HRV infection and diarrhea. It has many unique advantages that other animal models lack. First, humans and pigs share high homology in genome and proteome, omnivorous diet, analogous physiology of the gastrointestinal tract, and similar immune system.26–28 Second, no maternal antibodies can be transferred via the porcine placenta, and Gn piglets are devoid of sow colostrum or milk, altogether excluding the effects of maternal antibodies on experimental studies. Third, Gn pigs develop diarrhea and shed virus in feces after virulent Wa strain HRV oral infection, as well as recapitulating the pathologic hallmarks and immune responses of HRV infections in humans.29

Rice Bran Usage in Diarrhea Chapter | 21  259

The first report of rice bran’s effects on reducing viral diarrhea was a study using the Gn pig model of Wa (G1P[8]) HRV infection and disease. Heat-stabilized rice bran was added to the Gn pigs’ daily milk diet to replace 10% of total calorie intake starting at 5 days of age, the virulent HRV challenge was given at 33 days of age, and then all pigs were euthanized 7 days later. In the study, while the mock control Gn pigs experienced an average of 5.6 days of diarrhea, the rice bran–treated Gn pigs had significantly lower mean diarrhea duration of 0.2 days (Table 21.1). A significantly lower incidence of diarrhea (20%) was observed when compared with the control pigs (100%). The protective effect outperformed two dosages of attenuated HRV vaccination.9 Remarkably, Gn pigs were completely protected from HRV diarrhea when treated with rice bran feeding and attenuated HRV vaccinations (Table 21.1). In a follow-up study, two strains of probiotic bacteria, Lactobacillus rhamnosus GG (LGG) and Escherichia coli Nissle 1917 (EcN), were precolonized in Gn pigs to test their antidiarrheal activity together with rice bran feeding. While LGG + EcN colonization presented a significant protection against HRV diarrhea by lowering the mean duration to 0.7 days, rice bran completely prevented HRV diarrhea in the LGG + EcN precolonized Gn pigs (Table 21.1).30 Altogether, the high protective efficacy of rice bran, used alone or together with vaccine or probiotics, validated it as a novel and effective measure to prevent and treat HRV-induced diarrhea.

2.3 Human Noroviruses–Induced Diarrhea Human noroviruses (HuNoVs), nonenveloped single-stranded RNA viruses within the family Caliciviridae, are the predominant cause of epidemic acute gastroenteritis worldwide.31 HuNoVs are highly contagious and infectious to people of all ages, with a higher infection incidence in children and underdeveloped areas.32 Viral transmission is fecal–oral route via contaminated food or water supplies and person-to-person contact,33 leading to generally self-limiting HuNoV gastroenteritis characterized by 2–3 days of nausea, vomiting, and moderate to severe acute diarrhea episodes.34 But the disease can become prolonged and life-threatening in specific risk groups, including infants, young children, elderly, and immunocompromised patients.35 HuNoV infections cause 685 million illnesses and an estimated 212,489 deaths annually worldwide. Among them, 29% of the illnesses and 26% of deaths are in children <5 years old.36 In the United States, HuNoV gastroenteritis accounts for ∼21 million cases, ∼2 million hospital visits, ∼800 deaths, and estimated $284–$493 million in health care cost.37–39 Despite the tremendous disease burden and financial cost, currently no vaccines or antiviral drugs are available to prevent or treat HuNoV gastroenteritis,40 resulting partially from the long lack of a readily reproducible cell culture system and a suitable small animal model. Knowledge on HuNoV infection and disease is primarily from limited viral challenge studies in immunodeficient mice,41,42 Gn calves and pigs,43–45 chimpanzees,46,47 and human volunteers.35 Notably, the neonatal Gn pig model is well suited for the exploration of HuNoV pathogenesis and the evaluation of vaccine efficacy; it is the only animal model that recapitulates HuNoV biology in terms of natural oral route of infection, clinical occurrence of diarrhea, transient viremia, virus shedding in stool, and prolonged infection in immunocompromised host.44,45,48,49 The first evaluation of rice bran on reducing HuNoV-induced diarrhea was performed using the Gn pig model of GII.4 HuNoV infection and diarrhea. Daily rice bran feeding started 7 days before the HuNoV challenge in Gn pigs, and the dosage was 10% replacement of pigs’ daily calorie intake as well. During the 7 days post HuNoV infection, pigs in the rice bran–fed group had an average of 1.3 days of diarrhea as compared with 2.2 days in the control group. Moreover, in the cocktail group where Gn pigs were precolonized with probiotics LGG + EcN, the mean duration of diarrhea was further lowered to 0.2 days (Table 21.1). Intriguingly, LGG + EcN precolonization alone had minimal effect on reducing HuNoV diarrhea, indicating a synergistic action between rice bran and LGG + EcN. Additionally, the rice bran and probiotic cocktail regimen also exerted strong protection against HuNoV shedding; only 1.0 day of shedding was observed as compared with 3.2 days in the control group.10 The protection provided by the rice bran plus LGG + EcN regimen is greater than that provided by HuNoV vaccine candidates. The first HuNoV vaccine under evaluation was an adjuvant monovalent virus-like particle derived from genotype GI.1, which showed a 47% and 26% protection rates against HuNoV gastroenteritis and infection, respectively.50 Another virus-like particle–based vaccine candidate includes both GI.1 and GII.4 components, and the bivalent vaccine induced a 52% reduction in diarrhea and/or vomiting.51 Given the 78% protection rate against diarrhea in Gn pigs, the cocktail regimen containing rice bran and probiotics holds great promise in preventing and treating HuNoV gastroenteritis.10

3. MECHANISMS FOR RICE BRAN USAGE IN REDUCING DIARRHEA Rice bran comprises over 450 distinct phytochemicals,5 and the compositions and concentrations might differ across cultivars, cultivation regions, and extraction methods. Although numerous studies have demonstrated the beneficial effects of rice bran and extracts, the underlying mechanisms could vary case by case and depend on the experimental hosts and objectives. As to the diarrhea ameliorating property, we summarized the corresponding mechanisms in several aspects.

260  SECTION | V  Foods and Macro Dietary Materials in GI Function

3.1 Antimicrobial and Antiviral Activities A traditional first-line treatment for diarrhea caused by pathogen is to interfere or eliminate the malicious microorganisms. At least 15 metabolites identified in rice bran might contribute to its antimicrobial and antiviral ability,5 which have been evaluated on a variety of bacteria and viruses. For instance, rice bran extracts reduced the entry and replication of Salmonella in intestinal epithelial cells.52 Sulfated rice bran glucans exhibited strong anticytomegalovirus activity on preventing viral entry of target hosts,53 indicating the blockade by rice bran at the stage of pathogen entry. Moreover, rice bran or extracts inhibited the colonization and/or replication of Salmonella,54,55 Vibrio cholerae, Shigella spp, Escherichia coli,56 Clostridium,57 hepatitis C virus,14 and human immunodeficiency virus.58

3.2 Prebiotic and Microbiota Modulatory Properties Probiotic bacteria have been extensively studied as vaccine adjuvants and therapeutic agents in alleviating diarrhea,59–61 and the prebiotic property of rice bran in enhancing the growth of probiotics was shown in many studies. Besides the Salmonella reducing effect, dietary rice bran promoted the colonization of native Lactobacillus spp in mice.7,55 Similarly, rice bran improved the health condition of weaning pigs by increasing intestinal Bifidobacterium spp.62 The prebiotic activity of rice bran was also observed in Gn pigs by promoting the colonization of LGG and/or EcN, which was associated with their protective effects on HRV and HuNoV diarrhea.10,30 Probiotic lactobacilli increase the production of colonic short-chain fatty acids (SCFAs).63,64 Rice bran also increases the production of SCFAs by colonic bacterial fermentation.65 SCFAs influence net intestinal Na+, Cl−, and water absorption by increasing Na+ absorption via upregulation of NHE3 (Na+/H+ exchanger) and Cl− absorption by upregulation of Cl−/HCO3 − exchanger downregulated in adenoma (DRA)66 and inhibiting Cl− secretion.67–69 Gn pigs fed with rice bran and probiotics had drastically reduced incidence, shortened duration, and reduced severity of HRV diarrhea, despite no reduction in virus shedding after challenge, suggesting modulation of ion transporter function by rice bran and/or probiotics as a possible mechanism.30 In addition to regulating the growth of certain bacterial species, rice bran has a global impact on the entire gut microbial composition.70,71 Gut microbiome has gained unprecedented attention for its close association with human health and immunity, especially with gastrointestinal health,72 and emerging data in recent years indicates that microbiota modulates enteric viral infections.73,74 There is no doubt that the potential mechanisms of rice bran in alleviating diarrhea in terms of modulating diarrhea pathophysiology and intestinal microbiome warrant further investigation.

3.3 Effects on Intestinal Immunity and Overall Health In general, the immunomodulatory role of rice bran largely accounts for its multifarious health benefits.6 Enhanced activity of B cells, T cells, dendritic cells, and natural killer cells was observed from the treatment by rice bran or extracts in vivo or in vitro,7,75–78 suggesting the potentially enhanced protective immunity against enteric infection. Specifically, in rice bran–fed mice, reduced Salmonella colonization was positively correlated with the induction of cellular immune responses in the small intestine and certain metabolites, such as α-linolenic acid and γ-tocotrienol.54,55 In rice bran–fed Gn pigs, the reduced HRV diarrhea could be attributed to the enhanced intestinal and systemic IFN-γ–producing T cell responses and the elevated virus-specific intestinal IgA antibody levels.9 Furthermore, the alterations of lipid and amino acid/peptide metabolism induced by rice bran consumption contributed to the complete protection against HRV diarrhea in Gn pigs.79 Similarly, significantly increased frequencies of intestinal and systemic IFN-γ–producing T cells were correlated with amelioration of HuNoV diarrhea.10 Due to the macronutrient and micronutrient richness, rice bran improved the growth of human infants and Gn pigs,30 indicating enhanced nutrient intake via the gut and overall health. The beneficial effects on the gut might be exerted by the maintenance or improvement of healthy intestinal morphology. For instance, rice bran–fed Gn pigs had significantly lower ileal villus width and mitotic index under HRV infection,30 as well as longer jejunal villus length under HuNoV infection,10 altogether indicating that rice bran prevented viral-induced damage on the intestine. Data from the pilot studies of rice bran intake in infants (personal communications) showed that rice bran–fed participants had markers of decreased intestinal permeability and inflammation and increased growth, including lower fecal alpha-1-antitrypsin (P = 0.02) and higher serum glucagon-like peptide-2 (P = 0.03), which is secreted from enteroendocrine L cells, associated with decreased inflammation, and promotes intestinal growth.80 More importantly, the rice bran group had significantly increased length-for-age Z-score from 6 to 12 months compared with control (P < 0.01). The diarrhea prevalence was 33% in the rice bran group compared with 79% in the control group (Table 21.1). In the safety evaluation, there were no serious adverse events, no increases in serum heavy metal concentrations, and no decreases in iron absorption in the rice bran group.

Rice Bran Usage in Diarrhea Chapter | 21  261

4. FUTURE PERSPECTIVE Rice is the most commonly used staple of the world, and rice bran is globally accessible and affordable. In the heatstabilized form, rice bran is stable without refrigeration. As an economical, natural, and safe dietary supplement, rice bran deserves further investigations to demonstrate it as an effective prophylactic agent to prevent viral gastroenteritis and potentially nonviral gastroenteritis and to reveal mechanisms of rice bran’s actions against diarrhea in both animals and humans. Notably, the prominent characteristic of rice bran is that it is a natural complex with more than 450 distinct phytochemicals, which are balanced nutrients such as fibers, oils, proteins, and vitamins.5 While component dissection and further functional investigation for each ingredient are in great demand to better understand the bioactive profile of rice bran, it merits our attention that the phytochemical components are likely working synergistically for the broad positive health benefits, including antioxidant, antimicrobial, antiviral, microbiota regulating, and/or immunomodulatory properties. In addition to mechanistic studies in animal models, large clinical trials are needed in a timely manner, especially in human infants. Given the safety evidence of rice bran supplementation, demonstrated feasibility in pilot studies (NCT02615886 and NCT02557373), and a pressing public health demand, it is the time for human clinical trials to move forward. The potential for highly effective and safe strategies that can be easily implemented to reduce the risk of viral gastroenteritis for high-risk groups (i.e., young or immunocompromised) or during outbreaks (i.e., in hospitals, day cares, or schools) merits studies using both animal models and translational assessments in humans. Reducing morbidity and mortality of diarrhea, associated with enteric pathogens or complex syndromes, by rice bran supplementation with or without probiotics would improve quality of life for people of all age. Additionally, these dietary interventions may improve the nutritional status and growth of children and thus could serve as a potential measure to improve their cognitive outcomes.81,82

REFERENCES 1. Muthayya S, Sugimoto JD, Montgomery S, Maberly GF. An overview of global rice production, supply, trade, and consumption. Ann NY Acad Sci 2014;1324:7–14. 2. da Silva MA, Sanches C, Amante ER. Prevention of hydrolytic rancidity in rice bran. J Food Eng 2006;75(4):487–91. 3. Ramezanzadeh FM, Rao RM, Windhauser M, Prinyawiwatkul W, Tulley R, Marshall WE. Prevention of hydrolytic rancidity in rice bran during storage. J Agric Food Chem 1999;47(8):3050–2. 4. Prasad MN, Sanjay K, Khatokar MS, Vismaya M, Swamy SN. Health benefits of rice bran - a review. J Nutr Food Sci 2011;01(03). 5. Zarei I, Brown DG, Nealon NJ, Ryan EP. Rice bran metabolome contains amino acids, vitamins & cofactors, and phytochemicals with medicinal and nutritional properties. Rice (NY) 2017;10(1):24. 6. Park HY, Lee KW, Choi HD. Rice bran constituents: immunomodulatory and therapeutic activities. Food Funct 2017;8(3):935–43. 7. Henderson AJ, Kumar A, Barnett B, Dow SW, Ryan EP. Consumption of rice bran increases mucosal immunoglobulin A concentrations and numbers of intestinal Lactobacillus spp. J Med Food 2012;15(5):469–75. 8. Park HY, Yu AR, Hong HD, Kim HH, Lee KW, Choi HD. Immunomodulatory effects of nontoxic glycoprotein fraction isolated from rice bran. Planta Med 2016;82(7):606–11. 9. Yang X, Wen K, Tin C, et al. Dietary rice bran protects against rotavirus diarrhea and promotes Th1-type immune responses to human rotavirus vaccine in gnotobiotic pigs. Clin Vaccine Immunol 2014;21(10):1396–403. 10. Lei S, Ramesh A, Twitchell E, et al. High protective efficacy of probiotics and rice bran against human norovirus infection and diarrhea in gnotobiotic pigs. Front Microbiol 2016;7(1699). 11. Cheng HH, Huang HY, Chen YY, et al. Ameliorative effects of stabilized rice bran on type 2 diabetes patients. Ann Nutr Metab 2010;56(1):45–51. 12. de Munter JS, Hu FB, Spiegelman D, Franz M, van Dam RM. Whole grain, bran, and germ intake and risk of type 2 diabetes: a prospective cohort study and systematic review. PLoS Med 2007;4(8):e261. 13. Kamiya T, Shikano M, Tanaka M, et al. Therapeutic effects of biobran, modified arabinoxylan rice bran, in improving symptoms of diarrhea predominant or mixed type irritable bowel syndrome: a pilot, randomized controlled study. Evid Based Complement Altern Med 2014;2014:828137. 14. Salama H, Medhat E, Shaheen M, Zekri AN, Darwish T, Ghoneum M. Arabinoxylan rice bran (Biobran) suppresses the viremia level in patients with chronic HCV infection: a randomized trial. Int J Immunopathol Pharmacol 2016;29(4):647–53. 15. Henderson AJ, Ollila CA, Kumar A, et al. Chemopreventive properties of dietary rice bran: current status and future prospects. Adv Nutr 2012;3(5):643–53. 16. Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol 2016;1(2):133–46. 17. Ford AC, Lacy BE, Talley NJ. Irritable bowel syndrome. N Engl J Med 2017;376(26):2566–78. 18. Canavan C, West J, Card T. Review article: the economic impact of the irritable bowel syndrome. Aliment Pharmacol Ther 2014;40(9):1023–34. 19. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 2012;10(7). 712–721 e714. 20. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States part I: overall and upper gastrointestinal diseases. Gastroenterology 2009;136(2):376–86.

262  SECTION | V  Foods and Macro Dietary Materials in GI Function

21. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109(Suppl. 1):S2–26. quiz S27. 22. Desselberger U, Huppertz HI. Immune responses to rotavirus infection and vaccination and associated correlates of protection. J Infect Dis 2011;203(2):188–95. 23. Tate JE, Burton AH, Boschi-Pinto C, Steele AD, Duque J, Parashar UD. 2008 estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis 2012;12(2):136–41. 24. Crawford SE, Ramani S, Tate JE, et al. Rotavirus infection. Nat Rev Dis Prim 2017;3:17083. 25. Desselberger U. Rotaviruses. Virus Res 2014;190(Suppl. C):75–96. 26. Wang M, Donovan SM. Human microbiota-associated swine: current progress and future opportunities. ILAR J 2015;56(1):63–73. 27. Saif LJ, Ward LA, Yuan L, Rosen BI, To TL. The gnotobiotic piglet as a model for studies of disease pathogenesis and immunity to human rotaviruses. Arch Virol Suppl 1996;12:153–61. 28. Ball RO, House JD, Wykes LJ, Pencharz PB. A piglet model for neonatal amino acid metabolism during total parenteral nutrition. In: Tumbleson ME, Schook LB, editors. Advances in swine in biomedical research, vol. 2. New York: Plenum Press; 1996. p. 713–31. 29. Yuan L, Wen K. Rotavirus. In: Liu D, editor. Laboratory models for foodborne infections. Boca Raton (FL): CRC Press, Taylor & Francis; 2017. p. 95–107. 30. Yang X, Twitchell E, Li G, et al. High protective efficacy of rice bran against human rotavirus diarrhea via enhancing probiotic growth, gut barrier function, and innate immunity. Sci Rep 2015;5:15004. 31. Hall AJ, Glass RI, Parashar UD. New insights into the global burden of noroviruses and opportunities for prevention. Expert Rev Vaccine 2016;15(8):949–51. 32. Pringle K, Lopman B, Vega E, Vinje J, Parashar UD, Hall AJ. Noroviruses: epidemiology, immunity and prospects for prevention. Futur Microbiol 2015;10(1):53–67. 33. Patel MM, Hall AJ, Vinje J, Parashar UD. Noroviruses: a comprehensive review. J Clin Virol 2009;44(1):1–8. 34. Lopman BA, Reacher MH, Vipond IB, Sarangi J, Brown DW. Clinical manifestation of norovirus gastroenteritis in health care settings. Clin Infect Dis 2004;39(3):318–24. 35. Karst SM. Pathogenesis of noroviruses, emerging RNA viruses. Viruses 2010;2(3):748–81. 36. Hall AJ, Glass RI, Parashar UD. New insights into the global burden of noroviruses and opportunities for prevention. Expert Rev Vaccine 2016:1–3. 37. Patel MM, Widdowson MA, Glass RI, Akazawa K, Vinje J, Parashar UD. Systematic literature review of role of noroviruses in sporadic gastroenteritis. Emerg Infect Dis 2008;14(8):1224–31. 38. Gastanaduy PA, Hall AJ, Curns AT, Parashar UD, Lopman BA. Burden of norovirus gastroenteritis in the ambulatory setting–United States, 20012009. J Infect Dis 2013;207(7):1058–65. 39. Hall AJ, Lopman BA, Payne DC, et al. Norovirus disease in the United States. Emerg Infect Dis 2013;19(8):1198–205. 40. Riddle MS, Walker RI. Status of vaccine research and development for norovirus. Vaccine 2016;34(26):2895–9. 41. Taube S, Kolawole AO, Hohne M, et al. A mouse model for human norovirus. mBio 2013;4(4). e00450–00413. 42. Kolawole AO, Rocha-Pereira J, Elftman MD, Neyts J, Wobus CE. Inhibition of human norovirus by a viral polymerase inhibitor in the B cell culture system and in the mouse model. Antiviral Res 2016;132:46–9. 43. Souza M, Azevedo MS, Jung K, Cheetham S, Saif LJ. Pathogenesis and immune responses in gnotobiotic calves after infection with the genogroup II.4-HS66 strain of human norovirus. J Virol 2008;82(4):1777–86. 44. Bui T, Kocher J, Li Y, et al. Median infectious dose of human norovirus GII.4 in gnotobiotic pigs is decreased by simvastatin treatment and increased by age. J Gen Virol 2013;94(Pt 9):2005–16. 45. Cheetham S, Souza M, Meulia T, Grimes S, Han MG, Saif LJ. Pathogenesis of a genogroup II human norovirus in gnotobiotic pigs. J Virol 2006;80(21):10372–81. 46. Wyatt RG, Greenberg HB, Dalgard DW, et al. Experimental infection of chimpanzees with the Norwalk agent of epidemic viral gastroenteritis. J Med Virol 1978;2(2):89–96. 47. Bok K, Parra GI, Mitra T, et al. Chimpanzees as an animal model for human norovirus infection and vaccine development. Proc Natl Acad Sci USA 2011;108(1):325–30. 48. Kocher J, Bui T, Giri-Rachman E, et al. Intranasal P particle vaccine provided partial cross-variant protection against human GII.4 norovirus diarrhea in gnotobiotic pigs. J Virol 2014;88(17):9728–43. 49. Lei S, Ryu J, Wen K, et al. Increased and prolonged human norovirus infection in RAG2/IL2RG deficient gnotobiotic pigs with severe combined immunodeficiency. Sci Rep 2016;6:25222. 50. Atmar RL, Bernstein DI, Harro CD, et al. Norovirus vaccine against experimental human Norwalk Virus illness. N Engl J Med 2011;365(23):2178–87. 51. Debbink K, Lindesmith LC, Baric RS. The state of norovirus vaccines. Clin Infect Dis 2014;58(12):1746–52. 52. Ghazi IA, Zarei I, Mapesa JO, et al. Rice bran extracts inhibit invasion and intracellular replication ofSalmonella typhimurium in mouse and porcine intestinal epithelial cells. Med Aromat Plants (Los Angel) 2016;5:271. 53. Ray B, Hutterer C, Bandyopadhyay SS, et al. Chemically engineered sulfated glucans from rice bran exert strong antiviral activity at the stage of viral entry. J Nat Prod 2013;76(12):2180–8. 54. Goodyear A, Kumar A, Ehrhart EJ, et al. Dietary rice bran supplementation prevents Salmonella colonization differentially across varieties and by priming intestinal immunity. J Funct Foods 2015;18(Part A):653–64.

Rice Bran Usage in Diarrhea Chapter | 21  263

55. Kumar A, Henderson A, Forster GM, et al. Dietary rice bran promotes resistance to Salmonella enterica serovar Typhimurium colonization in mice. BMC Microbiol 2012;12:71. 56. Kondo S, Teongtip R, Srichana D, Itharat A. Antimicrobial activity of rice bran extracts for diarrheal disease. J Med Assoc Thail Chotmaihet Thangphaet 2011;94(Suppl. 7):S117–21. 57. Komiyama Y, Andoh A, Fujiwara D, et al. New prebiotics from rice bran ameliorate inflammation in murine colitis models through the modulation of intestinal homeostasis and the mucosal immune system. Scand J Gastroenterol 2011;46(1):40–52. 58. Ghoneum M. Anti-HIV activity in vitro of MGN-3, an activated arabinoxylane from rice bran. Biochem Biophys Res Commun 1998;243(1):25–9. 59. de Vrese M, Marteau PR. Probiotics and prebiotics: effects on diarrhea. J Nutr 2007;137(3 Suppl. 2):803S–11S. 60. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev 2010;(11):CD003048. 61. Licciardi PV, Tang ML. Vaccine adjuvant properties of probiotic bacteria. Discov Med 2011;12(67):525–33. 62. Herfel T, Jacobi S, Lin X, van Heugten E, Fellner V, Odle J. Stabilized rice bran improves weaning pig performance via a prebiotic mechanism. J Anim Sci 2013;91(2):907–13. 63. Tsukahara T, Hashizume K, Koyama H, Ushida K. Stimulation of butyrate production through the metabolic interaction among lactic acid bacteria, Lactobacillus acidophilus, and lactic acid-utilizing bacteria, Megasphaera elsdenii, in porcine cecal digesta. Anim Sci J 2006;77(4):454–61. 64. Wullt M, Johansson Hagslatt ML, Odenholt I, Berggren A. Lactobacillus plantarum 299v enhances the concentrations of fecal short-chain fatty acids in patients with recurrent clostridium difficile-associated diarrhea. Dig Dis Sci 2007;52(9):2082–6. 65. Fukushima M, Fujii S, Yoshimura Y, Endo T, Nakano M. Effect of rice bran on intraintestinal fermentation and cholesterol metabolism in cecectomized rats. Nutr Res 1999;19(2):235–45. 66. Malakooti J, Saksena S, Gill RK, Dudeja PK. Transcriptional regulation of the intestinal luminal Na(+) and Cl(-) transporters. Biochem J 2011;435(2):313–25. 67. Binder HJ. Role of colonic short-chain fatty acid transport in diarrhea. Annu Rev Physiol 2010;72:297–313. 68. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 2013;54(9):2325–40. 69. Musch MW, Bookstein C, Xie Y, Sellin JH, Chang EB. SCFA increase intestinal Na absorption by induction of NHE3 in rat colon and human intestinal C2/bbe cells. Am J Physiol Gastrointest Liver Physiol 2001;280(4):G687–93. 70. Sheflin AM, Borresen EC, Kirkwood JS, et al. Dietary supplementation with rice bran or navy bean alters gut bacterial metabolism in colorectal cancer survivors. Mol Nutr Food Res 2017;61(1). 71. Sheflin AM, Borresen EC, Wdowik MJ, et al. Pilot dietary intervention with heat-stabilized rice bran modulates stool microbiota and metabolites in healthy adults. Nutrients 2015;7(2):1282–300. 72. Thaiss CA, Zmora N, Levy M, Elinav E. The microbiome and innate immunity. Nature 2016;535(7610):65–74. 73. Pfeiffer JK, Virgin HW. Viral immunity. Transkingdom control of viral infection and immunity in the mammalian intestine. Science 2016;351(6270). 74. Uchiyama R, Chassaing B, Zhang B, Gewirtz AT. Antibiotic treatment suppresses rotavirus infection and enhances specific humoral immunity. J Infect Dis 2014;210(2):171–82. 75. Ghoneum M, Gollapudi S. Modified arabinoxylan rice bran (MGN-3/Biobran) sensitizes human T cell leukemia cells to death receptor (CD95)induced apoptosis. Cancer Lett 2003;201(1):41–9. 76. Ghoneum M, Abedi S. Enhancement of natural killer cell activity of aged mice by modified arabinoxylan rice bran (MGN-3/Biobran). J Pharm Pharmacol 2004;56(12):1581–8. 77. Ghoneum M, Agrawal S. Activation of human monocyte-derived dendritic cells in vitro by the biological response modifier arabinoxylan rice bran (MGN-3/Biobran). Int J Immunopathol Pharmacol 2011;24(4):941–8. 78. Cholujova D, Jakubikova J, Sedlak J. BioBran-augmented maturation of human monocyte-derived dendritic cells. Neoplasma 2009;56(2):89–95. 79. Nealon NJ, Yuan L, Yang X, Ryan EP. Rice bran and probiotics alter the porcine large intestine and serum Metabolomes for protection against human rotavirus diarrhea. Front Microbiol 2017;8:653. 80. Burrin DG, Petersen Y, Stoll B, Sangild P. Glucagon-like peptide 2: a nutrient-responsive gut growth factor. J Nutr 2001;131(3):709–12. 81. Pinkerton R, Oria RB, Lima AA, et al. Early childhood diarrhea predicts cognitive delays in later childhood independently of malnutrition. Am J Trop Med Hyg 2016;95(5):1004–10. 82. Lorntz B, Soares AM, Moore SR, et al. Early childhood diarrhea predicts impaired school performance. Pediatr Infect Dis J 2006;25(6):513–20.