Butyric acid in irritable bowel syndrome

Abstract

Butyric acid (butanoic acid) belongs to a group of short-chain fatty acids and is thought to play several beneficial roles in the gastrointestinal tract. Butyric anion is easily absorbed by enteric cells and used as a main source of energy. Moreover, butyric acid is an important regulator of colonocyte proliferation and apoptosis, gastrointestinal tract motility and bacterial microflora composition in addition to its involvement in many other processes including immunoregulation and anti-inflammatory activity. The pathogenesis of irritable bowel syndrome (IBS), the most commonly diagnosed functional gastrointestinal condition, is complex, and its precise mechanisms are still unclear. This article describes the potential benefits of butyric acid in IBS.

Full text

Przegląd Gastroenterologiczny 2013; 8 (6)
Review paper
Irritable bowel syndrome
Irritable bowel syndrome (IBS) is afunctional bow-
el disorder that generates asignificant health care
burden and is the most commonly diagnosed func-
tional gastrointestinal condition. Approximately 12%
of adults in the general population experience symp-
toms of IBS [1, 2]. Several definitions of IBS exist. Table
Ishows the most commonly used diagnostic criteria,
the so-called Rome III Criteria, for IBS in adults [3]. Ac-
cording to these criteria, IBS is classified into four sub-
types based on predominant stool patterns, as shown
in Table II. An American College of Gastroenterology
position statement published in 2009 defines IBS as an
abdominal pain or discomfort that occurs in associa-
tion with altered bowel habits over aperiod of at least
3 months [4]. The pathophysiological mechanisms of
IBS are still unknown. Brain–gut interactions, visceral
hypersensitivity, abnormal motility, intestinal inflam-
mation, post-infectious disturbances and alteration of
microflora have all been suspected to play arole in the
pathogenesis of this syndrome [5, 6]. Visceral hyper-
sensitivity is believed to be amajor contributing factor
to abdominal pain in patients with IBS. Psychosocial
factors seem to be also involved in the pathogenesis
of IBS [7].
Butyric acid in irritable bowel syndrome
Andrzej Załęski
1
, Aleksandra Banaszkiewicz
1
, Jarosław Walkowiak
2
1
Department of Paediatric Gastroenterology and Nutrition, Medical University of Warsaw, Poland
2
Department of Paediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poland
Prz Gastroenterol 2013; 8 (6): 350–353
DOI: 10.5114/pg.2013.39917
Key words: butyric acid, sodium butyrate, irritable bowel syndrome.
Address for correspondence: Aleksandra Banaszkiewicz MD, PhD, Department of Paediatric Gastroenterology and Nutrition,
Medical University of Warsaw, 1 Działdowska St, 01-184 Warsaw, Poland, phone/fax: +48 22 452 33 10,
e-mail: aleksandra.banaszkiewicz@wum.edu.pl
Abstract
Butyric acid (butanoic acid) belongs to agroup of short-chain fatty acids and is thought to play several beneficial roles
in the gastrointestinal tract. Butyric anion is easily absorbed by enteric cells and used as amain source of energy. Moreover,
butyric acid is an important regulator of colonocyte proliferation and apoptosis, gastrointestinal tract motility and bacterial
microflora composition in addition to its involvement in many other processes including immunoregulation and anti-inflam-
matory activity. The pathogenesis of irritable bowel syndrome (IBS), the most commonly diagnosed functional gastrointestinal
condition, is complex, and its precise mechanisms are still unclear. This article describes the potential benefits of butyric
acid in IBS.
Irritable bowel syndrome
management
Because the pathogenesis of IBS is unclear, treat-
ment focuses on the relief of symptoms such as bloat-
ing, abdominal pain, diarrhoea and constipation. Treat-
ment difficulties are increased by the heterogeneity
of the IBS population (wide range of patient ages and
complaints, varying degrees of symptom severity), lack
of unequivocal treatment algorithms, and remarkably
high placebo response rate with short-term trials re-
porting response rates of 16–71.4% [8]. Therefore,
treatment strategies should be individualized with an
emphasis on developing agood doctor-patient rela-
tionship. The management of IBS consists of changes
in lifestyle, including eliminating high-gas foods such
as carbonated beverages, salads, raw fruits and veg-
etables (especially cabbage, broccoli and cauliflower),
and increasing physical activity. Ahigh-fibre diet, as
well as fibre supplements and osmotic laxatives that
increase stool frequency are recommended for consti-
pation-predominant IBS, while anti-diarrheal treatment
is recommended for diarrhoea-predominant IBS. More-
over, various medications, including anticholinergics, an-
tidepressants, antibiotics, simethicone and probiotics,
have all been used in the treatment of IBS. The vast

Przegląd Gastroenterologiczny 2013; 8 (6)
351
Butyric acid in irritable bowel syndrome
majority of these medications provide short-term relief,
but evidence for their long-term efficacy has not been
established. Evidence of the safety and tolerability of
these drugs is limited. For all of these reasons, there is
agreat need for new IBS therapies.
Butyrates in the treatment of irritable
bowel syndrome
Butyrates represent apotential new IBS therapy. To
date, afew trials have been performed to evaluate the
effectiveness of sodium butyrate on clinical symptoms
and quality of life in patients with IBS. Banasiewicz et
al. performed adouble-blind, randomized, placebo-con-
trolled study in which 66 adult patients with IBS re-
ceived microcapsulated butyric acid at adose of 300 mg
per day or placebo as an adjunct to standard therapy. At
four weeks, there was astatistically significant decrease
in the frequency of abdominal pain during defecation
in the butyric acid group (p = 0.0032). At 12 weeks, de-
creases in the frequency of spontaneous abdominal pain
(p = 0.0132), postprandial abdominal pain (p = 0.0031),
abdominal pain during defecation (p = 0.0002) and urge
after defecation (p = 0.0100) were observed [9, 10]. In
apreliminary report, Tarnowski et al. demonstrated an
improvement of abdominal pain, abdominal discom-
fort and defecation rhythm in patients with IBS treat-
ed with microcapsulated sodium butyrate for 6 weeks,
compared to those treated with placebo. In the same
study, higher quality of life was noted in patients treat-
ed with butyrate [11]. It is worth noting that no side
effects were observed during treatment with protected
sodium butyrate, which confirms the safety of its use in
clinical practice. Although the results of these two trials
seem to be promising, the effectiveness of butyrate in
the treatment of IBS needs to be confirmed. There is
also aneed for studies of the effectiveness of butyrate
in children and adolescents.
Butyric acid
Butyric, acetic and propionic acids account for ap-
proximately 83% of the short-chain fatty acids (SCFAs)
in the human colon [12].The concentration of these ac-
ids in the intestinal lumen ranges from 60 mmol/kg to
150 mmol/kg [13], and the acetate-propionate-butyrate
balance is relatively constant, with atypical ratio of 60
: 25 : 10 [14]. Short-chain fatty acids are rapidly ab-
sorbed by the epithelium of the gastrointestinal tract.
In the large bowel, absorption reaches peak levels in
the caecum and ascending colon by both active and
passive transport [15, 16]. Production levels of butyr-
ic acid in the sigmoid colon and the rectum are low.
Butyrate is the preferred energy source for colonic epi-
thelial cells [17]. Awell-balanced diet, rich in probiotics,
prebiotics and fibre, is the preferred source of butyrate.
Similarly to other SCFAs (acetic, propionic), endogenous
butyric acid is produced by the bacterial fermentation
of non-digestible carbohydrates and hexose oligomers
with varying degrees of polymerization, such as non-
starch polysaccharides, resistant starch, oligosaccha-
rides (inulin and oligofructose), disaccharides (lactose)
and sugar alcohols (sorbitol and mannitol) [13, 15]. Re-
sistant starch has been found to be particularly butyr-
ogenic. It occurs naturally in partially milled grains and
seeds, uncooked potatoes, green bananas and various
vegetables. The species of bacteria involved in the pro-
duction of butyrate are Clostridium spp., Eubacterium
spp., Fusobacterium spp., Butyrivibrio spp., Megasphaera
elsdenii, Mitsuokella multiacida, Roseburia intestinalis,
Faecalibacterium prausnitzii and Eubacterium hallii
[18]. Recently, an increased intake of highly processed,
low-fibre food products rich in simple sugars has been
observed, resulting in low levels of butyrate production
in the intestinal lumen. Therefore, butyrate supple-
mentation potentially represents agood alternative to
Table I. Diagnostic criteria* for irritable bowel syndrome
Recurrent abdominal pain or discomfort** at least 3 days per month in the last 3 months associated with 2 or more of the following:
1. Improvement with defecation
2. Onset associated with a change in frequency of stools
3. Onset associated with a change in form (appearance) of stools
*Criteria fulfilled for the last 3 months with symptom/s onset at least 6 months prior to diagnosis
**Discomfort means an uncomfortable sensation not described as pain
In pathophysiology research and clinical trials, apain/discomfort frequency of at least 2 days aweek during screening evaluation for subject eligibility.
Table II. Subtyping IBS by predominant stool pattern
1. IBS with constipation (IBS-C) – hard or lumpy stools ≥ 25% and loose (mushy) or watery stools < 25% of bowel movements
2. IBS with diarrhoea (IBS-D) – loose (mushy) or watery stools ≥ 25% and hard or lumpy stool < 25% of bowel movements
3. Mixed IBS (IBS-M) – hard or lumpy stools ≥ 25% and loose (mushy) or watery stools ≥ 25% of bowel movement
4. Unsubtyped IBS – insufficient abnormality of stool consistency to meet criteria for IBS-C, D or M

Przegląd Gastroenterologiczny 2013; 8 (6)
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Andrzej Załęski, Aleksandra Banaszkiewicz, Jarosław Walkowiak
dietary intake. Bird et al. documented an association
between increased consumption of resistant starch and
the amount of butyrate in faeces, and alack of associ-
ation with the incidence of diet-dependent disorders
[19].
Pure butyric acid has an extremely pungent smell,
which makes it very difficult to handle. It is quickly ab-
sorbed in the upper part of the gastrointestinal tract,
which reduces its positive effects in the colon. These
characteristics limit the clinical utility of pure butyric
acid. Recently, anew range of products has been de-
veloped, in which butyric acid is encapsulated in atri-
glyceride matrix, resulting in slow release during its
transport through the intestinal tract. Considering the
potential pathophysiological factors involved in the aeti-
ology of IBS, which include brain-intestine interactions,
visceral hypersensitivity, abnormal motility, intestinal in-
flammation, post-infectious disturbances and alteration
of microflora, in the next paragraph, we briefly summa-
rize the possible mechanisms of action of butyrate that
may be useful in the treatment of IBS.
Potential butyrate mechanisms
of action
Butyratedirectly influences the gastrointestinal
flora. The presence of butyrate-producing bacteria
species suppresses the growth of Escherichia coli,
Campylobacter spp., Salmonella spp. and Shigella spp.
[20]. Butyric acid may also play abeneficial role in
the treatment of gastrointestinal infections. In exper-
imental shigellosis, enteric supplementation of SCFAs
reduced congestion, infiltration of inflammatory cells,
and necrotizing features in the mucosa, which resulted
in areduced amount of faecal blood and mucus [21].
The efficacy of butyric acid in the prevention of water,
sodium, chlorine and potassium loss confirms observa-
tions made in animals with cholera [22]. The fact that
the passive absorption of water in the colon depends on
the presence of SCFAs may explain the potential role of
butyrate in clinical conditions involving diarrhoea [23].
The trophic effects of butyrate on intestinal cell pro-
liferation have been demonstrated in animal models.
Dietary supplementation with butyrate stimulated the
elongation of the villi in the ileum and crypt depth in
the caecum [24, 25]. Butyric acid has also been shown
to exert potent anti-inflammatory effects both in vitro
and in vivo. Its immunoregulatory and anti-inflammato-
ry activity is presumably based on the topical inhibition
of inflammatory mediators in the epithelium. The ability
of butyrate to decrease concentrations of pro-inflam-
matory cytokines such as interleukin 8 (IL-8) and tumor
necrosis factor-α (TNF-α) has been documented [26].
In mice, the intrarectal administration of butyric acid
during an acute phase of experimental colitis attenu-
ated intestinal inflammatory parameters [27]. Some
anti-inflammatory effects of butyrate in the treatment
of ulcerative colitis and radiation proctitis were also
observed [28, 29]. The precise mechanisms underlying
these effects have not been fully elucidated. The relief
of abdominal pain seems to be avery important aspect
of IBS treatment. Butyrate has aprobable beneficial in-
fluence on the hypersensitivity of intestinal receptors,
which results in adecrease of intraintestinal pressure. It
improves bowel peristalsis and retractility of the circular
muscle layer [9].
In summary, butyrate supplementation seems to be
apromising therapy for IBS. However, data on its effec-
tiveness are still very limited.
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Received: 2.11.2013
Accepted: 5.12.2013