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Beneficial Effects of Probiotics, Prebiotics, Synbiotics, and
Beneficial Effects of Probiotics, Prebiotics, Synbiotics, and
Abstract: Inflammatory bowel disease (IBD) is a group of diseases characterized by inflammation of the small and large intestine and primarily includes
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Inflamm Bowel Dis Volume 21, Number 7, July 2015 Prebiotics, Probiotics, and Synbiotics in IBD
involved in the transformation of steroids and fatty acids, as well Other potential etiologic factors for IBD may include Che-
as in fermentation of dietary fiber and ions. In addition, intestinal lonia Mycobacterium species, Mycobacterium fortuitum and
bacteria synthesize several B-group vitamins and vitamin K.9 Mycobacterium kansasii19 and pathogenic strains of Escherichia
coli, primarily O157 and H7.20 The latter produce enzymes that
break down mucin, which forms a protective gel layer within GIT
GUT MICROBIOTA VERSUS IBD: FRIENDS and constitutes a semipermeable barrier between the lumen and
OR FOES? the epithelium. The changes in the mucus barrier increase perme-
Inflammatory bowel diseases (IBD) refer principally to 2 ability for bacteria and their metabolites that cause damage of
chronic diseases that manifest with intestinal inflammation: epithelial cells and lead to an inflammatory process in patients
ulcerative colitis (UC) and Crohn’s disease (CD). The incidence with UC,21 whereas hyperproduction of mucins and abnormal
of IBD is increasing, in particular, in developed countries. glycosylation is observed in patients with CD.22,23 Moreover,
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Wasilewski et al Inflamm Bowel Dis Volume 21, Number 7, July 2015
yogurt. The levels of IL-1b, TNF-a, and C-reactive protein in studies, stimulation of human lymphoid and myeloid dendritic
serum were significantly decreased in the group receiving pro- cells led to the induction of IL-10 and inhibition of IFN-g
biotic yogurt after 8 weeks of administration, whereas IL-6 and release, and the Th1-type cellular response. It was also found
IL-10 concentrations were significantly increased after the treat- that the use of VSL#3 strengthens the integrity of the intestinal
ment when compared with the placebo group. These results sug- epithelial barrier by increasing the expression of proteins
gest that probiotics may contribute to the maintenance of the responsible for the formation of tight junctions and a reduction
homeostasis in GIT and regulate pro- and anti-inflammatory of the number of apoptotic epithelial cells.49 In children with
responses of the intestinal immunocytes. Another study UC, administration of VSL#3 resulted in the induction and
that involved 21 patients with UC showed that Bifidobacteria- maintenance of remission (92.8%), compared with the placebo
fermented milk administered once per day in a volume of 100 group.50 Moreover, according to a recent study conducted by
mL for 1 year has a possible preventive effect on recurrence of Shen et al.51 VSL#3 has beneficial effect on the induction and
UC and helps maintaining its remission.44 Furthermore, Zocco the maintenance of UC remission in adults. To date, the role of
et al investigated the effect of L. rhamnosus GG, a strain of L. VSL#3 in the treatment of CD has not been investigated.52,53
rhamnosus isolated in 1983, on IBD symptoms. In this study, However, VSL#3 was found to increase the variety of bacteria
executed on a group of 187 patients with UC, the effect of the species in GIT of patients with IBD.54
administration of Lactobacillus GG and Lactobacillus GG in
combination with mesalamine versus mesalamine alone have been
compared. It has been shown that the combined treatment is more PREBIOTICS
effective in prolonging the relapse-free time than the treatment Prebiotics are defined as nondigestible food ingredients
with Lactobacillus GG and mesalazine alone.45 that beneficially affect the host by selectively stimulating the
Most of the presently published trials on probiotics were growth and/or activity of one or a limited number of bacteria in
carried out using a preparation named VSL#3, containing 8 GIT, and thus improve the host’s condition.55 These functional
strains, namely Lactobacillus casei, Lactobacillus plantarum, food components include oligosaccharides, which further
L. acidophilus, Lactobacillus bulgaricus, Bifidobacterium divide into fructo-oligosaccharides (FOS) (oligofructose and
longum, Bifidobacterium brevis, Bifidobacterium infantis, and inulin), galacto-oligosaccharides (lactulose), and gluco- and
Streptococcus thermophilus. It has been found that the admin- xylo-oligosaccharides. The main features of prebiotics are their
istration of VSL#3 greatly increased the secretion of IL-10, resistance to digestive enzymes produced by the human body,
IL-1b, and inhibited the production of IL-12.48 In the in vitro while remaining susceptible to colonic microflora fermentation.
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Inflamm Bowel Dis Volume 21, Number 7, July 2015 Prebiotics, Probiotics, and Synbiotics in IBD
Long-chain oligosaccharides (e.g., inulin) and short-chain butyrate administration alone or as a mixture results in an increased
oligosaccharides (e.g., oligofructose) are neither digested nor number of Treg cells and increased level of IL-10 within the
absorbed by the upper GIT. However, they undergo fermenta- colonic interstitium.72 Smith et al72 suggested that SCFAs, in par-
tion in the colon by anaerobic bacteria, which metabolize these ticular propionate, exert their effects by inhibiting histone deacety-
oligosaccharides to SCFAs, such as acetate, propionate, and lases 6 and 9 in a GPR43-mediated process.
butyrate, and selectively stimulate the growth of bifidobacteria.
This leads to bifidogenic effects and a decrease in intraluminal
pH.56,57 The latter is particularly important for the prevention SYNBIOTICS
from diarrhea and inhibition of some strains of potentially path- A combination of prebiotics and probiotics, named syn-
ogenic bacteria, e.g., Clostridium sp56 (Tables 2 and 3). biotics, is believed to exert synergistic effects. Namely, synbiotics
Gibson et al69 demonstrated that the administration of FOS influence the development of beneficial intestinal microflora
TABLE 2. Main Benefits of Prebiotics and Potential Mechanisms of Their Action in Animal Models of IBD
Animal Model Prebiotics Dose of Prebiotics Effects References
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Wasilewski et al Inflamm Bowel Dis Volume 21, Number 7, July 2015
TABLE 3. Main Benefits of Prebiotics and Potential Mechanisms of Their Action in Clinical Studies
Participants and Duration of Dose of
Disease Prebiotics Study Prebiotics Effects References
indicated that the prebiotic Synergy 1, in combination with brain, e.g., the solitary tract nucleus.86 In turn, efferent innervation
Bifidobacterium longum, led to an improvement of sigmoidos- can mediate the inflammatory response, affecting inter alia the a-7
copy scores and a decrease in b-defensin, TNF-a, and IL-1a in nicotinic receptor in immune cells, thereby reducing cytokine
biopsy samples from patients with UC. The study provides strong secretion.87 A crucial role is played here by the vagus nerve,
preliminary evidence that synbiotic administration may be bene- a parasympathetic branch of autonomic nervous system, which
ficial in IBD treatment. In another trial,80 35 patients with CD constitutes a vital line of communication between the gut micro-
were divided into 2 groups, those who received a combination of biota and CNS, as described below.
Bifidobacterium longum and a prebiotic Synergy 1 (containing The endocrine factors regulating MGBA include, among
FOS/inulin mix) and a placebo group. A significant histological others, cortisol. Its secretion is regulated by the hypothalamic–
improvement was observed in the synbiotic group compared with pituitary–adrenal axis under stress conditions. Cortisol may affect
controls (tissue samples for histological evaluation were collected immune cells by modulating the secretion of cytokines, as well as
at initiation of the study and after 3 and 6 mo). Although the the composition and functions of the microbiota. However, intes-
synbiotic had little effect on mucosal IL-18, IFN-g, and IL-1b, tinal bacteria have the ability to produce a number of neurohor-
there was a significant decrease in TNF-a expression after 3 mones, such as serotonin, melatonin, g-aminobutyric acid
months (P ¼ 0.041). Interestingly, the level of TNF-a did not (GABA), catecholamines, histamine, acetylcholine, and SCFAs.
change further after 6 months of the symbiotic treatment. These All of these likely participate in the communication between the
studies show the potential beneficial effect of synbiotics, but their gut microbiota and may also exert peripheral and systemic action
role in anti-IBD therapy remains to be determined. and affect behavior and brain function.88
GABA, which is the main inhibitory neurotransmitter in the
CNS, seems to play the most important role in physiological
PSYCHOBIOTICS processes within MGBA. Changes in the expression of GABA
Frequent coexistence of intestinal disorders, such as receptors are associated with the pathogenesis of anxiety and
irritable bowel syndrome or IBD and mental disorders, especially depression that often co-occur with functional GI disorders.
depression and anxiety,81 suggests a specific connection between Noteworthy, the effect of a prebiotic L. rhamnosus (JB-1) on
GIT and the central nervous system (CNS), often termed the gut– the expression of GABA receptors in the CNS has been demon-
brain axis.82 The importance of the microflora in the regulation of strated in the animal model of depression. This modulation occurs
GIT function reflects the need to extend this concept to a term through the vagus nerve. In addition, the administration of the
microbiota–gut–brain axis (MGBA).83 MGBA constitutes a bidi- probiotic resulted in the reduction of the content of corticosterone
rectional communication pathway including neural, endocrine, and restricted behaviors associated with depression and anxiety,
and immune mechanisms. Neuronal mechanisms include the hence the term psychobiotic has been applied. Importantly, neu-
enteric nervous system with several neurotransmitters and neuro- rochemical and behavioral influences of JB-1 were absent in mice
modulators, such as serotonin, acetylcholine, and corticotropin- after vagotomy, indicating that the vagus nerve is a key element of
releasing factor (Fig. 1). The latter is particularly noteworthy communication between intestinal microbiota and CNS.89
because of its participation in the increase of the permeability In another study, a mouse model of colitis induced by
of the intestinal barrier under stress conditions.84,85 The autonomic dextran sulfate sodium has been used to assess the influence of the
nervous system, which is another component of MGBA, consists strain Bifidobacterium longum NCC 3001 on animal behavior.90
of sympathetic and parasympathetic branches. Several studies Administration of the probiotic decreased anxiety behavior in
have shown that proinflammatory cytokines may have a direct dextran sulfate sodium–treated mice but did not affect intestinal
effect on the CNS through the activation of afferent nerve inflammation or the expression of brain-derived neurotrophic fac-
fibers, which transmit impulses to the specified regions of the tor mRNA.91 As in the previous case, the behavioral changes were
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Inflamm Bowel Dis Volume 21, Number 7, July 2015 Prebiotics, Probiotics, and Synbiotics in IBD
lost in mice after vagotomy. Thus, the anxiolytic effect of Bifido- Microbiota and probiotics may exert an effect on MGBA
bacterium longum NCC 3001 involves vagal integrity and may through the immune system.95,96 A number of studies have shown
involve MGBA but is independent of gut immunomodulation or that intestinal bacteria can reduce the concentration of proinflam-
brain-derived neurotrophic factor production. matory cytokines, such as TNF-a, IFN-g, and IL-6 and modulate
Wall et al92 demonstrated that the administration of Bifido- the concentration of anti-inflammatory cytokines, e.g., IL-10.97
bacterium strain to mice affects the fatty acid composition of the The proinflammatory cytokines play a key role in the activation
brain. Mice receiving Bifidobacterium for 8 weeks had a higher of hypothalamic–pituitary–adrenal axis; namely IL-1b, IL-6, and
concentration of arachidonic acid and docosahexaenoic acid, TNF-a increase the permeability of the intestinal barrier and
compared with control group. Arachidonic acid and docosahex- aggravate inflammation, whereas IFN-a, IFN-g, and TNF-a acti-
aenoic acid are important in brain development and play a role in vate an enzyme of the kynurenic pathway, indoleamine 2,3-
neurotransmission and protection against oxidative stress.93,94 dioxygenase, which transfers tryptophan from the serotonin
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Wasilewski et al Inflamm Bowel Dis Volume 21, Number 7, July 2015
synthesis cycle to metabolism in the kynurenine pathway, reduc- 12. Sartor RB. Therapeutic manipulation of the enteric microflora in inflam-
ing its concentration.98–100 In addition, cytokines can exert a direct matory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroen-
terology. 2004;126:1620–1633.
effect on the CNS through a variety of mechanisms, including 13. Chandran P, Satthaporn S, Robins A, et al. Inflammatory bowel disease:
passing through the permeable regions for some cytokines in the dysfunction of GALT and gut bacterial flora (II). Surgeon. 2003;1:125–136.
blood–brain barrier or by activating the afferent nerve fibers, e.g., 14. Sellon RK, Tonkonogy S, Schultz M, et al. Resident enteric bacteria are
necessary for development of spontaneous colitis and immune system acti-
the vagus nerve.86 vation in interleukin-10-deficient mice. Infect Immun. 1998;66:5224–5231.
The ECS has also been implicated in the MGBA. ECS 15. Scribano ML, Prantera C. Antibiotics and inflammatory bowel diseases.
consists of the endogenous arachidonate-based lipids, enzymes Dig Dis. 2013;31:379–384.
16. D’Haens GR, Geboes K, Peeters M, et al. Early lesions of recurrent
that synthesize and degrade the endocannabinoids and cannabi- Crohn’s disease caused by infusion of intestinal contents in excluded
noid receptors. At present, it is clear that ECS is involved in ileum. Gastroenterology. 1998;114:262–267.
maintenance of the gut homeostasis through modulation of GIT 17. Greenstein RJ. Is Crohn’s disease caused by a mycobacterium? Compar-
isons with leprosy, tuberculosis, and Johne’s disease. Lancet Infect Dis.
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Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
Inflamm Bowel Dis Volume 21, Number 7, July 2015 Prebiotics, Probiotics, and Synbiotics in IBD
37. Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative 60. Moreau NM, Martin LJ, Toquet CS, et al. Restoration of the integrity of
colitis with the probiotic Escherichia coli Nissle 1917 is as effective as rat caeco-colonic mucosa by resistant starch, but not by fructo-
with standard mesalazine. Gut. 2004;53:1617–1623. oligosaccharides, in dextran sulfate sodium-induced experimental colitis.
38. Guslandi M, Mezzi G, Sorghi M, et al. Saccharomyces boulardii in Br J Nutr. 2003;90:75–85.
maintenance treatment of Crohn’s disease. Dig Dis Sci. 2000;45: 61. Hoentjen F, Welling GW, Harmsen HJ, et al. Reduction of colitis by
1462–1464. prebiotics in HLA-B27 transgenic rats is associated with microflora
39. Prantera C, Scribano ML. Probiotics and Crohn’s disease. Dig Liver Dis. changes and immunomodulation. Inflamm Bowel Dis. 2005;11:977–985.
2002;34(suppl 2):S66–S67. 62. Koleva PT, Valcheva RS, Sun X, et al. Inulin and fructo-
40. Bousvaros A, Guandalini S, Baldassano RN, et al. A randomized, oligosaccharides have divergent effects on colitis and commensal micro-
double-blind trial of Lactobacillus GG versus placebo in addition to biota in HLA-B27 transgenic rats. Br J Nutr. 2012;108:1633–1643.
standard maintenance therapy for children with Crohn’s disease. Inflamm 63. Lara-Villoslada F, Debras E, Nieto A, et al. Oligosaccharides isolated
Bowel Dis. 2005;11:833–839. from goat milk reduce intestinal inflammation in a rat model of dextran
41. Marteau P, Lemann M, Seksik P, et al. Ineffectiveness of Lactobacillus sodium sulfate-induced colitis. Clin Nutr. 2006;25:477–488.
johnsonii LA1 for prophylaxis of postoperative recurrence in Crohn’s 64. Rumi G, Tsubouchi R, Okayama M, et al. Protective effect of lactulose
disease: a randomised, double blind, placebo controlled GETAID trial. on dextran sulfate sodium-induced colonic inflammation in rats. Dig Dis
www.ibdjournal.org | 1681
Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
Wasilewski et al Inflamm Bowel Dis Volume 21, Number 7, July 2015
84. Gareau MG, Jury J, MacQueen G, et al. Probiotic treatment of rat pups 96. Duerkop BA, Vaishnava S, Hooper LV. Immune responses to the micro-
normalises corticosterone release and ameliorates colonic dysfunction biota at the intestinal mucosal surface. Immunity. 2009;31:368–376.
induced by maternal separation. Gut. 2007;56:1522–1528. 97. Desbonnet L, Garrett L, Clarke G, et al. The probiotic Bifidobacteria
85. Collins SM, Surette M, Bercik P. The interplay between the intestinal infantis: an assessment of potential antidepressant properties in the rat.
microbiota and the brain. Nat Rev Microbiol. 2012;10:735–742. J Psychiatr Res. 2008;43:164–174.
86. Irwin MR, Miller AH. Depressive disorders and immunity: 20 years of 98. Wichers MC, Maes M. The role of indoleamine 2,3-dioxygenase (IDO)
progress and discovery. Brain Behav Immun. 2007;21:374–383. in the pathophysiology of interferon-alpha-induced depression.
87. Pavlov VA, Tracey KJ. Neural regulators of innate immune responses J Psychiatry Neurosci. 2004;29:11–17.
and inflammation. Cell Mol Life Sci. 2004;61:2322–2331. 99. Maes M, Leonard BE, Myint AM, et al. The new “5-HT” hypothesis of
88. Iyer LM, Aravind L, Coon SL, et al. Evolution of cell-cell signaling in depression: cell-mediated immune activation induces indoleamine 2,3-
animals: did late horizontal gene transfer from bacteria have a role? dioxygenase, which leads to lower plasma tryptophan and an increased
Trends Genet. 2004;20:292–299. synthesis of detrimental tryptophan catabolites (TRYCATs), both of
89. Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain which contribute to the onset of depression. Prog Neuropsychopharma-
regulates emotional behavior and central GABA receptor expression in col Biol Psychiatry. 2011;35:702–721.
a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011;108: 100. Myint AM, Kim YK, Verkerk R, et al. Kynurenine pathway in major
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