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					Nutrifocus                  VALIO Ltd 1/2008




Perspectives on irritable
bowel syndrome
    Nutrifocus                                               Dear reader,
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    Kajsa Kajander,
    M.Sc., Consept Manager,
    Valio Ltd, International Operations   Riitta Korpela
    and Innovations                       Vice President, Ph.D.,
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    Leena Seppo
    M.Sc., Research Nutritionist          Hippocrates, the father of western medi-
    Valio Ltd, R&D,                       cal science, emphasised the importance
    Nutrition Innovations,                of the digestive tract to staying healthy,
    Nutrition & Health                    saying at a time before the Common Era
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                                          ing that among all patient groups, those
    Tuula Tuure
                                          suffering from abdominal or intestinal
    Ph.D., Senior Nutritionist,
    Valio Ltd, R&D,                       diseases often have the poorest quality of
    Nutrition Innovations,                life. The intestine is sometimes referred
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    Fax +358 10 381 3019                  One of the most common causes of                syndrome is challenging since extant
    www.valio.fi                          abdominal symptoms is irritable bowel           medication is fairly ineffective. A healthy
    www.valio.com                         syndrome (IBS). It is the most frequent         and unhurried lifestyle combined with a
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                                          adult in the western world suffers from
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    Fax +358 10 381 3019                  function. The syndrome is completely            by health care professionals and the Valio
                                          benign but has a major effect on the            research centre have produced promis-
    English translation by                quality of life and also generates a signifi-   ing evidence of the positive effect of a
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                                          cant financial burden in the form of costs      probiotic combination containing four
    alex.frost@comword.fi
                                          incurred through the use of health care         bacterial strains.
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    Valio Ltd                             The underlying cause of irritable bowel         able and thought-provoking time in the
                                          syndrome is still not fully known, but          fascinating world of Hippocrates and our
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    Edita, 2008

    Cover photo: Nina Dodd




2                                                    Nutrifocus • 1/2008
                                                                      Content
Irritable bowel syndrome:                                                                                                    Findings
A multiform and                                                                                                              on probiotics
common complaint
                                                                                                                             Probiotics are live microbes that have
Irritable bowel syndrome (IBS) is a                                                                                          positive, scientifically proven functional
functional abdominal disorder involving                                                                                      effects. The best documented health
abdominal pain and alternating bowel                                                                                         effects include the prevention and treat-
movement. As many as every fifth adult                                                                                       ment of different kinds of diarrhoea.
suffers from irritable bowel syndrome.                                                                                       Recent studies show that certain, though
Many factors affect the IBS onset mecha-                                                                                     not all probiotics can help relieve IBS
nism, such as abnormal motor function,                                                                                       symptoms. Promising scientific evidence
visceral algesia, a sequela of intestinal                                                                                    has been obtained concerning the health
infection, and psychosocial factors. Even                                                                                    effects of a probiotic combination con-
though IBS is a benign disorder, capri-                                                                                      taining four bacterial strains.
cious bowel movement considerably
impacts our quality of life. IBS is further-
more a significant financial burden on
the public health care system.                                                                                               Page ............................................... 11


Page ................................................. 4


                                                               Treatment of irritable
                                                               bowel syndrome
                                                               IBS is a long-lasting disorder and the
                                                               primary treatment goals are alleviation
                                                               or control of the abdominal symptoms.
                                                               A good, confidential doctor-patient
                                                               relationship is a key factor in treatment.
                                                               Patients are advised to attend to their
                                                               lifestyle and habits: a sufficient intake of                  New research:
                                                               fibre and fluids, regular and unhurried
                                                               eating, physical exercise and the avoid-
                                                                                                                             Serotonergic
                                                               ance of excessive stress often calms the                      signalling and brain-
                                                               intestine. Possible medication is selected                    gut communication in
                                                               according to the predominant symptom,
                                                               but in many cases drug therapy is not
                                                                                                                             irritable bowel syndrome
                                                               sufficiently effective.                                       In recent years, research has focused on
                                                               Page ................................................. 7      disturbance in the interaction between
                                                                                                                             the central nervous system and gastroin-
Microbiota of the gastrointestinal tract in irritable                                                                        testinal tract as the pathophysiological
                                                                                                                             basis of irritable bowel syndrome. To sim-
bowel syndrome                                                                                                               plify, brain-gut communication describes
The microbiota of the gastrointestinal tract may comprise as many as 900 species of                                          the frequent and bidirectional commu-
bacteria. The intestinal bacteria are known to play a role in maintaining the normal                                         nication between the central nervous sys-
sensory and motoric functions of the gastrointestinal tract, both of which are sig-                                          tem and gastrointestinal tract. Changes in
nificant factors with regard to IBS symptoms. Microbiotic comparisons show that                                              this system at either the central nervous
the microbiota of IBS patients seem to differ from that of healthy subjects in many                                          system or the gastrointestinal tract level
ways, which have been observed both in the composition and stability of the bacterial                                        may partly illuminate the development of
population.                                                                                                                  IBS symptoms.

Page ................................................................................................................... 9   Page ............................................... 13


                                                                             Nutrifocus • 1/2008                                                                                 3
    Irritable bowel syndrome:
A multiform and common complaint
Markku Hillilä, M.D,                         cases, psychological stress worsens the ab-   fer moreso than the rest of the population
Specialist in Gastroenterology               dominal symptoms; some people find that       from various, often functional somatic
Helsinki University Central                  the symptoms are aggravated by certain        disorders, such as headache, fibromyalgia,
Hospital, Meilahti                           foods and liquids, such as coffee, alcohol,   backache, functional urinary tract symp-
Department of Gastroenterology               onions, leguminous plants, spicy dishes or    toms and heart palpitation. Furthermore,
                                             dairy products.                               psychological symptoms such as depres-
General                                                                                    sion and anxiety are more common than
                                             IBS is described, in accordance with          in the rest of the population.
Typical symptoms of irritable bowel syn-     the leading symptom, as diarrhoea-
drome (IBS) include abdominal pain, and      predominant, constipation-predominant,        Irritable bowel syndrome is common in
abnormal bowel function such as consti-      or alternating stool patterns. Apart from     the western world, its prevalence varying
pation or diarrhoea or both alternatingly.   abdominal pain, a patient with diarrhoea-     from 5 to 25% of the population depend-
In addition to abdominal pain, the patient   predominant symptoms may suffer from          ing on the research methods applied and
may suffer abdominal bloating and flatu-     loose stools and frequent bowel function.     IBS definition. The syndrome is more
lence, which usually get worse as the day    In the constipation-predominant pattern,      common in women than in men. In Fin-
progresses. Abdominal pain is typically      the stools are hard and the bowel function    land, IBS prevalence is 5–17%, depending
relieved after defecation. The discomfort    slow. The alternating pattern comprises       on the criteria1.
is functional, in other words, the symp-     both functional disturbances; a period of
toms are not explained by organic disorder   constipation may be followed by a period      Aetiology and pathophysiology
or biochemical deviation. The symptoms       of diarrhoea and so on.
are also long-lasting, often coming in                                                     The aetiology and pathophysiology of
waves with alternating periods of a higher   In addition to abdominal symptoms,            IBS are not very well understood. Many
and lower degree of symptoms. In many        persons with irritable bowel syndrome suf-    studies have shown that the bowels of IBS

4                                                      Nutrifocus • 1/2008
patients have stronger motoric response to      In the last few years, more assumptions      functions at the intestinal mucous mem-
e.g. eating and stress. Moreover, visceral      have been gathered about the pathophysi-     brane level, for example due to a mild
hypersensitivity is involved in the syn-        ology of IBS. Mild inflammation that         inflammation, even if the proof thereof is
drome, meaning a lowered pain threshold         cannot be seen endoscopically and in         still insufficient.
for sensations in the gastrointestinal tract.   routine biopsies may have significance in
The evacuation of intestinal gas may be         the aetiology of the symptoms. Increased     Diagnostics
slowed in people with IBS symptoms,             amounts of inflammatory cells (mast cells,
probably related to motility disturbance.       T lymphocytes, macrophages) on the mu-       IBS diagnostics are based on typical symp-
Furthermore, even a normal amount               cous membrane of the colon and ileum,        toms and a narrow assortment of tests to
of intestinal gas may cause abdominal           and in the myenteric nervous plexus in       exclude any organic disease that may lie
discomfort due to visceral hypersensitiv-       the area of proximal jejunum, have been      (lies) behind the symptoms. Instead of
ity2. In about 15% of those suffering from      described in people suffering from IBS       aiming at a negative exclusion diagnosis, it
IBS, the symptoms occurred after acute          symptoms3,4. The severity and frequency      is important to target a positive diagnosis
gastroenteritis. Campylobacter or Shigella      of abdominal symptoms have correlated        based on symptoms, which means that
infections seem to cause post-infectious        with the number of activated mast cells      IBS diagnosis can be confirmed as the
IBS more easily than Salmonella. The            in proximity to the nerve endings of the     symptom criteria are fulfilled, provided
diarrhoea-predominant pattern is more           colonic mucosa5.                             that the anamnesis and concise examina-
common in post-infectious than other                                                         tion do not reveal anything that would
types of IBS. Psychosocial factors are       Furthermore, proof is starting to be seen       make organic aetiology seem likely. The
significant particularly in the worsening of of the fact that the intestinal microbiota      syndrome is diagnosed using the Rome
the irritable bowel syndrome; stress affects of IBS patients differs from that of healthy    Criteria, first published in 1989 and
the motor functions of the gastrointestinal  subjects; even different IBS subtypes may       updated twice since then. At present, the
tract and visceral sensation.                differ from each other as far as the bacte-     Rome III Criteria are recommended for
                                             rial flora of the bowel is concerned6. At       IBS diagnostics (Table 1).
The enteral nervous system lining the        present, however, research on the micro-
gastrointestinal tract is formed of two lay- biota is sparse, and the results cannot         Anaemia and hypersedimentation should
ers of nervous plexus, which are connected necessarily be generalised to concern all         be ruled out in all patients with IBS symp-
to each other via interneurons. The system IBS patients.                                     toms. Lactose intolerance may cause the
adjusts the motor functions of the bowel                                                     same symptoms as IBS, and consequently
and mediates visceral sensation to the       Functional MRI (magnetic resonance              there is a need to conduct a lactose toler-
central nervous system. The enteral nerv-    imaging) and PET (positron emission             ance test or gene test, if these have not
ous system contains several transmitters,    tomography) studies have shown that the         been performed earlier. It is also advisable
of which serotonin has aroused interest      activation of the central nervous system        to exclude celiac disease serologically. The
in recent years. Drugs affecting different   caused by a visceral pain signal in IBS pa-     existence of so-called alarm signs refers to
serotonin receptors have been developed      tients differs from that of healthy subjects.   possible increased organic aetiology and
for the treatment of IBS.                    IBS may also induce exceptional signal          requires further examination, usually at



        Table 1                                                             Table 2


        IBS diagnostics;                                                    Alarm signs in IBS diagnostics;
        The Rome III Criteria                                               indication for further examination
        Recurrent abdominal pain or discomfort at
        least 3 days per month in the last 3 months                               • Blood in the stool
        associated with two or more of the following:                             • Loss of weight
                                                                                  • Fever
        Abdominal pain or discomfort                                              • Constantly worsening symptoms
                                                                                  • Hard constipation
        • Improvement with defecation                                             • Diarrhoea
        • Onset associated with a change in                                       • A new symptom in a patient over 45 (50)
          frequency of stool                                                      • Family history of colorectal cancer,
        • Onset associated with a change in form                                    inflammatory bowel disease
          (appearance) of stool                                                   • Laboratory findings: anaemia,
                                                                                    hypersedimentation
        Furthermore, the symptoms have occurred
        for at least six months



                                                         Nutrifocus • 1/2008                                                          5
        least a colonoscopy (Table 2). It must be
        noted that diarrhoea-predominant IBS is                                       Intestinal symptoms
        an indication for colonoscopy since the
        symptoms may be caused by e.g. micro-
        scopic colitis or a mild inflammatory in-                       No alarm symptons                        Hb, ESR, laktose test
        testinal disease, such as ulcerative colitis or                                                         endomysium antibodies
        Crohn’s disease. Similarly, a new IBS-type
        symptom in a patient over 40–50 years                                                IBS
        of age requires colonoscopy, because the                                         Rome III Criteria
        incidence of colorectal carcinoma begins
        to increase at that age. If no alarm signals              Constipation       Abdominal pain, bloating                       Diarrhoea
        are observed, irritable bowel syndrome can
        be diagnosed on the basis of symptoms,
                                                                                 S-TSH                                                 Colonoscopy
        clinical examination and a few laboratory
        tests (Fig. 1).                                                                    Hb = haemoglobiin; ESR = erythrocyte sedimentation rate; S-TSH = tyreotropin


                                                          Fig 1: Irritable bowel syndrome diagnostics



                                                                                                              SUMMARY

                                                                                                              • Typical symptoms of IBS are
                                                                                                                abdominal pain and abnormal
                                                                                                                bowel movement.

                                                                                                              • The mechanism of
                                                                                                                the syndrome involves
                                                                                                                many factors.

                                                                                                              • The syndrome is diagnosed
                                                                                                                on the basis of the Rome III
                                                                                                                Criteria.

                                                                                                              • “Alarm signs” in diagnostics
                                                                                                                require further examination.



                                                                                                         References:

                                                                                                         1. Hillilä MT, Färkkilä MA. Prevalence of irritable
                                                                                                         bowel syndrome according to different diagnos-
                                                                                                         tic criteria in a non-selected adult population.
                                                                                                         Aliment Pharmacol Ther 2004; 20:339-345.

                                                                                                         2. Barbara G, De Giorgio R, Stanghellini V ym.
                                                                                                         New pathophysiological mechanisms in irritable
                                                                                                         bowel syndrome. Aliment Pharmacol Ther
                                                                                                         2004; 20 Suppl 2:1-9.

                                                                                                         3. Spiller RC. Irritable bowel syndrome. Br Med
                                                                                                         Bull 2005; 72:15-29.

                                                                                                         4. Tornblom H, Lindberg G, Nyberg B ym.
                                                                                                         Full-thickness biopsy of the jejunum reveals
                                                                                                         inflammation and enteric neuropathy in irritable
                                                                                                         bowel syndrome. Gastroenterology 2002;
                                                                                                         123:1972-1979.

                                                                                                         5. Barbara G, Stanghellini V, De Giorgio R ym.
                                                                                                         Activated mast cells in proximity to colonic
                                                                                                         nerves correlate with abdominal pain in irritable
                                                                                                         bowel syndrome. Gastroenterology 2004;
                                                                                                         126:693-702.

                                                                                                         6. Kassinen A, Krogius-Kurikka L, Mäkivuokko
                                                                                                         H ym. The fecal microbiota of irritable bowel
Nina Dodd




                                                                                                         syndrome patients differs significantly from that
                                                                                                         of healthy subjects. Gastroenterology 2007;
                                                                                                         133:24-33.


            6                                                      Nutrifocus • 1/2008
            Treatment of irritable bowel
                   syndrome
Jouni Silvennoinen, MD,                        and consequently, it would be advisable        tested, if the patient’s primary symptom is
Specialist in Internal Medicine and            for IBS sufferers drinking a lot of coffee     painless diarrhoea.
Gastroenterology                               to try to reduce their consumption2. Fibre
North Karelia Central Hospital                 products are suited to the treatment of        Treatment of abdominal pain and
                                               constipation symptoms, but do not seem         bloating
General                                        to relieve abdominal pain or diarrhoea6.       Drugs affecting colonic contraction have
                                               The recommended daily dose of fibre is         long been used to treat abdominal pain,
Irritable bowel symptoms affect the            20–30 grams. Some patients experienced         bloating and rectal urgency. However, the
patient’s quality of life as much as many      flatulence and abdominal bloating follow-      efficacy of most spasmolytic and anti-
diseases with a worse prognosis, and the       ing the intake of fibre products. Increasing   cholinergic products has not been shown
patient is often suffering from unneces-       the intake of dietary fibre gradually e.g.     in proper trials1, and the side effects of
sary fears of malignant symptoms. A good       during a month improves tolerability. A        the drugs (fatigue, dry mouth, increased
doctor-patient relationship is essential       soluble fibre of the Ispaghula type seems      intraocular pressure, problems in urinat-
for successful treatment. It is important      to be tolerated best2.                         ing) restrict their use. In an individual
to explain the mechanism behind the                                                           study, peppermint oil capsules have been
symptoms (see Hillilä in this journal)         Medication                                     observed to relieve the pain and bloating
and the positive prognosis to the patient.                                                    associated with irritable bowel syndrome,
The patient’s ungrounded fears should be       Treatment of diarrhoea                         but the efficacy has not been verified in
eliminated without resorting to unneces-       In diarrhoea predominant IBS symptoms          other studies9.
sary examinations. Medication helps            colonic transit time is shortened. Lop-
in the treatment of the most difficult         eramide is a synthetic opiate derivative       Psychopharmaceutical drugs
symptoms of irritable bowel syndrome.          that reduces the transit time, enhances        Depression and anxiety are more com-
Only a few treatment studies have been         water and ion absorption in the intestine,     mon in patients suffering from irritable
conducted, and a placebo response as           and improves the continence of the anal        bowel syndrome than in others, and
high as 40–70%1 makes evaluation of            sphincter7. When taken in doses of 2–4         consequently, the contribution of psycho-
the efficiency of treatment all the more       mg 1–4 times per day it significantly          logical factors in the syndrome should also
difficult. Medication is focused on the pri-   reduces the urge to defecate. The main         be evaluated. In some cases, psychotherapy
mary symptom (constipation, diarrhoea,         side effect of loperamide is constipation.     will significantly relieve intestinal symp-
abdominal pain). The severity and quality      In some diarrhoea predominant IBS              toms, too. If the dominating symptom
of the patient’s symptoms vary over the        patients, bile acids absorption at the end     is pain, the older “tricyclic” antidepres-
course of time, and the use of medication      of the small intestine is poorer than nor-     sants may help, even were the patient not
is divided into periods according to the       mal, leading to bile acid diarrhoea8. Bile     depressed1,3. With these drugs, pain relief
symptoms.                                      acid binding with cholestyramine can be        is achieved more quickly (even in a couple

Food and fibre

As eating enhances the function of the
gastrointestinal tract and often worsens
the patient’s symptoms at the same time, it
is common to place the blame on foods. It
may be worth experimenting with cutting
out individual foods, if the patient clearly
benefits from the dietary elimination; pa-
tients should not however be encouraged
to adopt too monotonous a diet. Foods
that cause symptoms include, for example,
dairy products, wheat, eggs, maize, po-
tatoes, onions, citrus fruit and yeast, but
scientific evidence of the efficacy of the
diet has been shown in only one study2.
In some patients, carbohydrates, sorbitol4
or xylitol may worsen the symptoms. The
unintentional swallowing of air while
                                                                                                                                           Nina Dodd




chewing gum is another potential culprit.
Caffeine stimulates colonic contraction,

                                                         Nutrifocus • 1/2008                                                           7
                                                                                                                                       7
of weeks) and with smaller doses than re-
quired for antidepressive effects3. The side
effects of tricyclic antidepressants include
constipation and fatigue. As for more
recent antidepressants affecting serotonin
metabolism, citalopram has been observed
to relieve abdominal pain and bloating
in patients suffering from irritable bowel
syndrome, as well as improving their
general well being10. If the symptoms are
clearly associated with psychological stress
or if the patient suffers from anxiety, ben-
zodiazepines may help. Continued use of
these drugs should, however, be avoided
due to addiction problems. In difficult
IBS cases, hypnosis and psychotherapy
have been reported useful for selected
patients; however, the efficacy of these
therapies is disputed11.

Other medications and treatments

Serotonin or 5-hydroxytryptamine
(5-HT) receptors mediate the sensation
of pain on the intestinal wall and regulate
colonic contraction. There are receptors
on both the intestinal wall and in the
central nervous system. Particularly the
5-HT3 and 5-HT4 receptors seem to
play an important role in the regulation
of bowel movement. 5-HT3 antagonists
alosetron and cilansetron are efficient in
the treatment of diarrhoea and abdominal
pain and rectal urgency related thereto12,
but the clinical use of these drugs has




                                                                                                                                                              Nina Dodd
been prevented by their serious side ef-
fects. Tegaserod is a partial 5-HT4 agonist
that increases the peristaltic reflex and
alleviates constipation-related symptoms            References:                                          8. Luman W, Williams A, Merrick M ym.
                                                                                                         Idiopathic bile acid malabsorption: long-
as well as bloating and abdominal pain;             1. Akehurst R, Kaltenthaler E. Treatment of ir-      term outcome. Eur J Gastroenterol Hepatol
however, the efficacy is only slightly bet-         ritable bowel syndrome: a review of randomised       1995;7:641–645.
                                                    controlled trials. Gut 2001;48:272–282.
ter than that of placebo13. Tegaserod was                                                                9. Pittler M, Ernst E. Peppermint oil for ir-
previously marketed in some countries,              2. Burden S. Dietary treatment of irritable          ritable bowel syndrome: a critical review
                                                    bowel syndrome: current evidence and                 and meta-analysis. Am J Gastroenterol
but due to it’s limited efficacy and side ef-       guidelines for future practice. J Hum Nutr Dietet    1998;93:1131–1135.
fects, it was drawn from the market. There          2001;14:231–241
                                                                                                         10. Tack J, Broekaert D, Fischler B ym. A con-
is no convincing scientific evidence of             3. Camilleri M. Management of the ir-                trolled crossover study of the selective serotonin
the usefulness of acupuncture for patients          ritable bowel syndrome. Gastroenterology             reuptake inhibitor citalopram in irritable bowel
                                                    2001;120:652–668.                                    syndrome. Gut 2006;55:1095-1103.
with irritable bowel syndrome14.
                                                    4. Nelis G, Vermeeran M, Jansen W. Role              11. Webb A, Kukurozovic R, Catto-Smith A ym.
                                                    of fructose-sorbitol mixtures in the symp-           Hypnotherapy for treatment of irritable bowel
 SUMMARY                                            toms of the irritable bowel. Gastroenterology        syndrome. Cochrane database system rev.
                                                    1990;99:1016–1020.                                   2007;4:CD005110.
 •	 The treatment of irritable bowel
 	 syndrome requires a confidential                 5. Bandt LJ, Bjorkman D, Fennerty MB ym.             12. Camilleri M, Mayer E, Drossman D ym.
    doctor patient relationship.                    Systematic review on the management of ir-           Improvement in pain and bowel function in
 •	 Many different products and therapies           ritable bowel syndrome in North America. Am J        female irritable bowel patients with alosetron, a
    have been tried in the treatment of             Gastroenterol 2002;97:S7-S26.                        5HT3-receptor antagonist. Aliment Pharmacol
                                                                                                         Ther 1999;13:1149–1159.
    irritable bowel syndrome; however               6. Jailwala J, Imperiale T, Kroenke K. Pharmaco-
    there is relatively little proper, scientific   logical treatment of the irritable bowel syndrome:   13. Evans BW, Clark WK, Moore DJ ym.
    evidence of efficacy. Placebo is also           a systematic review of randomized, controlled        Tegaserod for the treatment of irritable bowel
    effective in many cases.                        trials. Ann Intern Med 2000;133:136-147.             syndrome. Cochrane database system rev.
 •	 Medication is focused on the primary                                                                 2004;1:CD003960.
    symptom, taking the quality and                 7. Cann P, Read N, Holdsworth C ym. Role
    severity of the patient’s symptoms              of loperamide and placebo in management              14. Lim B, Manheimer E, Lao L ym. Acu-
    into account.                                   of irritable bowel syndrome. Dig Dis Sci             puncture for treatment of irritable bowel
                                                    1984;29:239–247.                                     syndrome. Cochrane database system rev.
                                                                                                         2006;4:CD005111.

8
8                                                              Nutrifocus • 1/2008
                                                               Nutrifocus • 1/2008
Microbiota of the gastrointestinal
tract in irritable bowel syndrome
Erja Malinen, FT,                             composing nutrients, producing certain         Evidence of abnormal microbiota
Postdoctoral Researcher                       vitamins, protecting the host from patho-      in patients with IBS
University of Helsinki,                       genic microbes, and affecting the normal
Faculty of Veterinary Medicine,               development of the immune system (Fig.         The composition of the microbiota of
Department of                                 1). It is estimated that there is a total      IBS patients has recently been analysed
Basic Veterinary Sciences                     of nearly 900 species of bacteria in the       primarily using techniques based on the
                                              intestine, and one person is likely to carry   analysis of the genotype of the bacteria, i.e.
                                              about 300 species. The microbiotic com-        the DNA. Comparison of the microbiotic
                                              position is relatively well known at group     composition shows that the microbiota
Intestinal microbiota: a versatile            and family levels, but proceeding towards      of IBS patients differs significantly from
and vital ecosystem                           species level the picture of normal intes-     that of healthy control subjects1,2. Com-
                                              tinal microbiota becomes less clear. The       pared with healthy subjects, the patients’
Although the mechanisms causing and           bacterial families found in the intestine      microbiota is considerable more versatile.
maintaining irritable bowel syndrome are      include, among others, Bacteroides, Bifi-      Furthermore, different IBS subtypes often
poorly known, unbalanced intestinal           dobacterium, Clostridium, Eubacterium,         differ from each other more than from
microbiota may be one of the factors          Faecalibacterium, Peptostreptococcuc and       healthy controls, so that patients with
behind the syndrome. Mainly comprised         Ruminococcus. Detailed description of the      diarrhoea- and constipation-predominant
of bacteria, the intestinal microbiota is     extremely multiform community of intes-        symptoms form the two extremes in the
extremely significant for the well-being of   tinal bacteria is a demanding task, since      microbiotic composition2,3. The micro-
the host. The majority of the bacteria live   we have not even been able to culture          biota of patients suffering from diarrhoea
in the large intestine, where the number      most of these organisms thus far. Conse-       differs most from healthy controls, a con-
of microbes may be as high as 1,000           quently, many bacteria are only known on       sistent finding when taking into account
billion organisms per one gram of bowel       the basis of the alkaline order of a certain   the wide variety of symptoms typical of
content. The bacteria play a role in de-      gene (the ribosomal RNA coding gene).          this group2. Similarly, the temporal varia-




                                                                     METABOLISM: Fermentation of the insoluble parts of food
                                                                     and the intestinal mucus (e.g. production of energy in the
                                                                     form of short-chained fatty acids, production of vitamins).




                                                                     DEFENCE: Protection against pathogens, i.e. colonisation
                                                                     resistance.




                                                                     GROWTH AND DEVELOPMENT: Regulation of the growth
                                                                     and differentiation of epithelial cells. Development and
                                                                     maintenance of the immune system.




Fig. 1

                                                        Nutrifocus • 1/2008                                                             9
tion of microbiota is also greater in IBS       to be induced by a bacterial infection of
patients4,5.                                    the gastrointestinal tract. Estimates of the
                                                number of such cases vary a great deal,           SUMMARY
A certain instability is typical of the         but as many as 6–17% of the patients
microbiota of IBS patients, whereas the         believe that the symptoms were induced            • Intestinal microbiota is
microbiotic composition of a healthy            by bacterial gastroenteritis, which is              currently considered to
adult is considered to be fairly stable.        most typically caused by Campylobacter,             comprise about 900
The amount of aerobic bacteria has              Salmonella or Shigella9. After the infec-           bacterial species.
increased, which supports the concept of        tion has calmed, a low-level inflamma-            • Based on microbiotic
disturbances in the normal bowel move-          tory condition of the gastrointestinal              comparisons, it seems that the
ment2,5. Differences between IBS patients       tract persists, which may be maintained             microbiota of IBS patients
and healthy subjects are observed in            through the intestinal microbiota9.                 differ from those of healthy
clostrides, the bacterial group constitut-                                                          subjects in a variety of ways.
                                                                                                    Differences have been
ing the highest quantity in the intestine.      The challenges and future pros-                     obser ved both in the com-
There are less bacteria of the Clostridium      pects in microbiotic research                       position and stability of the
coccoides group in patients suffering from                                                          bacterial population.
IBS2,3,4; the observed change is related        Can it be said on the basis of the results
in particular to patients suffering from        that a certain type of microbiota is typical      • Similarly, differences in the
                                                                                                    final products of bacterial
constipation2,4. The group is known to          of irritable bowel syndrome? No bacteria            metabolism, such as intestinal
include e.g. butyrate-producing organ-          or group of bacteria have been observed             gases and short-chained fatty
isms but the majority of the bacteria           to be exclusively absent or present in              acids, suggest that the
are unknown. As for the quantitatively          patients; moreover, the quantities of               microbiota is a significant
largest groups of intestinal bacteria, the      different bacteria in intestinal samples            factor in irritable bowel
                                                                                                    syndrome.
amount belonging to the Bacteroides             vary greatly both in healthy persons and
family is also decreased in IBS patients2.      in IBS patients. For example, health-
Species level changes have been observed        promoting bifidobacteria may be totally
in bifidobacteria, suggesting a decrease        absent from a healthy person. Similarly,
of Bifidobacterium catenulatum in IBS           there is individual variation in the stabil-   References:
patients1,3. In the actinobacteria group,       ity of the bacterial population. The struc-    1. Kassinen A, Krogius-Kurikka L, Mäkivuokko
the quantities of Collinsella aerofaciens       ture of the intestinal bacterial population    H ym. The fecal microbiota of irritable bowel
                                                                                               syndrome patients differs significantly from
(Eubacteria aerofaciens) are smaller in IBS     is known to be highly individualised, and      that of healthy subjects. Gastroenterology
patients1. When studying IBS patients           microbiotic individuality is one of the        2007;124-133.
in accordance with the subtype based on         biggest challenges in the research work.       2. Rajilić-Stojanović M. Diversity of the hu-
bowel function, it has been observed that       It is difficult to observe the differences     man gastrointestinal microbiota: Novel per-
                                                                                               spectives from high throughput analyses.
the abundant occurrence of the Veillonel-       between the groups of subjects, because        2007;Wageningen University and Research
la family of bacteria is typical for patients   there are big differences in the microbiota    Centre, Wageningen, The Netherlands. ISBN:
                                                                                               978-90-8504-663-9.
suffering from constipation3.                   between individuals alone. The same
                                                microbiotic deviations are not always          3. Malinen E, Rinttilä T, Kajander K ym. Analysis
                                                                                               of the fecal microbiota of irritable bowel syn-
The significance of bacterial fer-              observed, which is probably due to both        drome patients and healthy controls with real-
mentation and gastroenteritis                   the individual differences between the         time PCR. Am J Gastroenterol 2005;100:1-10.
                                                test subjects and factors related to the       4. Maukonen J, Satokari R, Mättö J ym.
In addition to actual comparisons of the        research methods employed.                     Prevalence and temporal stability of selected
                                                                                               clostridial groups in irritable bowel syndrome in
microbiotic composition, determining                                                           relation to predominant faecal bacteria. J Med
the final products of bacterial metabolism      In spite of the problems, however, the         Microbiol 2006;55:625-633.
provides indirect evidence of abnormal          results obtained from different studies        5. Mättö J, Maunuksela L, Kajander K ym.
microbiota in irritable bowel syndrome.         mainly support each other and refer to         Composition and temporal stability of gas-
                                                                                               trointestinal microbiota in irritable bowel
An increased production of gases, par-          microbial changes in IBS. The signifi-         syndrome – a longitudinal study in IBS and
ticularly hydrogen, is often observed in        cance of microbes in the aetiology of IBS      control subjects. FEMS Immunol Med Microbiol
                                                                                               2005;43:213-222.
the IBS patients’ bowels, which suggests        is also suggested by the results from
disturbances in normal microbial activ-         recent studies on the successful use of        6. King TS, Elia M, Hunter JO. Abnormal
                                                                                               colonic fermentation in irritable bowel syndrome.
ity in the large intestine6. On the other       probiotics to alleviate the syndrome. The      The Lancet 1998;352:1187-1189.
hand, bacterial overgrowth of the small         next important step in IBS research is to
                                                                                               7. Pimentel M, Chow E J, Lin H C. Eradication
intestine and unusual microbial fermen-         compare the occurrence of bacterial genes      of small intestinal bacterial overgrowth reduces
tation related thereto have been suggested      between the microbiota of healthy con-         symptoms of irritable bowel syndrome. Am J
                                                                                               Gastroenterol 2000;95:3503-3506.
to have a role in inducing the symptoms7.       trols and the patients. The significance
Disturbances in the production of vola-         of the differences observed in the studies     8. Treem W R, Ahsan N, Kastoff G ym. Fecal
                                                                                               short-chain fatty acids in patients with diarrhea-
tile fatty acids (butyrate, acetate, propi-     cannot be found through identification         predominant irritable bowel syndrome: in vitro
onate) occurring as a result of microbial       of the bacteria at the family or species       studies of carbohydrate fermentation. J Pediatr
                                                                                               Gastroenterol Nutr 1996;23:280-286.
metabolism have been observed in some           level alone, but through a better under-
IBS patients8. Furthermore, irritable           standing of their functional significance.     9. Spiller R. Role of infection in irritable bowel
                                                                                               syndrome. J Gastroenterol 2007;42(Suppl
bowel syndrome has often been observed                                                         XVII):41-47.


10                                                        Nutrifocus • 1/2008
                      Findings on probiotics
Kajsa Kajander, M.S. (Food Sciences),          gastrointestinal tract. The best document-      placebo-controlled trials, this probiotic
Concept Manager and Researcher,                ed health effects of probiotics are derived     combination alleviated IBS symptoms
Valio Ltd, International Operations and        from studies on prevention and treatment        significantly more than the placebo
Innovations, and University of Helsinki,       of diarrhea. In discussing probiotics, it is,   product (Fig. 1). In the first study, 103
Institute of Biomedicine                       however, important to realise that they are     patients with diagnosed IBS took a capsule
                                               individuals just like human beings, and         containing the probiotic combination or
                                               consequently, their health effects are bacte-   a placebo daily for six months7. Abdomi-
Probiotics in a nutshell                       rial strain specific. The most studied and      nal symptoms were tracked during the
                                               best known probiotic strain nowadays is         study from diaries kept by the patients.
Probiotics are live microbes that have         Lactobacillus rhamnosus GG (LGG®).              Compared with the initial situation, the
positive, scientifically proven functional                                                     total sum of IBS symptoms – abdominal
effects. Lactobacilli have been used in        Clinical proof on probiotics                    pain, distension, flatulence and rumbling
cooking and food preservation for centu-                                                       of the stomach – had decreased by 42% in
ries, so employing bacteria in food prod-      Recent studies show that certain, though        the group receiring probiotics and by 6%
ucts is not a new phenomenon. Plenty           not all, probiotics can help relieve IBS        in the placebo group (p=0.015). When
of promising scientific evidence has been      symptoms. The lactobacilli L.plantarum          investigating the proportion of those
obtained about the health effects of bacte-    299v1,2 and the bifidobacteria B. infantis      patients whose symptoms had been allevi-
ria in recent years. Most of the probiotics    356243,4 seem to alleviate patients’ symp-      ated, it was observed that this was the case
used in foods and nutrient supplements         toms. Similarly, the combination of eight       in 76% of the patients in the probiotic
are lactobacilli and bifidobacteria, but       bacterial strains, VSL#3, has been found        group, while the corresponding figure for
increasing numbers of other microbes           to have positive effects5,6.                    the placebo group was 43% (p=0.002).
are also in use and researched all over the                                                    In another study, 86 IBS patients were
world. Although most often found in            The most long-lasting IBS trials have been      given either a probiotic drink, or a pla-
the context of fermented milk products,        published on a probiotic combination            cebo drink, daily for five months8. The
probiotics are nowadays present e.g. in        containing four different bacterial strains     same form of diary regarding abdominal
certain milks, cheeses, juices and berry       (Lactobacillus rhamnosus GG, Lactobacillus      symptoms was used as in the first study.
soups. For a microbe to have potential         rhamnosus Lc705, Lactobacillus rhamno-          The result was almost identical with that
as a probiotic it must fulfil certain basic    sus GG, Propionibacterium freudenreichii        of the first study, as the total sum of IBS
criteria, the most important of which are      subsp. shermanii JS and a Bifidobacterium       symptoms had decreased by 37% in the
safety and the ability to survive in the       strain). In two randomised, double-blind,       probiotic group and by 9% in the pla-




Fig. 1: The effect of a product containing a combination of four probiotic strains (Lactobacillus rhamnosus GG, Lactobacillus rhamnosus
Lc705, Lactobacillus rhamnosus GG, Propionibacterium freudenreichii subsp. shermanii JS and a Bifidobacterium strain) and the pla-
cebo on the sum of IBS symptoms in six (a) and five (b) month clinical interventions. In each treatment group, the first column indicates
the amount of symptoms prior to the intervention, and the second column the amount at the end of the intervention.


                                                         Nutrifocus • 1/2008                                                           11
cebo group (p=0.008). This study also




                                                                                                                                                             Nina Dodd
showed that health-related quality of life
improved significantly in the probiotic
group, particularly with regard to bowel
symptoms. The composition of intestinal
microbiota was monitored using a new
microarray method that makes it pos-
sible to identify all the presently known,
approximately 1,100 species of bacteria
at the same time. During the study, the
microbiota composition remained more
stable in the probiotic group than in the
placebo group; it is therefore possible
that one of the effective mechanisms of
the studied probiotic combination is
balancing the microbiota.

How do probiotics act?

The effective mechanisms underlying
probiotics treatment with regard to
IBS are not as yet very well known; it
is likely, however, that there are several
mechanisms in action. The balancing of
intestinal microbiota may account for
part of the positive effects of the probiot-
ics, because intestinal bacteria and their
metabolic output are known to affect
the sensory and motoric functions of
the gastrointestinal tract. Both of these                 SUMMARY
functions are significant factors in IBS.                 • Certain probiotic strains and combinations have positive effects on
Certain probiotics may act through the                      IBS symptoms. However, not all probiotics are effective.
immune system, for example, by affect-
ing the secretion of cytokines which act                  • The probiotic combination (Lactobacillus rhamnosus GG,
as inflammatory mediators3. On the basis                    Lactobacillus rhamnosus Lc705, Lactobacillus rhamnosus GG,
of mainly experimental research, it is also                 Propionibacterium freudenreichii subsp. shermanii JS and
known that probiotics affect the motoric                    a Bifidobacterium strain) has alleviated IBS symptoms significantly
functions9, visceral sensitivity10 and pain                 more than the placebo product in two clinical studies.
receptors11 of the gastrointestinal tract.
                                                          • Being safe and effective, certain probiotics are suitable for use
                                                            alongside other lifestyle treatments for IBS.



References:

1. Niedzielin K, Kordecki H, Birkenfeld B. A        5. Kim HJ, Camilleri M, McKinzie S ym. A ran-       9. Massi M, Ioan P, Budriesi R ym. Effects of
controlled, double-blind, randomized study on       domized controlled trial of a probiotic, VSL#3,     probiotic bacteria on gastrointestinal motility in
the efficacy of Lactobacillus plantarum 299V        on gut transit and symptoms in diarrhoea-           guinea-pig isolated tissue. World J Gastroen-
in patients with irritable bowel syndrome. Eur J    predominant irritable bowel syndrome. Aliment       terol 2006;12:5987-5994.
Gastroenterol Hepatol 2001;13:1143-1147.            Pharmacol Ther 2003;17:895-904.
                                                                                                        10. Eutamene H, Lamine F, Chabo C ym. Syn-
2. Nobaek S, Johansson M-L, Molin G ym.             6. Kim HJ, Vazquez Roque MI, Camilleri M ym.        ergy between Lactobacillus paracasei and its
Alteration of intestinal microflora is associated   A randomized controlled trial of a probiotic com-   bacterial products to counteract stress-induced
with reduction in abdominal bloating and pain       bination VSL# 3 and placebo in irritable bowel      gut permeability and sensitivity increase in rats.
in patients with irritable bowel syndrome. Am J     syndrome with bloating. Neurogastroenterol          J Nutr 2007;137:1901-1907.
Gastroenterol 2000;95:1231-1238.                    Motil 2005;17:687-696.
                                                                                                        11. Rousseaux C, Thuru X, Gelot A ym. Lacto-
3. O’Mahony L, McCarthy J, Kelly P ym. Lacto-       7. Kajander K, Hatakka K, Poussa T ym. A            bacillus acidophilus modulates intestinal pain
bacillus and bifidobacterium in irritable bowel     probiotic mixture alleviates symptoms in ir-        and induces opioid and cannabinoid receptors.
syndrome: symptom responses and relation-           ritable bowel syndrome patients: a controlled       Nat Med 2007;13:35-37.
ship to cytokine profiles. Gastroenterology         6-month intervention. Aliment Pharmacol Ther
2005;128:541-551.                                   2005;22:387-394.

4. Whorwell PJ, Altringer L, Morel J ym.            8. Kajander K, Myllyluoma E, Rajilić-Stojanović
Efficacy of an encapsulated probiotic Bifi-         M ym. Clinical trial: multispecies probiotic sup-
dobacterium infantis 35624 in women with            plementation alleviates the symptoms of irritable
irritable bowel syndrome. Am J Gastroenterol        bowel syndrome and stabilizes intestinal micro-
2006;101:1581-1590.                                 biota. Aliment Pharmacol Ther 2008;27:48-57.


12
12                                                              Nutrifocus • 1/2008
                                                               Nutrifocus • 1/2008
                                              SCIENCE HIGH LIGHT:
               Serotonergic signalling and
                the brain-gut axis in IBS
Prof. Robert-Jan Brummer, MD, PhD                                   agreement that IBS patients are more                                 syndrome related to a chronic intestinal
Department of Internal Medicine,                                    sensitive to distension of the sigmoid                               disease.
University Hospital Maastricht,                                     colon, ileum and rectum than controls.
Maastricht, the Netherlands                                         Given the high prevalence of sensory ab-                             The brain-gut axis: a framework
                                                                    normalities in IBS, and the correlation of                           for understanding IBS
Changing pathophysiological                                         sensitivity with symptoms, altered rectal
view on IBS                                                         perception is considered to be a biological                          In recent years, research has centred on
                                                                    hallmark of IBS. Recently, also the occur-                           the dysregulation of brain-gut interactions
IBS research over the past half century                             rence of low-grade mucosal inflammation                              as the pathophysiological basis for IBS.
shows a changing focus from psycho-                                 has been linked to IBS. Enhanced visceral                            This brain-gut axis consists of bidirectional
logical and stress-related research to an                           perception and motor response may result                             communication pathways connecting the
emphasis on motility disturbances, to                               both from peripheral (e.g. infection,                                cognitive and emotional brain centres,
autonomic imbalance and visceral hy-                                inflammation) or central (e.g. attention,                            with neuroendocrine centres (e.g. hy-
persensitivity. Functional gastrointestinal                         anticipation and mood) sensitisation                                 pothalamus, pituitary gland), the enteric
(GI) disorders were initially attributed                            mechanisms. In addition to the intestinal                            nervous system, the autonomic nervous
to motor dysfunction. By the late 1980s                             symptomatology in IBS, a high co-occur-                              system, and the immune system. Hence,
it had become apparent that the cause                               rence of IBS with affective dysregulation,                           alterations at any level between the brain
of most functional GI disorders could                               mainly depression and anxiety, has been                              and the gut may influence IBS symp-
not be explained solely on the basis of                             reported both in a primary care as well                              toms by autonomic, cognitive-affective,
motility disturbances. A series of con-                             as in gastroenterological settings. Psycho-                          neuroendocrine-immune and intermediate
temporary studies suggested that patients                           social stressors play a prominent role in                            mechanisms. Serotonin (5-HT) is regard-
with functional GI disorders might have a                           symptom generation. We believe that the                              ed a key neurotransmitter involved in the
sensory dysfunction, which caused them                              high rates of affective dysregulation in IBS                         regulations of these domains (Fig 1).
to perceive physiological stimuli to the                            patients are a specific and integral part of
GI tract as GI symptoms. There is general                           IBS, rather than a non-specific co-morbid



                                                                                                   Brain-gut model


          Biomarkers

          Visceral perception
          Cognition
          Mood
          CNS processing/activity
          5-HT metabolism/signalling

          Sympatho- vagal balance
          Immune/inflammatory
          parameters
          Neuroendocrine hormones
          Lipid profile
          5-HT metabolism/signalling

          Motor function
          Low-grade inflammation
          Extrinsic nerve
          Autonomic activity
          5 HT-metabolism/signalling



Figure 1. Schematic presentation of the key elements of the brain-gut axis.
CNS=central nervous system; 5-HT=serotonin; ANS=autonomic nervous system; HPA=Hypothalamus-Pituitary-Adrenal cortex -axis; ENS=enteric nervous system



                                                                                   Nutrifocus • 1/2008                                                                            13
Serotonin is a major signalling               tonergic content, release and reuptake at      as well as for the lifestyle (including
molecule in the GI tract                      the level of the gut and systemically in       diet) and pharmacologic treatment of
                                              platelet-free plasma may be involved in        IBS. This should not only be directed at
Serotonin (5-hydroxytryptamine, 5-HT)         IBS pathophysiology. We have recently          improving symptoms in IBS but more
is involved in a number of diverse            shown1 that acute lowering of 5-HT             research and ultimately therapy should
physiologic functions including mood,         activity, by reducing the availability of      focus at preventing the development of
appetite, sleep, memory and learning,         tryptophan, results not only in enhanced       IBS after an intestinal infection or in
vasoconstriction, haemostasis, behaviour      visceral perception (Fig 2) but also in a      conjunction with very stressful physical
and immune responses. More than 80%           selective impairment of memory (word           as well as psychological conditions. The
of total body 5-HT is located in the GI       recall) related to positive annotations        integrated brain-gut concept offers a
tract. The remainder of 5-HT is located       (words with a positive context such as         framework that can be beneficially used
in blood platelets and the central nerv-      ‘nice’). Furthermore, we showed that           by researchers, clinicians, and ultimately
ous system. Serotonin is synthesized in       acute increase of 5-HT activity, by intra-     all subjects with or at risk to develop IBS.
a two-step reaction from the essential        venous administration of the antidepres-
amino acid tryptophan. The availabil-         sive drug citalopram, resulted in an im-
ity of tryptophan influences serotonin        provement of this type of memory2. This
synthesis. Gastrointestinal 5-HT may          pivotal role of disturbed 5-HT brain-gut
be released via a number of mechanisms        signalling in IBS, affecting both intestinal
including chemical stimuli, vagal stimu-      and extraintestinal symptom generation,
                                                                                             References:
lation and application of pressure to the     is also illustrated by the fact that antide-
gut mucosa. A 5-HT transporter called         pressive drugs, designed to increase 5-HT      1. Kilkens TO, Honig A, van Nieuwenhoven MA
serotonin reuptake transporter (SERT)         activity in the brain, have a positive         ym. Gut 2004;53:1794-1800.
mediates reuptake and hence affects           effect on IBS symptomatology in certain
                                                                                             2. Kilkens TO, Honig A, Fekkes D ym. Aliment
serotonergic activity. Modern antidepres-     patient populations. It is also known that     Pharmacol Ther 2005;22:865-874.
sive drugs act by blocking 5-HT reuptake      subjects with a major depression often
(selective seretonin reuptake inhibitors),    suffer from IBS-like symptoms.
and the polymorphism of SERT may be                                                          Further reading
involved in the dysregulation of seroton-     Future prospects
                                                                                             Mawe GM, Coates MD, Moses PL. Aliment
ergic signalling.                                                                            Pharmacol Ther 2006;23:1067-76.
                                              This new concept of a central role of
As indicated, 5-HT is heavily involved        altered brain-gut and 5-HT signalling          Brummer RJ. Scand J Nutr 2005;49:98-105.
in brain-gut signalling. Recent evidence                                                     Kilkens TO, Honig A, Rozendaal N, van Nieu-
                                              in the symptom generation of IBS has           wenhoven MA, Brummer RJ. Aliment Phamacol
indicates that various alterations in sero-   implications both for further research         Ther 2003;17:43-51.




Figure 2. Pressure-urge scores (mean SEM)) during intermittent pressure distension of the rectum in diarrhoea predominant irritable bowel
syndrome (d-IBS) patients and control subjects, during acute tryptophan depletion (ATD) and placebo. Overall, ATD did not significantly
affect urge scores compared with placebo. However, post hoc analysis associated with increased urge scores compared with placebo
(p<0.0001) (10-15 mm Hg).


14                                                       Nutrifocus • 1/2008
Nutrifocus • 1/2008   15

				
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