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Keywords:

  • Bifidobacterium;
  • butyrate;
  • dietary fiber;
  • Eubacterium limosum;
  • inflammation;
  • microflora;
  • prebiotics;
  • ulcerative colitis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical composition and physiological characteristics of GBF
  5. Anticolitis effects of GBF (prebiotics) in an animal model
  6. Clinical evaluation of GBF in patients with UC
  7. Mechanism for the improvement of colitis following GBF
  8. Conclusions
  9. References

Abstract  A germinated barley foodstuff (GBF) containing glutamine-rich protein and hemicellulose-rich fiber was made from brewer's spent grain, by physical isolation. Our previous studies demonstrated that GBF supported maintenance of epithelial cell populations, facilitated epithelial repair, and suppressed epithelial nuclear factor κB-DNA-binding activity through generating increased short-chain fatty acid (especially butyrate) production by luminal microflora, which includes Bifidobacterium and Eubacterium, thereby preventing experimental colonic injury. The fiber fraction also modulates stool water content because of its high water-holding capacity. The patients with mild to moderate active ulcerative colitis who had been unresponsive to or intolerant of standard treatment received 20–30 g GBF, feeding daily in a non-randomized, open-label fashion. At 4 weeks, this treatment resulted in a significant clinical and endoscopic improvement. The improvement was associated with an increase in stool butyrate concentrations. These results indicate that GBF feeding is a potentially new, attractive prebiotic treatment in patients with ulcerative colitis. The potency of GBF on modulating microflora, as well as the high water-holding capacity, may play an important role in treatment and prolongation of remission in ulcerative colitis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical composition and physiological characteristics of GBF
  5. Anticolitis effects of GBF (prebiotics) in an animal model
  6. Clinical evaluation of GBF in patients with UC
  7. Mechanism for the improvement of colitis following GBF
  8. Conclusions
  9. References

Ulcerative colitis (UC) is an idiopathic inflammatory disorder of the large intestine.1 Although detailed mechanisms of UC are not known, our understanding of the cellular and molecular mechanisms associated with UC has increased dramatically.1–4 Several drugs (corticosteroids, 5-aminosalicylate compounds and immune-suppressing agents) and new therapies (leukocytapheresis,5 anti-tumor necrosis factor (TNF)-α antibody6) have a proven efficacy in the treatment of UC. These treatments are based on the attenuation of local inflammation in the colon. In addition to these therapies, it has been reported recently7–10 that improvement or reinforcement of the colonic mucosal barrier may play an important role in the treatment of UC. The efficacy of the butyrate enema,7,8 which is considered as a primary fuel for the colonic mucosa, and trefoil peptide9 and glucagon-like peptide 2 (GLP-2),10 which accelerate the restitution of the colonic epithelium in inflammation, has been demonstrated in clinical trials and animal models. Furthermore, disruption of mucosal barrier function may induce pathological immune responses to luminal bacteria11,12 and their metabolite butyrate,13–16 resulting in acute and chronic inflammation.

Some prebiotics, including dietary fiber, which escapes digestion in the upper intestinal tract and is used as a substrate by the microflora, are also effective in the treatment of UC. It is generally accepted that dietary fiber induces the production of short-chain fatty acids (SCFA),13–16 important nutrients for epithelial cells, by intestinal flora.11,12 For example, psyllium husk and some types of oligosaccharides have been proven effective in maintaining remission or in reducing colonic damage.17,18 Among the SCFA, butyrate most effectively protects the intestinal mucosa against injury and promotes mucosal healing.13–16,19 Thus, it is considered that modulating the colonic luminal environment may play an important role in the treatment and prolongation of remission of UC.20

Germinated barley foodstuff (GBF), which is derived from the aleurone layer and scutellum fractions of malt, consists mainly of dietary fiber and glutamine (Gln)-rich protein.21,22 In previous studies, GBF administration to rats resulted in an increase in SCFA production and a reduction in bowel movements.21,23 Furthermore, GBF exhibited preventive and therapeutic effects in an experimental colitis model, especially improvement of severe bloody diarrhea and attenuation of colonic mucosal damage.23,24 In addition to animal experiments, clinical trials of GBF, which have been performed in patients with mild to moderate UC and GBF treatment, were shown to be potent in attenuating symptoms of colitis.25 In the present review, we summarize the effects of GBF on colitis and the mechanism for improving colitis, especially from the point of view of a modulator of an intestinal environment. In the present review, we summarize the effects of GBF on colitis and the mechanism for improving colitis, particularly in view of GBF as a modulator of the intestinal environment.

Chemical composition and physiological characteristics of GBF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical composition and physiological characteristics of GBF
  5. Anticolitis effects of GBF (prebiotics) in an animal model
  6. Clinical evaluation of GBF in patients with UC
  7. Mechanism for the improvement of colitis following GBF
  8. Conclusions
  9. References

The detailed process of producing GBF has been described elsewhere.21,24 Germinated barley foodstuff is the aleurone and scutellum fractions of germinated barley obtained by milling and sieving the residual brewer's spent grain (Fig. 1). Germinated barley foodstuff is insoluble and contains Gln-rich protein and hemicellulose-rich dietary fiber. Barley synthesizes the Gln-rich proteins and uses Gln as a major energy source during germination and, later, growth because Gln has two amino groups in one molecule and is one of the most efficient nitrogen transporters in plants.26

image

Figure 1. Schema of the production of germinated barley foodstuff (GBF) from barley and the chemical composition of GBF. Germinated barley foodstuff mainly contains an aleurone layer and a malt germ. Germinated barley foodstuff contains glutamine-rich protein and hemicellulose-rich fiber.

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Although Gln is characterized as a fragile amino acid in the gastrointestinal tract, Gln is known to have unique physiological functions in the intestine, as follows: (i) it is a major source of energy for intestinal epithelial cells; (ii) it stimulates the proliferation of intestinal epithelial cells; and (iii) it prevents bacterial translocation from the gut lumen into the internal milieu.27–29 Our previous study showed that feeding normal rats with Gln and Gln-rich proteins could not elevate mucosal protein contents and improve defecation comparing with feeding of GBF.21,22 Thus, Gln in GBF may exist very stably, being protected by coexisting dietary fibers, and so may be resistant to breakdown by gastric acid and digestive enzymes; thus, it may be able to act on the intestinal mucosa more effectively than Gln itself.

As for the dietary fiber of GBF, the barley produces much low-lignified hemicellulose, which is accumulated in the scutellum and aleurone fractions for stretching of the roots and shoots during the germination process.26 In this germination process, GBF acquires a conspicuous water-holding capacity.21,22 The dietary fiber fraction of GBF is considered to be able to modulate fecal water content appropriately, maintaining it at a normal level. In addition, GBF is used efficiently by the microflora and converted to SCFA, and these bacteria l organic acids preserve preferable intestinal conditions.30,31

The endogenous bacterial butyrate from GBF is immediately absorbed by colonic epithelial cells and is used as a metabolic fuel.32 The water-holding capacity of GBF (18 mL/g) is much higher than that of other representative water-insoluble dietary fibers, such as wheat bran (4.5 mL/g), cellulose powder (4.0 mL/g) and corn fiber (5.0 mL/g). Detailed methods used to determine the water holding-capacity have been described in our previous study.22 Briefly, 1 g of each sample of dietary fiber was dissolved in phosphate-buffered saline (pH 6.8) and the settling volume was measured volumetrically.22

Anticolitis effects of GBF (prebiotics) in an animal model

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical composition and physiological characteristics of GBF
  5. Anticolitis effects of GBF (prebiotics) in an animal model
  6. Clinical evaluation of GBF in patients with UC
  7. Mechanism for the improvement of colitis following GBF
  8. Conclusions
  9. References

Dextran sulfate sodium (DSS)-induced colitis in rats is commonly used to evaluate the efficacy of new drugs for the treatment of inflammatory bowel disease.2 Before the onset of DSS-induced colitis, GBF was administered to rats for 1 week, then 3.5% DSS was added to the diet and the preventive effects of GBF were evaluated 5–7 days after the induction of colitis, in terms of bowel movements and colonic mucosal damage. Oral administration of GBF improved the clinical and pathological signs of colitis, with a decrease in serum inflammatory parameters, interleukin (IL)-8 and α1-acid glycoprotein23 (Fig. 2). Notably, the improvement in colitis was associated with an increase in fecal butyrate and in the number of Bifidobacterium and Eubacterium in the luminal contents.31 Thus, it is speculated that GBF acts, at least in part, by promoting the endogenous production of butyrate by the microflora.

image

Figure 2. (a) Concentration of (□) serum interleukin-8 (red) and (▪) α1-acid glycoprotein in colitis rats fed control, germinated barley foodstuff (GBF) and sulfasalazine (SASP) diets. (b) Concentration of cecal short-chain fatty acids in colitis rats fed control, GBF and SASP diets. (bsl00022), Acetic acid; (bsl00005), propionic acid; (bsl00023), butyric acid. Data are expressed as the mean ± SEM. * P < 0.05 compared with the control (cellulose-fed) group.

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The human histocompatibility leukocyte antigen (HLA)-B27 transgenic rat developed colitis spontaneously, resembling human UC, between 6 and 20 weeks of age. The HLA-B27 transgenic rats are used as a representative chronic colitis model. The administration of GBF to these rats for 14 weeks resulted in an improvement in colonic injury and hyperplasia, with an increase in endogenous butyrate production, as well as an improvement of the diarrhea.33 Thus, GBF has been shown to have preventive effects against acute and chronic colitis.

In addition to the preventive effect of GBF on colitis, it is also important to determine whether GBF has a therapeutic effect or not. The pathophysiology of UC is strongly influenced by both disease duration and activity.20 In the study of Kanauchi et al., colitis was induced by the administration of DSS (3.5% of the diet) for 7 days, after which the DSS was reduced to 0.5% of the diet to maintain minimal colonic inflammation. After onset of colitis, GBF or salazosulfapyridine (SASP) was administered to colitis rats and the curative effects of GBF were evaluated.24

Following GBF administration, colonic mucosal healing was accelerated significantly, the same effects as seen with SASP treatment, compared with the control group. As for bowel movements, GBF showed a significant antidiarrheal effect compared with the control group. Although combined treatment with GBF and SASP showed a therapeutic effect against colitis, unfortunately no synergistic effect was observed between GBF and SASP. However, the most important element regarding treatment with GBF was that it did not interfere with the anti-inflammatory effect of SASP, which is the first-line treatment for UC.

Clinical evaluation of GBF in patients with UC

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical composition and physiological characteristics of GBF
  5. Anticolitis effects of GBF (prebiotics) in an animal model
  6. Clinical evaluation of GBF in patients with UC
  7. Mechanism for the improvement of colitis following GBF
  8. Conclusions
  9. References

The first clinical trial to evaluate the effects of GBF on UC enrolled 10 patients with mild to moderate active UC who had been unresponsive to or intolerant of standard treatment (three patients with pancolitis, four with left-sided colitis and three with proctitis). These patients received 30 g GBF feeding (given three times daily) for 4 weeks in a non-randomized, open-label fashion. Clinical34 and endoscopic35 evaluations were in accordance with results from previous studies. Briefly, the clinical score consisted of the sum of the following: (i) the number of episodes of diarrhea (0–4); (ii) the presence of nocturnal diarrhea (0–1); (iii) the degree of visible blood in the stools (0–3); (iv) the presence of fecal incontinence (0–1); (v) the degree of abdominal pain or cramping (0–3); (vi) general well-being (0–5); (vii) the degree of abdominal tenderness (0–3); and (viii) the need for antidiarrheal drugs (0–1). The endoscopic score was determined by the following five parameters: erythema, edema, friability, granularity and erosions. Each parameter was scored as absent (grade 0), mild (grade 1) or severe (grade 2). The sum of the scores was considered an endoscopic index, with a score range of 0–10. At 4 weeks, treatment with GBF resulted in clinical (Fig. 3) and endoscopic (Fig. 4) improvement, independent of disease extent. Furthermore, despite continued treatment with standard treatment for UC, the patients had an exacerbation of the disease within 4 weeks after the cessation of GBF treatment.25

image

Figure 3. Line graph showing stool concentrations of butyrate in 10 patients with ulcerative colitis (UC) before and after a 4-week period of feeding with germinated barley foodstuff (GBF). (bsl00005), Serial changes in clinical activity index scores; (bsl00022), endoscopic index scores in 10 patients with UC during the observation period. Patients with active UC received 30 g GBF daily for 4 weeks and were followed for more than 4 weeks thereafter. Clinical and endoscopic scores were determined as described in the section. Clinical evaluation of GBF in patients with UC. Data are expressed as the mean ± SEM. *Significantly different from the initial value (0 weeks).

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image

Figure 4. Endoscopic colonic mucosal appearance of the (a,b) ascending colon and (c,d) rectum. After the administration of germinated barley foodstuff (GBF), over (a,c) 0 week and (b,d) 4 weeks, erythema and edema were diminished. A vascular pattern was clearly observed after GBF treatment.

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After this pilot study, a multicenter trial was able to show a similar beneficial effect of GBF.36 Of note, the decrease in disease activity induced by GBF treatment was also associated with an increase in the concentrations of SCFA, especially butyrate.36 Germinated barley foodstuff was safe and well tolerated, although mild and transient abdominal distension, which is generally caused by the ingestion of dietary fiber in humans, was sometimes observed.

Mechanism for the improvement of colitis following GBF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical composition and physiological characteristics of GBF
  5. Anticolitis effects of GBF (prebiotics) in an animal model
  6. Clinical evaluation of GBF in patients with UC
  7. Mechanism for the improvement of colitis following GBF
  8. Conclusions
  9. References

Butyrate production by microflora

In a previous study, GBF and its fiber fraction drastically mitigated colonic mucosal damage and bloody diarrhea in a colitis model.24 In contrast, the protein fraction of GBF did not show any anticolitis effects. By administration of GBF or its fiber fraction, cecal butyrate production was significantly increased compared with the control and GBF-protein groups. In addition, this increment in butyrate production was considered to be closely related to the mitigation of diarrhea and mucosal damage in colitis. The administration of GBF significantly increased the number of Eubacterium and Bifidobacterium, with a decrease in colonic pH.30,31 As a result, the fiber fraction of GBF was considered to be efficiently dehydrated and converted to butyrate by Eubacterium and Bifidobacterium in this colitis model. Furthermore, GBF has a high water-holding capacity and expands well in the gastrointestinal tract, so that GBF may be well used by Eubacterium and Bifidobacterium. In fact, the dietary fiber fraction of GBF, which is mainly composed of an aleurone layer and contains low-lignified and arabinoxylan -rich hemicellulose, is specifically decomposed in the human gastrointestinal tract.37

Some other dietary fibers have been reported to improve the symptoms of colitis.17,18 We have compared the effects of these dietary fibers with GBF in a colitis model (T Bamba et al., unpubl. obs., 2001). The dietary fiber level in the different dietary groups was adjusted to 3% and the effects of these dietary fibers, including GBF, on colonic mucosal damage and bloody diarrhea were evaluated in DSS-induced colitis rats. Could GBF more efficiently produce bacterial butyrate and improve bloody diarrhea in colitis than the other dietary fibers? We compared the anticolitis effects of fructooligosaccharide (FO; Meiji-Seika, Tokyo, Japan), sugar beet fiber (SB; Nitten, Tokyo, Japan) and resistant starch (RS; Penford Australia, NSW, Australia) with GBF using DSS colitis rats (T Bamba et al., unpubl. obs., 2001).

The administration of RS, SB and FO did not increase the cecal butyrate content significantly compared with the control (cellulose; CE) group. However, the cecal butyrate concentration following the administration of GBF was significantly higher than that in all other groups. Resistant starch, SB and FO did not attenuate diarrhea in this model. Following GBF administration, there was significant improvement in diarrhea observed compared with all other groups. This difference in effect in attenuating diarrhea in colitis between GBF and other dietary fibers was considered to be related to the degree of bacterial butyrate production (Fig. 5).

image

Figure 5. (a) Diarrheal score (0, normal; 1, soft feces without visible blood; 2, soft feces with blood; 3, bloody diarrhea) in colitis rats fed control (cellulose; CE), germinated barley foodstuff (GBF)-, resistant starch (RS)-, sugar beet fiber (SB)- and fructooligosaccharide (FO)-containing diets. (b) Change in concentration of cecal short-chain fatty acids in colitis rats fed CE, GBF, RS, SB and FO diets. Data are expressed as the mean ± SEM. * P < 0.05 compared with the CE-fed (control) group. (bsl00023), Acetate; (▪), butyrate; (□), i-butyrate; (bsl00021), propionate.

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Role of butyrate in the intestinal tract

In a previous study, butyrate, administered intracecally, was able to prevent colonic injury in the DSS model, although oral butyrate did not show any preventive effects.32 Because butyrate is absorbed by the small intestine, orally administered butyrate may not reach the large intestine. This may be why butyrate administered orally did not preserve the integrity and proliferation of the intestinal mucosa.7 In some cases, a butyrate enema is effective in reducing mucosal damage, especially in the descending colon or rectum, in human UC.8

To confirm this butyrate role of GBF, the use of butyrate as epithelial fuel was blocked by the administration of ibuprofen, an inhibitor of SCFA β-oxidation, along with GBF feeding during the course of DSS colitis.32 As expected, the preventive effect of GBF against colonic injury was markedly suppressed by this procedure, although ibuprofen did not interfere with butyrate production in the GBF and control groups. This result indicates the importance of endogenous butyrate during GBF action. Furthermore, the two major components of GBF, namely the protein and fiber fractions, were isolated and each fraction was administered to DSS models to determine the most active ingredient of GBF.38 It was clear that the fiber fraction of GBF, but not the protein fraction, could induce endogenous butyrate production and prevent colonic injury.

Incidentally, butyrate administered either orally or cecally could not inhibit the severe bloody diarrhea because butyrate itself has no fecal-forming ability.32 Germinated barley foodstuff has fecal-forming potential in addition to inducing the production of bacterial butyrate.39 Taking these results into consideration, GBF may deliver butyrate to the entire colon by bacterial fermentation; thus, GBF exclusively reduces colonic mucosal damage.

Anti-inflammatory effects of GBF in colitis

The administration of GBF increased butyrate concentrations in the lower intestinal tract; this bacterial butyrate from GBF can inhibit the binding activity of nuclear factor (NF)-κB to DNA in colonic epithelium, a key transcription factor for pro-inflammatory cytokine production in HLA-B27 transgenic rats.33 As a result, there was a significant reduction in IL-8, which is regulated by NF-κB-DNA-binding activity. However, other inflammatory parameters, namely serum α1-acid glycoprotein (AAG) and mucosal myeloperoxidase (MPO) activity, were not attenuated by GBF administration because AAG and MPO are not regulated by NF-κB. To obtain a detailed understanding of the molecular biological anti-inflammatory mechanism of action of GBF in colitis, further studies are needed.

Regulation of bowel movements by GBF

The water-holding capacity of other dietary fibers (cellulose, SB and wheat bran) was compared with GBF and it was shown that GBF had the highest water-holding capacity.40 These data led us to speculate that GBF has a marked stool-forming ability in the colon. To confirm the fecal-forming ability of GBF, GBF was administered to cecocolectomized rats that lacked a large part of the colon.39 The diarrhea in these rats could be prevented completely by feeding rats GBF, suggesting that GBF also has a direct effect on stool formation, regardless of the presence of intestinal inflammation.

Other effects of GBF

Germinated barley foodstuff contains Gln-rich protein and the administration of Gln or Gln-containing foodstuffs has been shown to partly prevent mucosal damage in the methotrexate (MTX)-induced enteritis model.41 In MTX-induced enteritis, severe diarrhea, as well as small intestinal mucosal damage, is caused. In this model, GBF more effectively prevented diarrhea and mucosal damage and decreased small intestinal mucosal damage compared with control and Gln-containing stuffs. The anti-enteritis effect of GBF was considered to derive from Gln, which improves mucosal proliferation in the small intestine, and the stability of Gln in GBF is superior to Gln itself because of the coexisting dietary fiber in GBF.

In a previous study, approximately 50% of the GBF-protein fraction was easily digested by gastrointestinal enzymes; thereby, approximately one-half of the Gln was considered to be used in the small intestine.42 The residual GBF protein fraction (approximately 50%) was transferred to the colon and dehydrated by the microflora; thus, Gln in GBF was absorbed within the colonic mucosa. Some studies indicated that a Gln enema is effective for the attenuation of colonic mucosal damage in an experimental colitis model.43 The anti-inflammatory effect of GBF on UC may be explained, in part, by Gln in addition to the dietary fiber fraction of GBF.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical composition and physiological characteristics of GBF
  5. Anticolitis effects of GBF (prebiotics) in an animal model
  6. Clinical evaluation of GBF in patients with UC
  7. Mechanism for the improvement of colitis following GBF
  8. Conclusions
  9. References

Germinated barley foodstuff was efficiently converted to butyrate by Bifidobacterium and Eubacterium. This butyrate was well absorbed and used as a primary fuel in the entire colonic mucosa; thereby, GBF exhibited potent acceleration of colonic epithelial reconstitution. In addition, it is known that anaerobic bacteria mediate intestinal inflammation in the trinitrobenzene sulfonic acid colitis model and that treatment with metronidazole or broad-spectrum antibiotic therapy is effective.44 From these standpoints, part of the anticolitis effect of GBF could be explained by a role of the microflora modulator, in addition to butyrate production and high water-holding capacity. Finally, Gln in GBF may contribute to the improvement of colonic barrier function.

Germinated barley foodstuff has few adverse effects and has been approved as a special foodstuff for UC patients by the Ministry of Health and Welfare in Japan as of March 2000. The authors expect that GBF treatment will be added to standard medical strategies for the treatment of UC as a supportive nutraceutical treatment in the near future.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chemical composition and physiological characteristics of GBF
  5. Anticolitis effects of GBF (prebiotics) in an animal model
  6. Clinical evaluation of GBF in patients with UC
  7. Mechanism for the improvement of colitis following GBF
  8. Conclusions
  9. References
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