U.S. patent application number 14/834639 was filed with the patent office on 2015-12-17 for treatment of ibd and ibs using both probiotic bacteria and fermented cereal as treatment.
The applicant listed for this patent is Nordisk Rebalance A/S. Invention is credited to Hans Israelsen.
Application Number | 20150359836 14/834639 |
Document ID | / |
Family ID | 43385150 |
Filed Date | 2015-12-17 |
United States Patent
Application |
20150359836 |
Kind Code |
A1 |
Israelsen; Hans |
December 17, 2015 |
Treatment of IBD and IBS Using Both Probiotic Bacteria and
Fermented Cereal as Treatment
Abstract
The invention covers a novel treatment strategy that
considerably improves conventional probiotic treatments of
inflammatory bowel diseases, irritable bowel syndrome and other
gastrointestinal disorders. Both probiotic microorganisms and the
carrier of the probiotic microorganisms in form of a fermented
cereal gruel are used as treatment effectors. Phospholipids may
also be an effecter. The novel treatment strategy is capable of
removing the symptoms of inflammatory bowel diseases regardless of
a mild, moderate or severe stage of the disease.
Inventors: |
Israelsen; Hans; (Allerod,
DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nordisk Rebalance A/S |
Allerod |
|
DK |
|
|
Family ID: |
43385150 |
Appl. No.: |
14/834639 |
Filed: |
August 25, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13826208 |
Mar 14, 2013 |
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14834639 |
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13540827 |
Jul 3, 2012 |
8846029 |
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13826208 |
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12066246 |
Apr 16, 2008 |
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PCT/DK2006/000526 |
Sep 27, 2006 |
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13540827 |
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60744717 |
Apr 12, 2006 |
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60721276 |
Sep 28, 2005 |
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Current U.S.
Class: |
424/93.45 |
Current CPC
Class: |
A61P 1/10 20180101; A61K
31/196 20130101; A23L 33/135 20160801; A61P 1/04 20180101; A61K
35/744 20130101; A61K 35/742 20130101; A61K 35/747 20130101; A61K
36/899 20130101; A61P 1/12 20180101; A61K 45/06 20130101; A61P
29/00 20180101; A61K 35/74 20130101; A23V 2200/3204 20130101; A61K
31/685 20130101; A61K 35/745 20130101; Y02A 90/22 20180101; A61K
2035/115 20130101; Y02A 90/10 20180101; Y02A 90/26 20180101; A61P
43/00 20180101; A61P 1/06 20180101; A23L 7/152 20160801; A61P 1/14
20180101; A23V 2002/00 20130101; A61P 1/00 20180101; A61K 35/66
20130101; A61K 35/745 20130101; A61K 2300/00 20130101; A61K 35/747
20130101; A61K 2300/00 20130101; A61K 35/74 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 36/899 20060101
A61K036/899; A61K 31/196 20060101 A61K031/196; A61K 35/747 20060101
A61K035/747 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 28, 2005 |
EP |
05388079.5 |
Apr 12, 2006 |
DK |
PA200600529 |
Claims
1. A daily dosage form containing from 18 grams to 90 grams, by dry
weight, of a fermented cereal composition comprising at least
1.times.10.sup.11 colony forming units (CFU) of Lactobacillus
plantarum 299 or Lactobacillus plantarum 299v per 18 grams, by dry
weight, of said fermented cereal; wherein said fermented cereal is
obtained by fermenting a cereal gruel with a culture of said L.
plantarum 299 or L. plantarum 299v; and wherein the fermented
cereal composition has a pH of less than 5.5.
2. The dosage form according to claim 1, wherein said fermented
cereal is obtained by fermenting a cereal gruel with a culture of
L. plantarum 299 or L. plantarum 299v for at least 12 hours.
3. The dosage form according to claim 1, wherein said fermented
cereal is obtained by fermenting a cereal gruel with a culture of
L. plantarum 299 or L. plantarum 299v for at least 24 hours.
4. The dosage form according to claim 1 containing at least 0.05
gram, by dry weight, of said fermented cereal per mL of said
fermented cereal composition.
5. The dosage form according to claim 1 containing at least 0.10
gram, by dry weight, of said fermented cereal per mL of said
fermented cereal composition.
6. The dosage form according to claim 1 containing at least 0.18
gram, by dry weight, of said fermented cereal per mL of said
fermented cereal composition.
7. The dosage form according to claim 1, wherein the fermented
cereal comprises at least 1.times.10.sup.8 cfu/mL of L. plantarum
299 or L. plantarum 299v.
8. The dosage form according to claim 1, wherein the fermented
cereal comprises at least 1.times.10.sup.9 cfu/mL of L. plantarum
299 or L. plantarum 299v.
9. The dosage form according to claim 1, wherein the cereal gruel
that is fermented is selected from the group consisting of barley,
corn, millet, oats, oatmeal, quinoa, rice, rye, sorghum, triticale,
wheat, and cassava.
10. The dosage form according to claim 1, wherein the cereal gruel
that is fermented is oat or oatmeal.
11. A method for remission treatment of a gastrointestinal disease
in a human being caused by pro-inflammatory microorganisms, said
method comprising the step of administering to said human being, on
a daily basis, a therapeutically effective amount of the dosage
form according to claim 1.
12. The method of claim 11, wherein the gastrointestinal disease is
a chronic inflammatory disease.
13. The method of claim 11, wherein the gastrointestinal disease is
inflammatory bowel disease (IBD).
14. The method of claim 11, wherein the gastrointestinal disease is
irritable bowel syndrome (IBS).
15. The method of claim 11 further comprising administering to said
human being, on a daily basis, a therapeutically effective amount
of an active agent selected from the group consisting of
5-aminosalicylic acid (5-ASA), a corticosteroid, and an
immune-modulatory medicament.
16. The method of claim 15, wherein the active agent is
5-aminosalicylic acid (5-ASA).
17. A method for maintenance treatment of a gastrointestinal
disease in a human being caused by pro-inflammatory microorganisms,
said method comprising the step of administering to said human
being, on a daily basis for a period of from 1 to 25 weeks, a
therapeutically effective amount of the dosage form according to
claim 1.
18. The method of claim 17, wherein the gastrointestinal disease is
a chronic inflammatory disease.
19. The method of claim 17, wherein the gastrointestinal disease is
inflammatory bowel disease (IBD).
20. The method of claim 17, wherein the gastrointestinal disease is
irritable bowel syndrome (IBS).
21. The method of claim 17 further comprising administering to said
human being, on a daily basis, a therapeutically effective amount
of an active agent selected from the group consisting of
5-aminosalicylic acid (5-ASA), a corticosteroid, and an
immune-modulatory medicament.
22. The method of claim 21, wherein the active agent is
5-aminosalicylic acid (5-ASA).
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the treatment and
maintenance treatment of inflammatory bowel diseases (IBD) and
inflammatory bowel syndrome (IBS). In particular, it concerns the
use of both fermented cereals and probiotic, preferably
anti-inflammatory, microorganisms as treatment effectors for
combating IBD and IBS in a novel treatment concept. The invention
further concerns the use of phospholipid as a third treatment
effecter.
BACKGROUND OF THE INVENTION
[0002] Ulcerative colitis (UC) and Crohn's Disease (CD) are
inflammatory bowel diseases (IBD) characterized by chronic
inflammation in the intestines. UC occurs in the colon while CD may
be present in the entire gastrointestinal (GI) tract. The clinical
symptoms are diarrhea, abdominal pain, occasional rectal bleeding,
weight loss, tiredness and sometimes fever. Although occurring at
any age, IBD is most common in teenagers and young adults, which
consequently may suffer from delayed development and stunted
growth. The frequency of the disease is similar to type 1 diabetes
in Europe and the USA. The clinical course of IBD varies
considerably. Patients with mild to moderate symptoms may be
treated without hospitalization. However, 10-15% of patients
experience a severe course of the disease, which in many cases is
followed by surgery.
[0003] IBD is treated medically by reducing the inflammation and
thereby controlling the gastrointestinal symptoms. However, there
is currently no medical cure for IBD. Colonectomy may eliminate UC
but reduces life quality and increases the risk of complications.
The available medical treatments include the use of
5-aminosalicylic acid (5 ASA), corticosteroids and immunomodulatory
medicaments. Prolonged treatment of mild to moderate IBD symptoms
is usually carried out using 5 ASA while corticosteroids and
immunomodulatory medicaments are used to treat severe symptoms.
Diarrhea or abdominal pain appear as side effects of 5 ASA whereas
long term use of corticosteroids frequently shows serious side
effects including reduction in bone mass, infection, diabetes,
muscle wasting and psychiatric disturbances. Immunomodulatory
medicaments suppress the immune system, which controls the IBD
symptoms. However, the resulting immuno-compromised state leaves
the patient susceptible to many diseases.
[0004] IBD seems to be a result of an uncontrolled cascade in the
immune response. The successful treatment of CD patients with
antibodies against the pro-inflammatory cytokine TNF-.alpha.
supports this assumption (Rutgeerts et al. 2004 Gastroenterology
126:1593-610). However, a prolonged antibody treatment will result
in a general lowering of the TNF-.alpha. level, which eventually
will lead to susceptibility to other diseases.
[0005] The reason for the chronic uncontrolled immune response in
IBD has not been established. However, both genetic dispositions
and the composition of the microbial flora residing in the
intestinal tract of the patient are putative causes. Recently it
has been reported that several hundred genes may be involved in a
genetic disposition for IBD (Costello et al. 2005 PLoS Med 2(8):
e199), which makes the development of a successful treatments
through genetic strategies extremely difficult. Although it was
found that Helicobacter pylori is the cause for peptic ulcer
disease, no specific pathogens have been found to be the cause of
IBD. However, it is generally believed that the commensal
microorganisms in the GI tract are key factors in the exaggerated
immune response in IBD patients (Schultz et al. 2003 Dig. Dis. 21:
105-128).
[0006] In vitro tests have shown that immune competent cells react
differently upon contact to different bacteria (Christensen et al.
2002 J Immunol. 168:171-8). Bone marrow-derived dendritic cells
(DC) are exposed to microbial strains and following the cytokines
produced by the DC are determined. Predominant production of
proinflammatory interleukins such as IL 6, IL12 and TNF.alpha.
indicates a proinflammatory response upon exposure to a microbial
strain. In contrast, a predominant secretion of anti-inflammatory
interleukins such as IL4 and IL10 indicates an anti-inflammatory
response upon the exposure. In general, microorganisms can be
divided into two groups inducing pro-inflammatory or
anti-inflammatory cytokines, respectively. In the following, such
microorganisms are termed "pro-inflammatory" and
"anti-inflammatory" microorganisms, respectively.
[0007] Irritable Bowel Syndrome (IBS) is part of a spectrum of
diseases known as functional gastrointestinal disorders which
include diseases such as non-cardiac chest pain, non-ulcer
dyspepsia, and chronic constipation or diarrhea. These diseases are
all characterized by chronic or recurrent gastrointestinal symptoms
for which no structural or biochemical cause can be found. Patients
suffering from IBD and IBS share several kinds of symptoms.
[0008] In 1907, the inventor of the modern immunology Elias
Metchnikoff suggested that some intestinal bacteria have a
beneficial role on the health. Today, these bacteria are termed
probiotics defined as live microorganisms which administered in
adequate amounts confer a beneficial health effect on the host.
[0009] A long range of effects have been postulated for instance
that probiotics can help reduce the risk of certain diarrheal
illnesses, improve the immune function, reduce the risk of cancer
and cardiovascular diseases, assist lactose intolerant people etc.
Some of the postulated effects have been investigated
scientifically during the last two decades. In particular, research
has been intense on the treatment of gastrointestinal diseases
using probiotics. The rationale is that changing the microflora in
the GI tract of IBD and IBS patients may reduce the immune
aggressiveness thereby relieving the symptoms.
[0010] Today, three basic approaches exist for changing the
microflora of the intestine, namely the use of i) antibiotics, ii)
probiotics, and iii) synbiotics. The administration of antibiotics
kills a subpopulation of the microflora while probiotics--if
administered in appropriate amounts--are thought to displace some
of the existing microorganisms in the intestine. Antibiotics and
probiotics have also been used in combination. Synbiotics are
mixtures of probiotics and substances--socalled prebiotics--that
provide a substrate to specifically stimulate the growth of the
probiotic microorganisms. None of these approaches--alone or in
combination--have proven to be competent concerning a clear and a
long term reduction of IBD or IBS symptoms.
[0011] Several strains of Lactic Acid Bacteria and species from the
genus Bifidobacterium are probiotic, which implies that they one
way or another have been shown to promote a specific health effect.
Human clinical trials using probiotics alone or in combination with
antibiotics have been performed to identify strains and/or
formulations for the treatment of patients with IBD or IBS symptoms
or for keeping already treated IBD patients in remission.
[0012] WO96/29083 and EP 554418 disclose three intestine colonizing
lactobacillus strains including the two Lactobacillus plantarum
strains 299 (DSM 6595) and 299v (DSM 9843) and Lactobacillus casei
ssp. rhamnosus 271 (DSM 6594) which may be fermented in oat gruel.
It is speculated that these strains may be used to treat IBS. EP
415941 discloses methods for preparing nutrient composition
comprising treatment of oat gruel with enzymes before mixing with
lactobacilli
[0013] The results from trials with Lactobacillus plantarum strains
299v administered in a daily total amount of up to
2.times.10.sup.10 colony forming units (cfu) in a fruit drink are
ambiguous since some positive effects on IBS patients are reported
in two studies (Nobaek et al. 2000 Am J Gastroenterol. 95:1231-8
and Niedzielin et al. 2001 Eur J Gastroenterol Hepatol. 13:1143-7)
while a later study using the same strain showed no effect on the
IBS patients (Sen et al. 2002 Dig Dis Sci 47:2615-20).
[0014] Other species of Lactobacillus have been tested as for
instance Lactobacillus rhamnosus GG, which was administered in an
amount of 6.times.10.sup.9 bacteria twice a day for 52 weeks in a
double blinded RCT study for preventing recurrence after curative
resection for Crohn's disease (Prantera et al 2002 Gut 51:405-409).
This study showed that the probiotic treatment had no effect
compared to placebo.
[0015] Another strategy has been to use a combination of different
probiotic strains, of which one product is called VSL#3. It
consists of eight different bacterial strains and is administered
as capsules possibly with freeze or spray dried bacteria. A recent
study was performed with the administration to UC patients of
1.8.times.10.sup.12 VSL#3 bacteria twice a day for six weeks
(Bibiloni et al. 2005 American Journal of Gastroenterology
100:1539-46). The patients had mild to moderate UC symptoms and the
study was performed as an open study without placebo. Remission was
achieved in 53% of patients.
[0016] In another study, 250 mg of the yeast Saccharomyces
boulardii was administered three times a day for four weeks.
Remission was obtained in 71% of the 17 UC patients (Guslandi et
al. 2003 Eur J Gastroenterol Hepatol. 15:697-8). These results have
not been confirmed in controlled studies.
[0017] A RCT study on maintaining remission of UC was performed
recently using the E. coli Nissle strain (Kruis et al. 2004 Gut
53:1617-23).
[0018] Kato et al. (2004 Aliment Pharmacol Ther. 20:1133-41) and
Ishikawa et al. (2003 J Am Coll Nutr. 22:56-63) have disclosed
controlled trials assessing the effect of bifidobacteria-fermented
milk on ulcerative colitis.
[0019] The number of microorganisms in the GI tract is
approximately 10.sup.14 (Backhed et al. 2005 Science 307:1915-20).
As mentioned previously, the results from clinical trials have
shown that administration of large amount of probiotics may have a
positive effect on the IBD symptoms. However, administration to IBD
patients of more than 10.sup.12 VSL#3 microorganisms each day for
several weeks led to the identification of only small amounts of
only two of the provided eight strains in biopsies from the
patients (Bibiloni et al. 2005 American Journal of Gastroenterology
100:1539-46). No dramatic change in the composition of the
microflora was observed.
[0020] Hitherto, the general assumption in the scientific community
concerning the treatment of IBD and IBS is that probiotics have
shown some promising results but are not sufficient effective
(Schultz et al. 2003 Dig. Dis. 21:105-28 and Kim et al. 2003
Aliment Pharmacol Ther. 17:895-904).
[0021] In summary, the current applied strategies for treating IBD
or IBS using probiotics aiming to change the composition of the GI
microflora cover--alone or in combination--i) oral administration
of different amounts of probiotic microorganisms also including
concomitant administration of conventional medicines like 5 ASA,
ii) oral administration of substrates specifically favourable to
the growth of probiotic microorganisms, iii) short term oral
administration of antibiotics and iv) the use of probiotic
microorganisms capable of transiently colonizing the intestine
and/or producing compounds that are toxic to other bacterial
species. These strategies have not proven to be sufficiently
effective neither in reducing the symptoms experienced by IBD and
IBS patients nor changing the composition of the microflora in the
intestines.
[0022] Recently, it has been reported that a randomized controlled
trial (RCT) comprising a three months treatment of UC patients with
retarded release of phosphatidylcholine (PC) in the colon has shown
a remission in 53% of the patients (Stremmel et al. 2005 Gut
54:966-971).
DISCLOSURE OF THE INVENTION
Summary of the Invention
[0023] The previously described treatments of gastrointestinal
disease such as IBD and IBS using probiotics have not proven
sufficiently beneficial and therefore need to be improved in order
to be a serious supplement or even an alternative to traditional
treatment with chemical substances. One of the factors which
distinguish the present invention from the previously disclosed use
of probiotics in treating gastrointestinal diseases is the use of
high amounts of supplementary effectors combined with relatively
high amounts of the probiotics.
[0024] In one aspect, the present invention is thus based on the
discovery that a combined high intake of fermented oat gruel and
high intake of probiotic microorganisms by IBD and IBS patients
provides a surprising improvement over the previously described
results obtained with probiotic microorganisms. In the prior art
the probiotic bacteria were used in high amounts alone or in lower
amounts in what is considered to be with respect to the disease
inert carriers such as fermented oatmeal or milk.
[0025] It has been realised during the development of the present
invention that fermented cereal can play an important active role
in combating inflammatory disorders in the intestines most likely
caused by pro-inflammatory microorganisms, and should therefore be
used in an amount higher than previously taught. In the prior art
fermented cereal (oat gruel) was merely considered to be a growth
medium and carrier of the probiotics. The fermented cereal has not
previously been used in high amounts in the treatment of IBD and
IBS patients and nothing in the prior art suggests that fermented
cereals may play an important role in such a treatment.
[0026] In another aspect of the invention the addition of the
phospholipids, phosphatidylcholine (PC), lysophosphatidylcholine
(LPC), phosphatidylinositol (PI) and/or phosphatidylethanolamine
(PE) can be additionally beneficial in the treatment of IBD and IBS
patients, especially patients with a sub-optimal mucus layer in the
intestines.
[0027] Mucus constitutes a physical barrier to the epithelial cells
of the intestine and seems to be important in the balanced contact
between microorganisms and the surface cells of the GI tract.
Phospholipids are important components of the intestinal mucus.
Phospholipids in the mucus consist mainly of phosphatidylcholine
and lysophosphatidylcholine, but also phosphatidylinositol and
phosphatidylethanolamine. PC seems to play a major role in the so
called mucosal defence by establishing a protective hydrophobic
surface. It has been shown that phosphatidylcholine and
phosphatidylinositol have a therapeutic effect on the development
of acetic acid-induced colitis in rats (Fabia et al. 1992 Digestion
53:35-44). The content of PC and LPC in the colonic mucus of
patients with UC is significant lower compared to healthy controls
(Ehehalt et al. 2004). Peripheral blood leucocytes from patients
with Crohn's disease have abnormal essential fatty acid metabolism
apparently correlated to the zinc content (Cunnane et al. 1986) and
membranes of erythrocytes from patients with Crohn's disease have a
significant increase of sphingomyelin and a decrease of
phosphatidylcholine (Aozaki 1989).
[0028] Phosphatidylcholine, for example in the form of commercially
available lechitins (which also contains amounts of LPC, PI and PE)
is the preferred phospholipids to be added to the fermented
product. Although it has been shown that certain probiotic bacteria
may induce the production of mucus in the intestine (Mack et al.
1999), combining probiotics with phospholipids that specifically
support building up a functional intestinal mucus has not been
suggested previously.
[0029] In a further aspect of the present invention it has been
realised that in order to secure a beneficial effect of the
fermented cereal and the probiotic microorganisms, intake of
substances which disturb the desired effect should be avoided
during the treatment. Such substances may promote the growth of
intestinal pro-inflammatory microorganisms present in the patients
before and during the treatment or stimulate immunological
reactions in the intestines, which is unfavourable to the medical
treatment. Examples of such harmful substances are easily
fermentable sugars present in e.g. fruit drinks, fruit pulp, dried
or processed fruit and the like and milk and milk products.
[0030] The present invention thus concerns the use of i) high doses
of a fermented cereal and ii) high doses of probiotic
microorganisms in a novel treatment strategy that considerably
improves the conventional probiotic treatments of IBD and IBS
patients. The fermented cereal negatively change the growth and
life maintenance conditions for the residing microorganisms in the
intestine of IBD and IBS patient while the supply of probiotics
provides anti-inflammatory inducing microorganisms to displace
pro-inflammatory inducing microorganisms from the original
microflora, which have less favourable conditions in the fermented
cereal. The probiotic microorganisms are adapted to the environment
in the fermented cereal composition prior to administration to the
patients. In addition, phospholipids, in particular
phosphatidylcholine and lysophosphatidylcholine may be used to
further improve the treatment effect by building up or strengthen
the functional mucus layer in the intestines. The novel treatment
strategy may be applied alone or in combination with the
administration of conventional medicines like 5 ASA and
corticosteroids.
[0031] The novel concept for the treatment or the maintenance
treatment of IBD, IBD related diseases and IBS includes the
administration of an efficient amount of fermented cereal together
with an efficient amount of probiotic microorganisms and optionally
phospholipids. The probiotic microorganisms are non-pathogenic
microorganisms, preferably anti-inflammatory microorganisms. The
cereal may be any suitable cereal which is fermentable by suitable
non-pathogenic microorganisms and in its fermented state usable as
an active effecter. The probiotic microorganisms in the
ready-to-use product may be the cereal-fermenting microorganisms
per se. However, the probiotic microorganisms in the ready-to-use
product may also be other non-pathogenic, preferably
anti-inflammatory microorganisms that are added to the fermented
cereal composition. In the later case the cereal-fermenting
microorganisms may be alive or dead in the ready-to-use product.
The phospholipids may preferably be commercially available
lecithin--from soy beans--containing at least 20% PC.
[0032] A daily intake of an efficient amount of a fermented cereal
composition consisting of at least 10 grams dry weight of a
fermented cereal--for example fermented oat gruel--and at least
5.times.10.sup.10 colony forming units (cfu) of probiotic
microorganisms--for example lactic acid bacteria such as intestine
colonizing Lactobacillus or Bifidobacterium spp. The preferred
amount per day is at least 18 g dry weight of fermented cereal,
e.g. fermented oat gruel and 1.times.10.sup.11 cfu of probiotic
microorganisms, and more preferred 36 g dry weight of fermented
cereal, e.g. fermented oat gruel and 2.times.10.sup.11 cfu of
probiotic microorganisms. In another preferred embodiment, the
daily intake is about 90 g dry weight of fermented cereal e.g.
fermented oat gruel and about 5.times.10.sup.11 cfu of probiotic
microorganisms such as intestine colonizing Lactobacillus spp.
Larger amounts of fermented cereal e.g. fermented oat gruel and
numbers of colony forming units of probiotic microorganisms may be
used if desired (and accepted by the patient). Preferably the daily
intake is divided into two or more intakes. The first intake of the
ready-to-use product is preferably before breakfast and the last
intake is preferably after the last meal and drink of the day. The
last intake is chosen to allow the amount of fermented cereal and
microorganisms to be present in the intestine as long as possible
without being "diluted" by "normal" foods and drinks, which may
contain easy fermentable substrates. It is acceptable to drink
water after the last intake. Intake of the ready-to-use product in
connection with each meal during the day may also be an option.
[0033] When phospholipids are a part of the treatment regime, the
daily intake is at least 0.1 g phophatidylcholine, preferably more
than 0.5 g and most preferably more than 1 g per day. The
phospholipids may be added as a commercial lecithin product. When
using the ready to use product without added lecithin, fluctuations
between a state of obvious IBD-symptoms and remission have been
observed for patients for up to week number 12 in the treatment
period. In contrast, treatment with the ready to use product
containing added lecithin has shown a more stable remission and in
some cases a faster remission during the treatment period.
[0034] The probiotic microorganisms are preferably not freeze or
spray dried in the ready-to-use product because the microorganisms
preferably should be as robust as possible when entering the
intestines in order to successfully compete with the
pro-inflammatory part of the microflora already present in the
intestines. However, some strains may be sufficiently robust and/or
some protocols sufficiently gentle to allow spray or freeze dried
probiotic microorganisms in the ready-to-use product.
[0035] A more efficient treatment or maintenance treatment is
obtained if milk products, milk components and easily fermentable
sugars such as sucrose, lactose, glucose or fructose are omitted in
the ready-to-use product and otherwise avoided in the diet.
Accordingly, the ready-to-use product should not comprise any drink
containing large amounts of fruit, fruit pulp, dried fruit or
similar fruit additives or other energy-providing additives often
used in commercial products to enhance taste and nutrition value of
the final product. In the same way, large amounts of milk and
milk-based additives should not be used in the ready-to-use
product. Low- or non-calorie additives may be used in the product
for instance to enhance the properties relevant to patient
compliance.
[0036] The duration of the treatment is dependent on each
individual patient and the stage of the disease. The typical
treatment periods range from one to 25 weeks but there is no
limitation. A continued treatment for a certain period after
remission appears to provide better long term effects.
[0037] Accordingly the present invention concerns the use of an
efficient amount of a fermented cereal composition and an efficient
amount of probiotic microorganisms and optionally added
phospholipids in the preparation of a medical product for the
treatment of a gastrointestinal disease such as IBD, IBD related
diseases and IBS.
[0038] The cereal is preferably oat, which is fermented by
non-pathogenic microorganisms capable of fermenting cereals
resulting in a pH below 5.5, Such microorganisms may be lactic acid
bacteria, Propionibacterium spp and Bifidobacterium spp., e.g. one
or more Lactobacillus spp.
DETAILED DESCRIPTION OF THE INVENTION
[0039] IBD is very likely a result of imbalances in the immune
system, which may be initiated and preserved by the residing
microorganisms of the GI tract including pathogenic or
opportunistic pathogenic microorganisms. Attempts to change the
flora of microorganisms in the GI tract of IBD or IBS patients have
been performed by several scientific groups using probiotic
microorganisms and/or antibiotics and/or prebiotics. The previous
strategies have covered the administration to patients of large
amounts of probiotic microorganisms formulated in capsules (or milk
products) or a relative small amount of probiotic microorganisms
and fermented oatmeal formulated in fruit drinks. The new strategy
presented here, which includes administration of high amounts of
both fermented oatmeal and probiotic microorganisms and preferably
PC, shows superior results compared to the results presented in the
prior art.
[0040] The discovery of a positive correlation between a large
intake of a product consisting of fermented oatmeal and a
Lactobacillus strain and the clinical effects as described in
Example 2 has successfully been developed into the present
invention which offers a surprising novel and advantageous
treatment concept for the treatment of IBD, IBS and IBD related
diseases. However, the addition of lecithin to the product
consisting of fermented oatmeal and a Lactobacillus strain has been
found to provide an even more advantageous treatment concept with a
faster and/or a more stable state of remission obtained within the
treatment period as described in Examples 13 and 14. The products
used by Nobaek et al. (2000 Am J Gastroenterol. 95:1231-8) and
Niedzielin et al. (2001 Eur J Gastroenterol Hepatol. 13:1143-7)
contained a low amount (compared to the present invention) of
fermented oatmeal and a Lactobacillus strain mixed in a fruit
drink. These products lead to insufficient treatment.
[0041] The terms used in the present description of the invention
are defined below.
[0042] The term "inflammatory bowel disease" (IBD) includes
ulcerative colitis (UC) and Crohn's disease (CD) that are well
characterised diseases. As examples of "IBD-related diseases" may
be mentioned collagenous colitis and lymphocytic colitis. Others
will be known by the skilled medical doctors.
[0043] The term "irritable bowel syndrome" (IBS) is defined as a
spectrum of diseases known as functional gastrointestinal disorders
which include diseases such as noncardiac chest pain, nonulcer
dyspepsia, and chronic constipation or diarrhea. These diseases are
all characterized by chronic or recurrent gastrointestinal symptoms
for which no structural or biochemical cause can be found. The
symptoms are often the same as for IBD patients, except that
bleedings do not occur in connection with IBS.
[0044] The terms "treatment effecter" and "treatment effectors"
mean component(s) that exert(s) an effect in reducing IBD and/or
IBS symptoms.
[0045] The term "cereal" is defined as any plant from the grass
family that yields an edible grain (seed). The most common grains
are barley, corn, millet, oats, quinoa, rice, rye, sorghum,
triticale, wheat and rice. Most preferred is oats. However,
suitable parts of alternative plants such as cassava may also be
used.
[0046] The term "cereal gruel" is defined as cereal grains, flakes,
meal, extracts or flour boiled in a liquid, which preferably is
water. The cereal gruel is prepared in this way in order to
sterilize the suspended cereal and to prepare for the microbial
fermentation. Enzymes, compositions containing enzymes and/or
appropriate amounts of carbon and energy sources may be added to
further prepare for the microbial fermentation and/or provide a
desired rheology. By cereal gruel is meant any rheological form of
suspended and boiled cereal.
[0047] The term "fermented cereal composition" is defined as the
resulting product from the growth of one or more non-pathogenic
microorganisms on a cereal gruel and containing one or more
non-pathogenic microbial strains, which may be dead or alive.
Fermented cereal composition is also referred herein as "fermented
product" or "fermented oat gruel".
[0048] By the term "non-pathogenic microorganisms" is meant any
live microbial food or feed supplement that under normal conditions
is not harmful to humans or animals.
[0049] By the term "cereal-fermenting microorganisms" is meant
non-pathogenic microorganisms that are capable of fermenting a
cereal resulting in a pH<5.5.
[0050] By the term "probiotic microorganisms" is meant
non-pathogenic microorganisms that beneficially affect the patient
by improving the intestinal microbial balance. Such probiotic
microorganisms may preferably be anti-inflammatory microorganisms
and/or from the group consisting of Lactic Acid Bacteria and
Bifidobacterium spp.
[0051] Lactic Acid Bacteria are defined as all species, subspecies
and strains of the following genera: Carnobacterium, Enterococcus,
Lactobacillus, Lactococcus, Leuconostoc, Oenococcus and
Pediococcus. Also covered are non-pathogenic species, subspecies
and strains of the genus Streptococcus such as Streptococcus
salivarius subsp. thermophilus or Streptococcus thermophilus.
[0052] The term "Lactobacillus spp. includes any of the following
species: Lactobacillus acetotolerans, Lactobacillus acidipiscis,
Lactobacillus acidophilus, Lactobacillus agilis, Lactobacillus
algidus, Lactobacillus alimentarius, Lactobacillus amylolyticus,
Lactobacillus amylophilus, Lactobacillus amylovorus, Lactobacillus
animalis, Lactobacillus arizonensis, Lactobacillus aviarius,
Lactobacillus bifermentans, Lactobacillus brevis, Lactobacillus
buchneri, Lactobacillus casei, Lactobacillus coelohominis,
Lactobacillus collinoides, Lactobacillus coryniformis subsp.
coryniformis, Lactobacillus coryniformis subsp. torquens,
Lactobacillus crispatus, Lactobacillus curvatus, Lactobacillus
cypricasei, Lactobacillus delbrueckii subsp. bulgaricus,
Lactobacillus delbrueckii subsp delbrueckii, Lactobacillus
delbrueckii subsp. lactis, Lactobacillus durianus, Lactobacillus
equi, Lactobacillus farciminis, Lactobacillus ferintoshensis,
Lactobacillus fermentum, Lactobacillus fornicalis, Lactobacillus
fructivorans, Lactobacillus frumenti, Lactobacillus fuchuensis,
Lactobacillus gallinarum, Lactobacillus gasseri, Lactobacillus
graminis, Lactobacillus hamsteri, Lactobacillus helveticus,
Lactobacillus helveticus subsp. jugurti, Lactobacillus
heterohiochii, Lactobacillus hilgardii, Lactobacillus homohiochii,
Lactobacillus intestinalis, Lactobacillus japonicus, Lactobacillus
jensenii, Lactobacillus johnsonii, Lactobacillus kefiri,
Lactobacillus kimchii, Lactobacillus kunkeei, Lactobacillus
leichmannii, Lactobacillus letivazi, Lactobacillus lindneri,
Lactobacillus malefermentans, Lactobacillus mali, Lactobacillus
maltaromicus, Lactobacillus manihotivorans, Lactobacillus
mindensis, Lactobacillus mucosae, Lactobacillus murinus,
Lactobacillus nagelii, Lactobacillus oris, Lactobacillus panis,
Lactobacillus pantheri, Lactobacillus parabuchneri, Lactobacillus
paracasei subsp. paracasei, Lactobacillus paracasei subsp.
pseudoplantarum, Lactobacillus paracasei subsp. tolerans,
Lactobacillus parakefiri, Lactobacillus paralimentarius,
Lactobacillus paraplantarum, Lactobacillus pentosus, Lactobacillus
perolens, Lactobacillus plantarum, Lactobacillus pontis,
Lactobacillus psittaci, Lactobacillus reuteri, Lactobacillus
rhamnosus, Lactobacillus ruminis, Lactobacillus sakei,
Lactobacillus salivarius, Lactobacillus salivarius subsp.
salicinius, Lactobacillus salivarius subsp. salivarius,
Lactobacillus sanfranciscensis, Lactobacillus sharpeae,
Lactobacillus suebicus, Lactobacillus thermophilus, Lactobacillus
thermotolerans, Lactobacillus vaccinostercus, Lactobacillus
vaginalis, Lactobacillus versmoldensis, Lactobacillus vitulinus,
Lactobacillus vermiforme, Lactobacillus zeae. The preferred species
is Lactobacillus plantarum.
[0053] The term "Bifidobacterium spp." includes any of the
following species: Bifidobacterium adolescentis, Bifidobacterium
aerophilum, Bifidobacterium angulatum, Bifidobacterium animalis,
Bifidobacterium asteroides, Bifidobacterium bifidum,
Bifidobacterium boum, Bifidobacterium breve, Bifidobacterium
catenulatum, Bifidobacterium choerinum, Bifidobacterium
coryneforme, Bifidobacterium cuniculi, Bifidobacterium dentium,
Bifidobacterium gallicum, Bifidobacterium gallinarum,
Bifidobacterium indicum, Bifidobacterium longum, Bifidobacterium
longum bv Longum, Bifidobacterium longum bv. Infantis,
Bifidobacterium longum bv. Suis, Bifidobacterium magnum,
Bifidobacterium merycicum, Bifidobacterium minimum, Bifidobacterium
pseudocatenulatum, Bifidobacterium pseudolongum, Bifidobacterium
pseudolongum subsp. globosum, Bifidobacterium pseudolongum subsp.
pseudolongum, Bifidobacterium psychroaerophilum, Bifidobacterium
pullorum, Bifidobacterium ruminantium, Bifidobacterium saeculare,
Bifidobacterium scardovii, Bifidobacterium subtile, Bifidobacterium
thermoacidophilum, Bifidobacterium thermoacidophilum subsp. suis,
Bifidobacterium thermophilum, Bifidobacterium urinalis.
[0054] By the term "efficient amount" is to be understood an amount
of fermented cereal composition and an amount of one or more
probiotic microorganisms to be administered daily to the person to
results in a relatively fast reduction of the patient's symptoms.
The reduction in symptoms comprises stop of bloody stools and/or at
least a 25% reduction in the number of daily stools within seven
days from the treatment onset, if the treatment concept is
followed. Minor deviation from the present concept may lead to a
delay in the reduction of the symptoms. Major deviations may lead
to failure of any effect of the treatment.
[0055] Oat gruel used in the preparation of the product may be
prepared as disclosed in EP 415941. The oat gruel may for example
be prepared by using at least 5 g oatmeal per 100 ml liquid or more
preferred 10 g oatmeal per 100 ml liquid or even more preferred at
least 18 g oatmeal per 100 ml liquid.
[0056] The fermented cereal composition is produced by adding an
amount of cereal-fermenting microorganisms to the cereal gruel
resulting in a pH<5.5 following fermentation at an optimal
temperature for at least 12 hours or preferred at least 24
hours.
[0057] The term "(ready-to-use) product" is defined as the product
to be administered to a patient for instance as a drinkable,
eatable, anally administrable or tube administrable product. The
ready-to-use product consists of i) a fermented cereal composition,
ii) probiotic microorganisms and optionally iii) added
phospholipids. Drinkable ready-to-use products may for instance be
stored and available in suitable containers. Eatable products may
for instance be stored and available in a solid or semi-solid form
for example mixed with other eatable ingredients not being contrary
to the new treatment concept. Oat biscuits may be an example.
Anally administrable ready-to-use products may for instance be in
the form of a suppository and tube administrable ready-to-use
products may for instance be in a liquid form that is suitable for
tube administration via the oral or rectal route.
[0058] The cereal-fermenting microorganisms of the fermented cereal
composition may per se constitute the probiotic microorganisms in
the ready-to-use product. However, the probiotic microorganisms in
the ready-to-use product may also be microorganisms that are added
to the fermented cereal composition. In the later case the
cereal-fermenting microorganisms may be alive or dead in the
ready-to-use product. The microorganisms in the fermented cereal
composition may be killed for instance by heating the composition
before the addition of probiotic microorganism. The appropriate
temperature and time depend on the properties of the
cereal-fermenting strains. The efficient amount of probiotic
bacteria in the ready-to-use product is at least 10.sup.8 cfu/ml or
more preferred at least 10.sup.9 cfu/ml. Prior to the fermentation,
the cereal gruel may be treated with malted flour such as malted
barley flour and/or enzyme(s) e.g. amylase or/and added a
sufficient amount of energy and carbon source for the growth of the
cereal-fermenting microorganisms. Prior to or following the
fermentation, the cereal gruel may be treated with enzyme(s) and/or
treated physically/mechanically e.g. to reduce the viscosity, to
improve the availability of nutrient components, to break down
certain cereal molecules, to change the composition of
macromolecules and building block molecules, to improve the shelf
life or other improvements or modifications. Similarly, the cereal
gruel may prior to or following the fermentation be added
components to improve or modify the product e.g. by adding
phospholipids, proteins, amino acids and/or fibres that for
instance may improve the mucus barrier in patients or may improve
the transit time of the food in the GI tract.
[0059] The term "intestine colonizing" means that a microbial
strain must be present transiently or permanently in the intestine
upon at least one intake of a sufficient amount of cfu. The
analysis for intestine colonizing may be carried out for instance
by testing for the presence of a specific strain in the faeces on
the days and weeks following the intake. Some strains of
Lactobacillus spp. may colonize the human intestine for about 14
days.
[0060] The terms "one day's treatment", "daily treatment", "daily
administration" and "daily intake" are used interchangeably and
mean the total dose of the (ready-to-use) product to be taken by or
administered to the patient each day in the treatment period. If
the treatment is administered by the patient him/herself, the right
dose is preferably provided in a suitable container containing the
correct dose of the medical product. The total daily dose may
advantageously be divided into two or more containers containing
the right doses to be taken or administered during the day, for
example as the first and the last meal of the day. Alternatively,
the patient or the medical staff may measure the right dose for
each administration from a larger container comprising the
(ready-to-use) product.
[0061] The terms "milk products" and "dairy products" mean any
product that has been produced from mammal milk and "dairy
components" means any component derived, purified or extracted from
mammal milk or a dairy product.
[0062] The term "easily fermentable sugars" means sugars that
constitute an easily accessible source of energy and carbon for
microorganisms. Examples of easily fermentable sugars are sucrose,
lactose, glucose and fructose. Such sugars are for example present
in processed fruits, fruits drinks, dried fruit, marmalades and
otherwise treated fruits and should therefore be avoided in the
ready-to-use product.
[0063] The term "food or medical additives" means any substance
that may be added to improve the fermented product in terms of
activity towards the gastrointestinal disorder or towards one or
more other diseases. Also, "food or medical additives" means any
substance that may be added to improve the shelf life, taste,
color, or rheological properties of the product. Examples of
substances are taste enhancers, colors, pH and osmo-regulators,
vitamins, herbs, herbal components, minerals, trace elements,
viscosity regulators, lipids, emulsifiers, short chain fatty acids,
glutamine and other amino acids, antioxidants, blood pressure
regulators, pain relief substances etc. The skilled person would
readily know which additives would be suitable. The term minerals
comprises pharmaceutical acceptable minerals such as chrome, iron,
zinc, copper, calcium, potassium, sodium, manganese and molybdenum.
Especially zinc may be added to give a beneficial effect.
[0064] The term "lecithin" means both the chemical definition,
which is phosphatidylcholine or
1,2-diacyl-glycero-3-phosphocholine, and the commercial definition,
which refers to a natural mixture of neutral and polar lipids.
Phosphatidylcholine is present in commercial lecithin in
concentrations of 20 to 90%. Other components in commercial
lechithin are lysophosphatidylcholine, phosphatidylinositol and
phosphatidylethanolamine. Most commercial lecithin products contain
about 20% phosphatidylcholine. The fatty acids residues of
phosphatidylcholine may be saturated, mono-unsaturated or
poly-unsaturated. The term "lecithin" also means chemically or
commercially defined lecithin in any physical form including
liquid, granulated, encapsulated or mixed with any other
substances. In particular, the term "lecithin" also means any
formulation where lecithin is designed to be released at specific
locations in the gastrointestinal tract for instance as defined as
"retarded release" by Stremmel et al. 2005 Gut 54:966-971.
The Development of a Novel Concept for the Treatment or Maintenance
Treatment of IBD, IBS, and Related Diseases
[0065] During the development of the novel treatment concept it was
speculated how a pronounced clinical effect could be achieved
possibly by an efficient change in the composition and/or metabolic
activity of the microflora in the intestine. Intake of relatively
large amounts of appropriate fermented cereal together with
probiotics was surprisingly shown to have an advantageous clinical
effect most likely because it is disadvantageous to most of the
residing pro-inflammatory inducing microorganisms in the GI tract
in terms of substrate for growth and/or life maintenance and
advantageous to several probiotic microorganisms in terms of an
appropriate environment for life maintenance. In light of the
latter aspect, the probiotic microorganisms benefit physiologically
if the fermented cereal both constitutes the growth medium for the
microorganisms in the production phase and, concomitantly, used as
a treatment effecter in the medical product. Last but not least,
cereals contain a range of components important to man such as
carbohydrates, fibres and lipids. Cereals like oats and maize
contain relatively large amounts of lipids. It may be speculated
that a high amount of polar lipids in cereals may be co-responsible
for the positive effects of the novel treatment protocol described
here. Accordingly, cereals with a high amount of polar lipids, such
as oat, might be preferred. Also, lecithin may be added to the
fermented cereal composition to improve the functional properties
of the intestinal mucus. Consequently, higher amounts of
phospholipids should be added to fermented compositions prepared
from cereals with a low content of polar lipids compared to cereals
with high amounts of polar lipids.
[0066] According to the strategy on efficiently changing the
microflora in the GI tract, intake of components that stimulate the
growth and maintenance of the residing pro-inflammatory inducing
microorganisms should be avoided. Most milk components and sugars
like sucrose, lactose, glucose or fructose are easily utilized by
bacteria such as E. coli. For instance, in competition experiments
in flasks most E. coli strains would be much faster in utilizing
milk components and the sugars mentioned than most lactic acid
bacteria or Bifidobacterium strains. Therefore, milk products, milk
components and easily fermentable sugars should be omitted in the
present ready-to-use product and in the treatment or maintenance
treatment concept.
[0067] The applied probiotic microorganisms should preferably be
able--at least transiently--to reside in or colonize the GI tract.
Such probiotic microorganisms should also be physiologically
robust. There is a long range of probiotic products on the market
and many contain freeze or sprayed dried probiotic microorganisms
(DDS-Plus.RTM. (UAS Lab, MN, USA), VSL#3 (Sigma-Tau, MD, USA),
Lp299v (Quest, UK) etc.). Freeze or spray drying usually kills a
large percentage of the microorganisms and severely stresses the
surviving population (Wang et al. 2004 Int J Food Microbiol.
93:209-17). Although pre-treatment of several microorganisms under
mild stress conditions may be beneficial for the survival under
future harsh conditions--for instance in the GI tract--, freeze or
spray drying is in many cases too rough to result in probiotic
microorganisms that are physiologically robust.
[0068] One example of the novel concept for the treatment or
maintenance treatment of IBD, IBD related diseases and IBS includes
the following:
[0069] Each day the patient shall drink two or more portions each
of 100-250 ml oat gruel fermented with and containing about
10.sup.8-10.sup.9 cfu/ml of one or more intestine colonizing
Lactobacillus spp, for example L. plantarum 299 or L. plantarum
299v. The product should preferably contain 12 g lecithin with at
least 20% PC per litre fermented oat gruel to obtain a faster
remission and or a more stable state of remission during the
treatment period. The first intake of fermented oat gruel is
performed before breakfast and the last intake preferably performed
as the last meal and drink--except for water--of the day. The
treatment continues for e.g. 14 weeks.
[0070] A more efficient treatment or maintenance treatment is
obtained if milk products, milk components and easily fermentable
sugars such as sucrose, lactose, glucose or fructose are omitted in
the ready-to-use product and avoided in the diet during the
treatment period.
[0071] The duration of the treatment is dependent on each
individual patient and the stage of the disease. The typical
treatment periods range from one to 25 weeks but there is no
limitation.
[0072] The probiotics may be any probiotic microorganisms
preferably lactic acid bacteria and/or species from the genus of
Bifidobacterium and more preferably capable of at least transiently
colonizing the intestine. L. plantarum 299 and L. plantarum 299v
are two suitable strains which have been isolated due to their
ability to ferment oatmeal and intestine colonizing properties.
[0073] As mentioned, there are two reasons for using fermented
cereals as a treatment effecter. The first is to build up an
environment in the GI tract in which the properties for growth or
life maintenance for many microorganisms are unfavourable except
for selected microorganisms including many probiotics. The second
reason is to provide complex lipids, carbohydrates, proteins,
fibres and other molecules that may have a positive effect both in
providing material for production of physical barriers such as the
mucus layer and on the immune system response. The complex lipids,
carbohydrates, proteins and other molecules both originate from the
oat and probiotics per se but are also an outcome of the
fermentation process. The use of added lecithin in the ready-to-use
product may provide extra material for the production of an
effective intestinal mucus layer. The amount of added lecithin
should most likely be higher in the ready-to-use product based on
cereals with a low content of phospholipids than in products based
on cereals containing relatively large amounts of
phospholipids.
[0074] Administration of fermented cereal compositions containing
probiotic microorganisms and lecithin to IBD and IBS patients for
an appropriate period of time will most likely lead to i) a reduced
number and/or a reduced metabolic activity in pro-inflammatory
microorganisms of the intestine due to the development of specific
unfavorable environmental conditions ii) a gradual increase of
metabolic activity in and/or in the number of anti-inflammatory
microorganisms in the intestine due to the daily supply of
probiotics and the development of new intestinal environmental
conditions and iii) a reinforced protective mucus layer due to the
daily supply of polar lipids of the cereals and the added
lecithin.
[0075] Subsequent to the fermentation process, the probiotic
microorganisms do not grow further in the ready-to-use product.
Accordingly, the fermented cereal does not serve as a prebiotic
compound since it does not stimulate growth of the probiotics in
the intestine. The fermented cereal composition may have a pH below
5.5, which mildly stresses and prepares the probiotic
microorganisms for upcoming stress conditions, which for instance
will follow in the stomach and in the intestine of GI patients. The
pre-stress treatment in the production of probiotics is a matter of
a fine balance. Most probiotic products are available as freeze or
spray dried preparations. Freeze or spray drying is known as being
rough and in many cases kills a great deal of the population. The
surviving microorganisms may need time for adaptation when
presented to a fluid environment. In other words, freeze or spray
dried probiotics may not be prepared adequately for robustness to
passage of the stomach and/or competing for the colonization of the
intestine. However, it may be possible in certain situations to add
freeze or spray dried probiotics to the fermented cereal.
[0076] The novel treatment described herein may be initiated at any
stage of the IBD or IBS course. The treatment should be carried out
by following the novel treatment protocol accurately and the
duration may vary from one or few weeks to several months. However,
prolonged treatment period appears to provide better long term
effects. Following a gradual stop in the intake of the ready-to-use
product, IBD and IBS patients will usually experience that the
symptoms are absent and not reoccurring. However, some symptoms may
reoccur usually within months or years. These symptoms may be
treated by entering a maintenance treatment just by following the
novel treatment protocol for a shorter duration, which may be of
one or more weeks. Also, IBD and IBS patients may acquire
experience telling that symptoms may turn up under specific
circumstances for instance at specific times at the year, under
certain stress conditions or associated to diets in certain
communities. In such cases, patients may benefit from entering a
maintenance treatment before meeting the specific circumstances.
The duration of this maintenance treatment may also be relatively
short e.g. one or more weeks.
[0077] In the novel treatment both milk, milk components and easily
fermentable sugars are omitted in the ready-to-use product and
avoided in the diet to create an even more unfavourable environment
for microbial growth or life maintenance in the GI tract. Foods
that contain relatively large amounts of sugar and/or milk
components should be avoided. The foods cover sugar, soft drinks
(containing sugar), juice, syrups, candy, cakes, cookies, dried
fruit, muesli and other breakfast product with added sugar, ice
cream, milk, cream, fermented milks, butter, etc. The patients are
recommended to take a supplement of calcium since milk and milk
components should be avoided in the treatment. However, many
calcium tabs contain relatively large amounts of lactose.
Therefore, calcium tabs without lactose should be administered.
This is an example of unexpected added components in supplement and
foods, which the patients must pay attention to. Foods containing
traces of milk or milk components and/or very small amounts of
added sugar may be accepted in the diet when following the novel
treatment concept. However, no exact limits may be stated for the
concentration of added milk, milk components and/or sugar in the
foods due to the complexity of different foods and each individual
food intake.
[0078] The terms "novel treatment", "novel treatment strategy" and
"novel treatment concept" refer to the treatment of IBD,
IBD-related diseases or IBS.
[0079] The following examples are intended to illustrate the
present invention and should in no way limit the invention as
defined in the claims.
Examples
Example 1
[0080] A 66 year old man was suffering from abdominal pain and
diarrhea. He was examined by a physician who could not set up an
accurate diagnosis. The patient was consequently redirected to a
department of gastroenterology at the local hospital. In the
meantime, the symptoms were getting worse and at this time the
patient lost more than 2 kg in weight per week. The patient
underwent a colonoscopy. No signs of ulcers or necrosis were
detected in the lower intestine and the colon. The most likely
diagnosis was IBS. Following, the patient was redirected to a local
gastroenterologist. On top of the described symptoms, occasional
paralysis in the patient's legs began to show up.
[0081] The patient undertook a treatment based on a protocol that
uses probiotics for the treatment of IBS including abdominal pain
and diarrhea disclosed in WO96/29083 and in the scientific
literature (Niedzielin et al. 2001 Eur J Gastroenterol Hepatol.
13:1143-7). Instead of the described 200 ml fruit drink containing
5.times.10.sup.7 probiotic bacteria per mL and a minor amount of
oat gruel proscribed to be administered twice each day for four
weeks to treat gastrointestinal diseases, the patient took twice a
day 10 mL of a similar product containing 10.sup.9 cfu/ml of
Lactobacillus plantarum 299v in an oat gruel without added fruit.
This amount was chosen to match the number of cfu in Niedzielin et
al. 2001. The 10 ml was taken before breakfast and two hours after
the last meal in the evening. Having followed this conventional
protocol for two weeks, the patient did not experience any positive
effect. At that time, the patient had lost more than 30 kg in
weight during the three months period from the onset of the
disease.
Example 2
[0082] Due to the lack of any positive effects from the
conventional probiotic treatment, the patient mentioned in Example
1 initiated the novel treatment according to the present
invention.
[0083] The patient had a daily intake of 500 ml of a fermented oat
gruel containing about 90 g fermented oat gruel and
5.times.10.sup.11 Lactobacillus plantarum 299v. This amount of
fermented oat gruel and probiotic microorganisms is 50 times higher
than proscribed by Niedzielin et al. (2001 Eur J Gastroenterol
Hepatol. 13:1143-7) and WO96/29083. The 500 ml fermented product
was divided into two portions, which were taken each day before
breakfast and as the last meal or drink of the day. The patient
experienced a significant reduction of symptoms in less than one
week following initiation of the novel treatment. A complete
remission was obtained by following the novel treatment for eight
weeks. One year later the patient had gained the 30 kg in weight
and no relapse has occurred until now, which is about five years
subsequent to completion of the novel treatment.
Example 3
[0084] A colonoscopy revealed an ulcerative colitis in a 19 years
old woman. She was extremely tired and had abdominal pain and
bloody diarrheas with more than ten defecations a day. She was
hospitalized for 14 days and treated with prednisolon (cortisone)
and 5 ASA. This treatment was continued when the patient was sent
home. 18 weeks later the tiredness and abdominal pain were still
present. The diarrhea was also present but the number of
defecations per day was reduced to an average of five. Blood was
still present in the stools. The patient experienced severe side
effects from the prednisolon including a reduced immune status
resulting in continuous infections. She then decided to finish the
intake of prednisolon by a gradual reduction. The intake of 5 ASA
was continued.
[0085] One week following the termination of prednisolon intake,
the patient started to follow the novel treatment taking 250 ml of
a fermented oat gruel containing Lactobacillus plantarum 299v twice
a day as described in Example 2. The intake of 5 ASA was continued
in parallel for 12 weeks. One week after the treatment start, blood
was absent from the stools. On day No. 4 in the novel treatment,
the patient's tiredness disappeared. In the following three weeks,
the number of defecations varied from two to four. Abdominal pain
occurred occasionally during the first three weeks in the novel
treatment. During weeks Nos. 4-16, the number of defecations was
one or two. The patient experienced two courses of abdominal pain
during this period. These were characterized as short pain courses
similar to uncomplicated incidents experienced by the patient in
the childhood. The treatment was stopped 16 weeks after initiation
by a gradual reduction in the daily intake of the fermented oat
gruel containing probiotics.
[0086] The patient had no UC symptoms throughout the following
three and a half year. Subsequently, however, a relapse occurred
with a relatively mild diarrhea. The patient then followed the
novel treatment protocol for another three weeks resulting in a
remission that has continued since, which is 18 months after
completion of the second course of the novel treatment.
Example 4
Treatment of IBD Patients Using the Novel Concept for the Treatment
of IBD and IBS
[0087] A series of treatments was set up during a period of four
and a half years subsequent to the successful treatment of the 19
years old UC patient as described in Example No. 3. Additional nine
UC or CD patients were enrolled to follow the novel treatment
concept as described in Example 3. Data, results and comments from
the treatments are given in Table 1.
TABLE-US-00001 TABLE 1 Data, results and comments concerning nine
IBD patients enrolled for the novel treatment concept Treat- ment
Sex and Diag- period age (years) nosis* (weeks) Result Comments
Male, 20 CD, Two Partial The patient stopped the moderate remission
treatment twice after two weeks in each course when the symptoms
disappeared Female, 26 UC, 14 Remission Subsequently, the moderate
patient has once a year - for two years - followed a maintenance
treatment for three weeks. Female 16 UC, 16 Remission moderate
Female, 35 UC, Eight Remission moderate Female, 17 CD, One Positive
Drop out moderate response Female, 45 UC, mild Three Remission
Female, 16 UC, One Positive Bleeding stopped and severe response
diarrhea significantly reduced during the one week treatment. Then
drop out Male, 12 UC, 14 Remission severe Female, 35 UC, 14
Remission moderate *UC: Ulcerative colitis; CD: Crohn's disease.
The stage of the disease was judged prior to treatment start and
stated as mild (about 3 or below in SCCAI (SCCAI = Simple Colitis
Clinical Activity Index, Jowett et al. 2003 Scand J Gastroenterol.
38: 164-71), moderate (about 4-7 in SCCAI) or severe (about 8 or
more in SCCAI).
[0088] All patients had been in treatment with conventional
medicines such as 5 ASA and/or corticosteroids for more than one
year prior to the start of the novel treatment. During the
treatment period most patients continued concomitantly their
treatment with the conventional medicines due to ethical reasons.
They all responded positively to the novel treatment concept.
Remission was achieved in the cases where the patients followed the
treatment protocol accurately. The results strongly indicate that
the novel treatment--with or without combination with conventional
medicines--is capable of removing the symptoms from UC and CD
patients regardless of the stage of the disease.
Example 5
Treatment of IBS Patients Using the Novel Treatment Concept
[0089] Four women with IBS followed the novel treatment protocol
for two or three weeks. The first experienced diarrhea and
abdominal pain while the three had relatively mild or moderate
diarrheas. Data and results from the treatments are given in Table
2.
TABLE-US-00002 TABLE 2 Data and results concerning four female IBS
patients that followed the novel treatment concept Treatment Sex
and period age (years) Diagnosis (weeks) Result Female, 20 IBS
Three Remission Female, 47 IBS Three Remission Female, 49 IBS Two
Remission Female, 72 IBS Three Remission
[0090] The treated patients all achieved remission. Despite the
limited number of patient, the results strongly indicate that the
novel treatment concept is capable of turning IBS into
remission.
Example 6
Maintenance Treatment of IBS and IBD Patients Using the Novel
Treatment Concept
[0091] Three women who had previously completed a successful
treatment of either UC (Table 1) or IBS (Table 2) followed the
treatment protocol for maintenance reasons. Data, results and
comments from the treatments are shown in Table 3.
TABLE-US-00003 TABLE 3 Data, results and comments concerning three
female patients that followed the novel treatment concept for
maintenance Treatment Sex and Diag- period age (years) nosis
(weeks) Result Comments Female, 19 UC, 2 .times. three No UC The
patient has once a medium symptoms year - for two years - followed
the maintenance treatment for three weeks. Female, 47 IBS >20 No
IBS Previously experienced symptoms symptoms have not been present
since initiation of the maintenance treatment Female, 72 IBS >20
No IBS Previously experienced symptoms symptoms have not been
present since initiation of the maintenance treatment
[0092] The three women have not experienced any symptom from their
UC or IBS since the initiation of the maintenance treatment. The
results strongly indicate that the novel treatment concept is
efficient in the maintenance treatment of UC and GI disorders
despite the low number of patients
Example 7
Description of a RCT Study on Patients Suffering from Ulcerative
Colitis Using the Novel Concept for the Treatment of IBD and
IBS
[0093] In order to supplement the results described in the previous
examples, a randomized clinical trial (RCT) is planned. A Phase
IIa, double blinded placebo RCT study will be performed on UC or CD
patients essentially as described by for instance by Stremmel et
al. 2005 Gut, 54: 966-971. The novel treatment protocol will
include the use of fermented oat gruel, which has been fermented
with and contains L. plantarum 299v and/or similar probiotic
bacteria. The amount of intake in the morning and the evening may
be fixed at for instance 250 ml fermented oat gruel containing
10.sup.9 cfu/ml. The placebo may be cellulose beads in a water
solution in which the pH has been adjusted to about 5 with lactic
acid and/or acetic acid to mimic the active product, or any other
appropriate placebo means. The trial may for instance run for a
period between three and 20 weeks depending on the stage of the
enrolled UC or CD patients. One expected end point could be
remission of at least 50% of the patients to SSCAI values <4
(Jowett et al. 2003 Scand J Gastroenterol. 38:164-71) within eight
to 14 weeks.
Example 8
The Manufacture of a Ready-to-Use Product Consisting of Fermented
Oat Gruel with Probiotic Intestine Colonizing Lactobacillus
plantarum
[0094] The manufacture of a ready-to-use product consisting of
fermented oat gruel with probiotic intestine colonizing
Lactobacillus plantarum is divided into two steps according to this
recipe. This first step covers the preparation of oat gruel. This
step may be performed essentially as disclosed in EP 415941. An
alternative method is to mix 18.5% (w/w) oatmeal and 0.9-2.5% (w/w)
malted barley flour with water. The mixture is slowly stirred and
heated for 10-20 minutes at 37.degree. C. and following 15-30
minutes at 90-100.degree. C. The resulting oat gruel is cooled to a
temperature of about 37.degree. C. and is now ready for the second
step namely the fermentation process. A starter culture consisting
of Lactobacillus plantarum 299 or strain 299v is added to the oat
gruel to initiate the fermentation. The amount of added starter
culture with a cfu number of about 10.sup.9/ml is 0.01, 0.1 or 1.0%
(v/v). The fermentation is carried out with mild stirring at
37.degree. C. for 12-24 hrs. The resulting ready to use product
with a cfu number of about 10.sup.9/ml and pH below 5 is then
cooled at 4.degree. C. and packed for instance in sterile storage
containers of 250 ml, which have a shelf life of at least two
months when kept at 4.degree. C.
Example 9
The Manufacture of a Ready-to-Use Product Consisting of Fermented
Oat Gruel with Probiotic Microorganisms and Lecithin
[0095] A ready to use product consisting of fermented oat gruel
with probiotic microorganisms is manufactured as described in
Example 8. Subsequently, lecithin is added. 12 grams of granulated
lecithin such as "Lecithin Granulat" from Biosym A/S, DK-7430
Ikast, Denmark, are added per liter fermented oat gruel with
probiotic microorganisms. The mixture is stirred for about one
minute and kept overnight at 4.degree. C. resulting in a new
ready-to-use product consisting of fermented oat gruel with
probiotic microorganisms and lecithin with a cfu number of about
10.sup.9/ml and pH below 5. This product is packed for instance in
sterile storage containers of 250 ml, which have a shelf life of at
least two months when kept at 4.degree. C.
[0096] More or less amounts of lecithin and other physical forms
and qualities of lecithin can be used in this protocol. Numerous
commercial lecithins are available and most with different contents
of phosphatidylcholine, lysophosphatidylcholine,
phosphatidylinositol and phosphatidylethanolamine. The fatty acids
residues of these phospholipids may be saturated, mono-unsaturated
or poly-unsaturated. Also, the lecithin to be used in this protocol
may have different physical forms such as liquid, granulated,
encapsulated or mixed with any other substances such as vegetable
oils. Encapsulated lecithin include formulations where lecithin is
designed to be released at specific locations in the
gastrointestinal tract for instance as defined as "retarded
release" by Stremmel et al. 2005 Gut 54:966-971.
Example 10
The Manufacture of a Ready-to-Use Product Consisting of Fermented
Oat Gruel and Microorganisms Capable of Fermenting Oat Gruel
[0097] A protocol for the manufacture of a ready to use product
consisting of fermented oat gruel with probiotic intestine
colonizing Lactobacillus plantarum is described in Example 8. An
alternative ready to use product consisting of fermented oat gruel
with other microorganisms capable of fermenting oat gruel can be
manufactured using the following protocol.
[0098] Bacteria are isolated as starter culture candidates from
intestinal mucosa biopsies of healthy human volunteers that have
been on a one week diet with a daily intake of at least 25 g
oatmeal. The isolation and growth of the bacteria are essentially
carried out as described for intestinal bacteria of horses in U.S.
Pat. No. 6,537,544. A set of 20 strains belonging to the group
consisting of Lactic Acid Bacteria, non-pathogenic Streptococcus
spp, Pediococcus spp, Bifidobacterium spp. and Propionibacterium
spp. is selected for an analysis of fermentation performance. 20
samples of 500 ml oatmeal gruel prepared as described in Example 8
are each inoculated with a pure culture of one single strain from
the set to an initial cfu number of about 10.sup.5. The inoculated
samples are mildly stirred at 37.degree. C. for 24 hrs. Following,
the pH is measured and the cfu numbers determined in each sample.
The bacterial strains giving rise to cfu numbers at about 10.sup.9
or above and pH below 5 in the fermented product are termed
"oatmeal starter strains". Previously described cereal starter
cultures such as in WO9117672 are also included in "oatmeal starter
strains".
[0099] The manufacture of a ready to use product consisting of
fermented oat gruel with microorganisms capable of fermenting oat
gruel is essentially carried out as described in Example 8 except
for the use of the specific starter culture. Here, the starter
culture is consisting of one or more of the "oatmeal starter
strains" instead of Lactobacillus plantarum 299 or strain 299v. The
amount of the "oatmeal starter strains" with a cfu number of about
10.sup.9/ml is 0.01, 0.1 or 1.0% (v/v). The resulting ready to use
product with a cfu number of about 10.sup.9/ml and pH below 5 is
cooled at 4.degree. C. and packed for instance in sterile storage
containers of 250 ml. The shelf life is at least two months when
kept at 4.degree. C.
Example 11
The Manufacture of a Ready-to-Use Product Consisting of Fermented
Oat Gruel and a Variety of Microorganisms
[0100] As described, the fermented oat gruel contains two effectors
for combating IBD and IBS namely fermented oat and probiotic
microorganisms. Both effectors are present following fermentation
of the oat gruel as described in the previous examples. However,
additional microorganisms from other sources may be added
subsequent to the oat fermentation. The added microbial strains may
be a strong effecter in the intestine of IBD or IBS patients but
incapable of fermenting oats or competing with oat fermenting
strains.
[0101] A number of Bifidobacterium strains (and strains from other
bacterial species) have been shown to exert positive effects in IBD
or IBS patients (refs). However, these strains are not expected to
be capable of performing an effective fermentation in oats.
Therefore, the Bifidobacterium strains are grown in a conventional
growth medium such as MRS (ref) possibly with added
inulin-oligofructose (Furrie et al. 2005 Gut 54:1346). The
Bifidobacterium strains are grown at optimal growth conditions.
Subsequent to the end of growth, lactic acid is added to the medium
at a final concentration of 0.8% to make the bacteria adapt to an
acidic environment. Following two hours in the medium containing
lactic acid the bacteria are harvested by centrifugation at 5000
rpm for 10 minutes. The bacteria are resuspended in 1/100 of the
growth medium containing lactic acid resulting in a suspension
containing about 10.sup.12 cfu/ml. The suspension is termed "extra
microorganisms".
[0102] Fermented oat gruel with probiotic intestine colonizing
Lactobacillus plantarum and Bifidobacterium strain(s) may be
manufactured using the procedure described in Example 8 followed by
the addition of "extra microorganisms". An amount corresponding to
0.1% (v/v) of "extra microorganisms" is added to the product
consisting of fermented oat gruel with probiotic intestine
colonizing Lactobacillus plantarum if the ready to use product
shall contain equal amounts of Lactobacillus and Bifidobacterium.
The ready to use product is packed for instance in sterile storage
containers of 250 ml, which have a shelf life of at least two
months when kept at 4.degree. C.
[0103] If a ready to use fermented oat product should be preferred
containing essentially no living oat fermenting bacteria, the
product consisting of fermented oat gruel with probiotic intestine
colonizing Lactobacillus plantarum must be stirred and heated at
100.degree. C. for about 30 minutes before cooling at 4.degree. C.
and the subsequent addition of "extra microorganisms".
Example 12
The Manufacture of a Ready to Use Product Consisting of Fermented
Maize-Sorghum and Microorganisms Capable of Fermenting Maize and
Sorghum
[0104] Togwa is a fermented cereal gruel consisting of a mixture of
maize and sorghum including microorganisms capable of fermenting
these cereals (Mugula et al. 2003 Int J Food Microbiol. 83:307-18).
A maize-sorghum gruel is prepared by mixing 10-20% (w/w) maize and
sorghum flour with water. The mixture is stirred and heated for
about 10-15 minutes at 90-100.degree. C. followed by cooling to a
temperature of about 37.degree. C. A starter culture with a cfu
number of about 10'-10.sup.9/ml is added in the amount of 0.01, 0.1
or 1.0% (v/v). The starter culture may be produced as described in
Example 10 except that 20 samples of 500 ml maize-sorghum gruel are
inoculated with a pure culture of one single strain to an initial
cfu number of about 10.sup.5. The bacterial strains giving rise to
cfu numbers at least 10.sup.8 and pH below 5 in the fermented
maize-sorghum gruel are termed "togwa starter strains". Following
the addition of "togwa starter strains" to the maize-sorghum gruel
the fermentation is carried out with mild stirring at 37.degree. C.
for 12-24 hrs. The resulting ready to use product with a cfu number
of about 10.sup.8-10.sup.9/ml and pH below 5 is then cooled at
4.degree. C. and packed for instance in sterile storage containers
of 250 ml. The shelf life is at least two months when kept at
4.degree. C. It should be noted that traditional Togwa may contain
yeast strains as well as bacteria.
Example 13
Treatment of UC Patients with a Ready to Use Product Consisting of
Fermented Oat Gruel with Probiotic Microorganisms and Added
Lecithin Leads to a Faster and/or a More Stable Reduction in the
Symptoms Level
[0105] Two female UC patients of the age of 46 and 55 years with an
initial SCCAI score of 6 and 4, respectively, initiated the novel
treatment as described in Examples 3 and 4. However, the daily
intake used in this treatment was a 500 ml ready-to-use product
containing about 90 g fermented oat gruel, 5.times.10.sup.11
Lactobacillus plantarum 299v and 6 g added lecithin with about 23%
PC and 19% PI. The 500 ml ready-to-use product was divided into two
portions, which were taken each day before breakfast and as the
last meal or drink of the day. The UC symptoms of the 46 years old
woman were gradually reduced and remission was obtained within the
first 14 days following treatment start. The state of remission was
maintained throughout the treatment period.
[0106] The UC symptoms of the 55 years old woman fluctuated between
a SCCAI score of 4 and 1 during the first six weeks. However,
remission was obtained during the remaining treatment period except
for two days where the patient experienced a traveller's diarrhea
during a visit to Thailand.
[0107] These results show a much faster and/or a more stable
reduction in the symptoms levels during the treatment course
compared to patients that have been treated with the similar
product without added lecithin. The much faster and more stable
reduction of UC symptoms for the 46 years old woman was observed
already during the first two weeks following the treatment
onset.
[0108] The 55 years old woman in the study showed fluctuating
symptom levels during the first six weeks of the treatment course,
which was in accordance with patients treated with the ready to use
product without added lecithin. In contrast, however, the
subsequent state of remission was maintained without relapse
throughout the treatment period.
Example 14
A UC Patient Experienced a Faster and More Stable Reduction in UC
Symptoms when Treated with a Ready to Use Product Consisting of
Fermented Oat Gruel with Probiotic Microorganisms and Added
Lecithin Compared to the Similar Treatment with a Ready to Use
Product without Lecithin
[0109] A 33 years old woman with a severe UC was treated for 10
weeks with a daily intake of 500 ml of a ready-to-use product
containing about 90 g fermented oat gruel and 5.times.10.sup.11
Lactobacillus plantarum 299v. The 500 ml ready-to-use product was
divided into two portions, which were taken each day before
breakfast and as the last meal or drink of the day. During the 10
weeks treatment the symptoms were gradually reduced from initially
SCCAI about 8 to about 2-4. However, the fluctuations in the
symptoms level were significant during the treatment course, which
have been observed for several patients that have followed the
treatment with the ready to use product without lecithin. The 33
years old UC patient stopped the treatment in week no. 10 due to a
fortnight trip overseas. Accordingly, the termination of the
treatment was about one month earlier than recommended and too
early because of the unstable level of symptoms. During the trip
the patient experienced a complete relapse resulting in a SCCAI of
about 8. She then initiated a new treatment course but now with a
500 ml ready-to-use product containing about 90 g fermented oat
gruel, 5.times.10.sup.11 Lactobacillus plantarum 299v and 6 g added
lecithin with about 23% PC and 19% PI. The 500 ml ready-to-use
product with added lecithin was divided into two portions, which
were taken each day before breakfast and as the last meal or drink
of the day. At the end of the first week of the treatment course
with the ready to use product with added lecithin, the symptoms
level was reduced from SCCAI of about 8 to about 4 and during the
following two weeks the SCCAI level was constantly at 3-4. During
the following three weeks the symptoms level was gradually reduced
and remission obtained during the remaining eight weeks of the
treatment period.
[0110] This demonstrates that the ready to use product with added
lecithin exerted a faster and more stable reduction in the symptoms
level compared to the ready to use products without added
lecithin.
Example 15
Taste and Consistency of the Ready to Use Product Containing
Lecithin
[0111] A ready to use product consisting of fermented oat gruel
with probiotic microorganisms and added lecithin was manufactured
as described in Example 9. The product was expected to possess an
unpleasant greasy constitution and "fatty" taste compared to the
ready to use product without added lecithin. However, the ready to
use product with added lecithin surprisingly showed a much better
taste and a comfortable mouth feeling. The taste was round and free
of the acidic and bitter aftertaste that is a feature to the ready
to use product without added lecithin. Also, the mouth feeling was
experienced as nice and smooth as opposed to the ready to use
product without added lecithin. Four test persons declared
independently that the aroma and rheology of the ready to use
product with added lecithin is much more delicious than the ready
to use product without lecithin. This is important to patient
compliance since the ready to use product shall be administered
orally in relatively large amounts for long periods.
* * * * *