U.S. patent application number 14/710481 was filed with the patent office on 2015-08-27 for probiotic recolonisation therapy.
The applicant listed for this patent is Thomas Julius BORODY. Invention is credited to Thomas Julius BORODY.
Application Number | 20150238545 14/710481 |
Document ID | / |
Family ID | 3823057 |
Filed Date | 2015-08-27 |
United States Patent
Application |
20150238545 |
Kind Code |
A1 |
BORODY; Thomas Julius |
August 27, 2015 |
PROBIOTIC RECOLONISATION THERAPY
Abstract
The present invention relates to pharmaceutical compositions
suitable for the treatment of chronic diseases associated with the
presence of abnormal or an abnormal distribution of microflora in
the gastrointestinal tract of a mammalian host, which compositions
comprise viable non-pathogenic or attenuated pathogenic Clostridia.
The compositions further comprise one or more additional viable
non-pathogenic or attenuated pathogenic microorganisms selected
from the group consisting of Bacteroides, Eubacteria, Fusobacteria,
Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, E.
coli, Gemmiger, Desulfomonas, Peptostreptococcus, and fungi. The
present invention also provides pharmaceutical compositions
suitable for the treatment of the same chronic diseases comprising
viable non-pathogenic or attenuated pathogenic Escherichia coli, at
least one strain of viable non-pathogenic or attenuated pathogenic
Bacteroides and at least one strain of viable non-pathogenic or
attenuated pathogenic microorganism.
Inventors: |
BORODY; Thomas Julius; (Five
Dock, AU) |
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Applicant: |
Name |
City |
State |
Country |
Type |
BORODY; Thomas Julius |
Five Dock |
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AU |
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Family ID: |
3823057 |
Appl. No.: |
14/710481 |
Filed: |
May 12, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14270034 |
May 5, 2014 |
9050358 |
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14710481 |
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13910579 |
Jun 5, 2013 |
9040036 |
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14270034 |
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10332986 |
Aug 4, 2003 |
8460648 |
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PCT/AU01/00907 |
Jul 25, 2001 |
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13910579 |
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Current U.S.
Class: |
424/463 ;
424/490; 424/537; 424/93.3; 424/93.4; 424/93.41; 424/93.45;
424/93.48 |
Current CPC
Class: |
A61K 31/43 20130101;
A23L 33/135 20160801; A61P 1/00 20180101; A61K 38/14 20130101; A61P
1/12 20180101; A61K 51/1217 20130101; A61K 35/741 20130101; A23V
2002/00 20130101; A61K 39/00 20130101; A61K 31/495 20130101; A61K
9/5078 20130101; A61K 38/00 20130101; A61K 36/062 20130101; A61K
2035/115 20130101; A61K 35/74 20130101; A61K 35/744 20130101; A61K
9/0031 20130101; A61K 35/742 20130101; A61K 35/24 20130101; A61K
9/4891 20130101; A23C 9/13 20130101; C12N 2795/00032 20130101; A61K
38/4893 20130101; A61K 39/39 20130101; A23C 9/123 20130101; A61K
35/37 20130101; A23C 9/127 20130101; A61K 35/76 20130101; A61K
31/545 20130101; A61K 31/41 20130101; A61K 9/19 20130101; A61K
35/38 20130101; A23L 2/52 20130101; A61K 9/48 20130101; A61K
31/7034 20130101; A61K 9/0053 20130101; A61K 35/745 20130101; A61K
31/341 20130101; A61K 31/7048 20130101; Y02A 50/30 20180101; A61K
35/747 20130101; A61K 9/50 20130101; A61K 9/5005 20130101; A61K
45/06 20130101; A61K 35/742 20130101; A61K 2300/00 20130101; A61K
35/741 20130101; A61K 2300/00 20130101; A61K 35/747 20130101; A61K
2300/00 20130101; A61K 35/744 20130101; A61K 2300/00 20130101; A61K
36/062 20130101; A61K 2300/00 20130101; A61K 31/341 20130101; A61K
2300/00 20130101; A61K 31/495 20130101; A61K 2300/00 20130101; A61K
38/14 20130101; A61K 2300/00 20130101; A61K 31/41 20130101; A61K
2300/00 20130101; A61K 35/745 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 35/741 20060101
A61K035/741; A61K 35/38 20060101 A61K035/38; A23L 1/30 20060101
A23L001/30; A61K 35/747 20060101 A61K035/747 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 25, 2000 |
AU |
PQ8997 |
Claims
1.-182. (canceled)
183. A method for treating autism in a subject in need thereof, the
method comprising administering to the subject an amount of a
pharmaceutical composition effective for treating the autism,
wherein the pharmaceutical composition is selected from the group
consisting of: a. a disease screened fresh homologous feces; b. a
freeze-dried, or a freeze-dried and reconstituted feces; c. a
reconstituted feces, reconstituted using cultured viable
non-pathogenic or attenuated microorganisms; d. a synthetic fecal
composition of predetermined flora; e. a synthetic or reconstituted
fecal composition comprising a preparation of viable flora in
proportional content that resembles a normal healthy human fecal
flora, which does not include antibiotic resistant populations; f.
a composition comprising viable, non-pathogenic colonic bacterial
cells selected from the group consisting of a Clostridia, a
Collinsella, a Bacteroides, a Fusobacteria, a Propionibacteria, a
Lactobacilli, an anaerobic cocci, a Ruminococcus, an E. coli, a
Gemmiger, a Desulfomonas, a Peptostreptococcus, a Bifidobacteria
and any combination thereof; g. a composition comprising viable,
non-pathogenic colonic bacterial components of fecal flora, wherein
said bacterial components comprise Clostridium bifermentans,
Clostridium innocuum, Clostridium butyricum, Escherichia coli,
Bacteroides and Peptostreptococcus productus; h. a composition
comprising viable, non-pathogenic colonic bacterial components of
fecal flora, wherein said bacterial components comprise a
Bacteroides, an Escherichia coli, and a non-pathogenic Clostridia,
i. a composition comprising a plurality of viable non-pathogenic
Clostridia spores and a plurality of viable non-pathogenic
Collinsella cells, j. a composition comprising a plurality of
viable non-pathogenic Clostridia, k. a composition comprising a
plurality of viable non-pathogenic Clostridia and a plurality of
viable non-pathogenic Collinsella, l. a composition comprising
viable non-pathogenic Clostridia spores, a viable non-pathogenic
Bacteroides, and a viable non-pathogenic Escherichia coli.
184. The method of claim 083, wherein said viable non-pathogenic
Clostridia are from a species selected from the group consisting of
Clostridium absonum, Clostridium argentinense, Clostridium baratii,
Clostridium bifermentans, Clostridium botulinum, Clostridium
butyricum, Clostridium cadaveris, Clostridium camis, Clostridium
celatum, Clostridium chauvoei, Clostridium clostridioforme,
Clostridium cochlearium, Clostridium difficile, Clostridium fallax,
Clostridium felsineum, Clostridium ghonii, Clostridium glycolicum,
Clostridium haemolyticum, Clostridium hastiforme, Clostridium
histolyticum, Clostridium indolis, Clostridium innocuum,
Clostridium irregulare, Clostridium limosum, Clostridium
malenominatum, Clostridium novyi, Clostridium oroticum, Clostridium
paraputrificum, Clostridium perfringens, Clostridium piliforme,
Clostridium putrefaciens, Clostridium putrificum, Clostridium
ramosum, Clostridium sardiniense, Clostridium sartagoforme,
Clostridium scindens, Clostridium septicum, Clostridium sordellii,
Clostridium sphenoides, Clostridium spiroforme, Clostridium
sporogenes, Clostridium subterminale, Clostridium symbiosum,
Clostridium tertium, Clostridium tetani, Clostridium welchii, and
Clostridium villosum.
185. The method of claim 183, wherein said viable non-pathogenic
Clostridia are from a species selected from the group consisting of
Clostridium bifermentans, Clostridium innocuum, and Clostridium
butyricum.
186. The method of claim 183, wherein said viable non-pathogenic
Collinsella comprise Collinsella aerofaciens.
187. The method of claim 183, wherein said pharmaceutical
composition further comprises an acid suppressant, an antacid, an
H2 antagonist, a proton pump inhibitor or a combination
thereof.
188. The method of claim 183, wherein said pharmaceutical
composition is formulated as an enteric coated capsule, an enteric
coated microcapsule, a powder suitable for reconstitution, a
naso-duodenal infusion, or for delivery in the form of an enema or
a colonoscopic infusion.
189. The method of claim 1830, wherein said pharmaceutical
composition is added to a food, a food additive, a dairy-based
product, a soy-based product or a derivative thereof, a jelly, or a
yogurt.
190. The method of claim 183, wherein no existing enteric
microflora is removed from said subject prior to administration of
said pharmaceutical composition.
191. The method of claim 183, wherein some existing enteric
microflora is removed from said subject prior to administration of
said pharmaceutical composition.
192. The method of claim 183, wherein the subject is pretreated
with an antibiotic prior to administration of said pharmaceutical
composition.
193. The method of claim 183, wherein the subject is pretreated
with an acid suppressant prior to administration of the
pharmaceutical composition.
194. The method of claim 183, wherein the pharmaceutical
composition is administered three times daily (tid).
195. The method of claim 183, wherein the subject is pretreated
with an orthostatic lavage prior to administration of the
pharmaceutical composition.
196. The method of claim 183, wherein the subject is pretreated
with an orthostatic lavage and antibiotic treatment prior to
administration of the pharmaceutical composition.
197. The method of claim 183, wherein the subject is pretreated
with an orthostatic lavage and antibiotic treatment prior to
administration of the pharmaceutical composition, and the
pharmaceutical composition comprises a plurality of bacteria
comprising a Bacteroides, an Escherichia coli, and a non-pathogenic
Clostridia, and the pharmaceutical composition at a concentration
of 10.sup.9 through to 10.sup.10.
198. The method of claim 183, wherein the subject is pretreated
with an antibiotic prior to administration of the pharmaceutical
composition, and after the pre-treatment with the antibiotic the
subject is pretreated with an orthostatic lavage prior to
administration of the pharmaceutical composition.
199. The method of claim 183, wherein the pharmaceutical
composition comprises between about 10.sup.3 and about 10.sup.13
viable bacterial cells.
200. The method of claim 199, wherein the pharmaceutical
composition comprises between about 10.sup.5 and about 10.sup.11
viable bacterial cells.
201. The method claim 200, wherein the pharmaceutical composition
comprises between about 10.sup.9 and about 10.sup.11 viable
bacterial cells.
202. The method of claim 201, wherein the pharmaceutical
composition comprises about 10.sup.10 viable bacterial cells.
203. The method of claim 183, wherein the autism is associated with
Irritable Bowel Syndrome or gastrointestinal symptoms.
Description
TECHNICAL FIELD
[0001] The present invention relates to pharmaceutical compositions
suitable for the treatment of diseases in mammals, in particular to
the treatment of chronic disorders associated with the presence of
abnormal or an abnormal distribution of microflora in the
gastrointestinal tract. The invention also relates to methods of
treating such diseases.
BACKGROUND ART
[0002] There are large numbers of patients suffering from
gastro-intestinal symptoms referable to the lower small bowel and
large bowel which to date have eluded explanation. These disorders
include irritable bowel syndrome (IBS) or spastic colon, idiopathic
ulcerative colitis, mucous colitis, collagenous colitis, Crohn's
disease, inflammatory bowel disease in general, microscopic
colitis, antibiotic-associated colitis, idiopathic or simple
constipation, diverticular disease, and AIDS enteropathy.
Pathophysiology of these disorders eludes logical explanation in
spite of decades of research and millions of dollars of research
funds. A common underlying factor shared by all these disorders
observed by the present inventor is their onset or aggravation
following some extraneous invading infection eg travelers
diarrhoea. In all the disorders, a specific causal infection
generally cannot be demonstrated due to our inability to detect
infecting agents whose cultural characteristics are unknown to
medical science.
[0003] Circumstantial evidence which suggests that these disorders
are "infection-related" includes:
[0004] (a) onset following a gastro-intestinal infection which
failed to completely resolve;
[0005] (b) transient improvement with use of certain antibiotics,
but recurrence upon cessation of antibiotics;
[0006] (c) transient improvement following orthostatic lavage prior
to colonoscopy and;
[0007] (d) transient symptom improvement with use of "colonic"
irrigation.
[0008] It is impractical to use long-term antibiotic therapy (with
its associated complications) in such patients since cure is not
obtained with its use. Furthermore, chronic gut infections with
recognised, specific pathogens such as Clostridium difficile,
Yersinia enterocolitica or Campylobacter jejuni/coli are generally
not eradicated with antibiotics. Some previous attempts have been
made to alter the enteric microflora in order to eradicate such
chronic infections. These measures nevertheless indicate that
alteration of bacterial flora may effect dramatic clinical
improvement in conditions characterised by chronic, resistant
enterocolitic infection. However there remain many chronic
disorders of uncertain aetiology or causation, which are resistant
to cure by current therapeutic techniques.
[0009] The use of probiotics in the human population has been
largely confined to the inclusion in various foods of live organism
of Lactobacilli and Bifidobacteria and less frequently
Streptococcus faecalis or several strains of Escherichia coli.
These organisms are thought to promote health via immune
stimulation and reconstitution of what is presumed to be normal
flora. Such usage stems back to the beliefs generated by Mechnikov
in the early 1900s. The use of probiotics to treat established
infections in the gastrointestinal tract has been lesser but a
growing part of the use of probiotics. Fungal agents such as
Saccharomyces boulardii have been used to treat, albeit
inefficiently, Clostridium difficile infection and Lactobacillus GG
has also been used for this purpose (Floch M. Probiotics and
Dietary Fibre. J Clin Gastroenterol 1998; 27(2):99-100). Various
patents have claimed the use of probiotics for narrow disease
conditions including treatment of Clostridium difficile with a
combination of Vancomycin and butyric acid bacteria (U.S. Pat. No.
5,266,315), diarrhoea prevention using Lactobacillus (U.S. Pat. No.
5,837,238) or Bifidobacterium (U.S. Pat. No. 5,902,743),
Lactobacillus acidophilus to inhibit cryptosporidium (U.S. Pat. No.
5,858,356) and mixtures of Lactobacilli and Bifidobacteria in
infants to prevent diarrhoea. Enterococcus faecium has been claimed
to be useful in alleviating symptoms of Irritable Bowel Syndrome in
humans (U.S. Pat. No. 5,902,578) (U.S. Pat. No. 5,728,380) but this
has not recognised Clostridium as the underlying agent in this
condition. Clostridium butyricum as a single agent has been claimed
to be a biological intestinal antiseptic for treatment of bacterial
food poisonings (U.S. Pat. No. 4,892,731), but its use in chronic
disease treatment was not contemplated.
[0010] Previous attempts to alter the enteric microflora of a
patient have prescribed the removal of at least a part of the
host's existing enteric microflora, for instance by lavage, prior
to substitution with predetermined desired microflora. This
procedure, which was the preferred embodiment of WO90/01335 has the
distinct disadvantages of complicating the treatment and of causing
further discomfort to the patient. This patent also advocated the
use of dried, reconstituted faeces or a synthetic mixture
comprising Bacteroides sp. and Escherichia coli. It has now been
surprisingly found that lavage or other methods of removal of at
least a part of the host's existing enteric microflora can be
omitted provided a non-pathogenic Clostridium sp. is included
within the probiotic replacement mixture. Such a replacement
mixture has the dual ability of displacing pathogenic bacteria,
frequently Clostridial in nature and also establishing a normal
environment in which commensal bacteria can establish. Such a
treatment permits long-term recovery both from gastrointestinal
disorders and from systemic afflictions not hitherto considered to
be caused by harmful enteric flora. These are also called
`para-infective` phenomena and can include rheumatological,
neurological, regressive, hepatic, and dermatological conditions
among others.
[0011] Autism is a regressive disorder of childhood, affecting boys
four times more often than girls. It has been observed that the
onset of autism is often preceded by broad spectrum antibiotic use
eg for recurrent ear infections. Antibiotic therapy is
non-discriminatory in its action and apart from treating the ear
infection the microflora of the healthy gastrointestinal tract can
be severely disrupted by such treatment. This creates an
environment where vulnerability to opportunistic microorganism
colonisation is heightened.
[0012] Clostridium tetani is a widely distributed, spore forming
anaerobe. Toxigenic strains of Clostridium tetani produce the
extremely potent tetanus neurotoxin which is known to enter the
central nervous system from the intestinal tract via the vagus
nerve (Hensel B et al. Naunyn Schmeidebergs Arch Pharmocol 1973;
276:395). Bolte (Med Hypotheses 1998; 51:133) has hypothesised that
opportunistic infection by Clostridium tetani may be responsible
for the behavioural and medical symptoms present in a sub-group of
individuals diagnosed with autism. Others have also raised the
possibility of clostridia in general as a cause of disease
(Borriello S P. Clin Infect Dis 1995; Suppl 2:5242).
[0013] Sandler et al. (Fourth Int. Symp. Brain-Gut Interactions.
1998; 10: 363) report a trial in which children with delayed onset
autism were treated with vancomycin over an 8 week period. All
children in the trial had had antecedent broad-spectrum antibiotic
exposure, followed by chronic persistent diarrhoea and then onset
of autistic features. Although significant post-treatment
improvement was noted, all children eventually regressed towards
baseline.
[0014] It is on the background of these known facts and later the
results of trials of treatment, that the present invention was
formulated. In brief, it was noted that autistic children (as well
as related syndromes) who were referred for treatment of refractory
`irritable bowel syndrome` (IBS) viz diarrhoea, flatulence,
constipation, distension, abdominal pains etc--responded to
treatment of their IBS when treated with a novel mix of probiotics.
However, not only did their IBS improve dramatically but also their
autistic features progressively regressed. Even after the initial
2-6 weeks of treatment eye contact was re-established, repetitive
movements were much reduced, and word power (observed vocabulary)
expanded--initially 20 words and ultimately >600 words at 12
months (estimated), creating ability of the autistic children to
form long sentences. Continuing improvement was observed to occur
over 12 months of treatment. These observations (to a lesser but
definite degree at this stage of observations) also applied to
those with Rett syndrome and children with Attention
Deficit/Hyperactivity Disorder (ADHD), Attention Deficit Disorder
(ADD), and autism variant Asbergers syndrome. The observations
strongly suggest that the treatment of presumed enteric infection/s
(eg Clostridial) in these conditions not only improves the IBS
present but also the attendant neurological `para-infective`
phenomena called collectively autism, Asbergers, Rett syndrome, ADD
or ADHD.
[0015] The inclusion within this specification of reference to
published documents is not to be taken to be an admission that any
one or more of those documents, nor the disclosure of any one or
more of those documents, is part of the common general
knowledge.
Objects of the Invention
[0016] It is thus an object of the present invention to provide
novel pharmaceutical compositions suitable for the treatment of
various disease states related to the presence of `abnormal`
microflora in the gastrointestinal tract. It is a further object of
the invention to propose the use of these pharmaceutical
compositions in various disease states which have not previously
been considered to owe their causation to the presence of abnormal
flora in the gastrointestinal tract.
Disclosure of the Invention
[0017] The present invention recognises chronic
infection/infestation as the underlying pathological process in a
wide range of chronic disorders such as irritable bowel syndrome,
particularly when characterised by chronic abdominal pain,
bloating, or excessive flatulence, together with chronic diarrhoea
or alternating constipation/diarrhoea, and also in spastic colon,
mucous colitis, collagenous colitis, ulcerative colitis, Crohn's
colitis, microscopic colitis, idiopathic inflammatory bowel
disease, antibiotic-associated colitis, idiopathic or simple
constipation, diverticular disease and AIDS enteropathy.
[0018] The invention has also been found to relate to other
gastrointestinal disorders of unexplained aetiology such as
polyposis coli and colonic polyps, which may well be influenced by
the local bowel microflora.
[0019] In addition the present invention also provides a method of
treatment of chronic gastrointestinal infections with specific
microorganisms such as Clostridium difficile, Yersinia spp,
Campylobacter spp, Aeromonas spp, Escherichia coli, Cryptosporidium
spp, Amoebae, Blastocystitis hominis, Giardia and even chronic
viral infections, and of small bowel bacterial overgrowth.
[0020] The present invention furthermore, recognises the close
association between the intestine and liver disease, and the
intestine and migraines and chronic fatigue syndrome, and possibly
other neurological syndromes such as, multiple sclerosis,
amyotrophic lateral sclerosis, myasthenia gravis, Parkinson's
disease, Alzheimer's disease, Chronic Inflammatory Demyelinating
Polyneuropathy (CIDP), Guillain Barre Syndrome, and other
degenerative disorders. Hence, it is proposed that a considerable
proportion of currently unexplained diseases of the liver and
nervous system of unknown aetiology may be explicable by the
chronic growth of pathogens within the small/large intestine and
the subsequent passage of antigenic material, pathogenic toxins or
biological response modifiers (BRMs) into the portal system (liver
damage) or systemic circulation with antibody formation
(neurological conditions). Specifically, such hepato/biliary system
disorders as primary biliary cirrhosis, primary sclerosing
cholangitis, fatty liver of unknown aetiology, or cryptogenic
cirrhosis, may be secondary to chronic pathogen carrier state in
the intestine.
[0021] The links between the intestine and joint disease are also
recognised. Joint diseases such as rheumatoid arthritis, the
non-rheumatoid arthritidies including, ankylosing spondylitis, and
Reiter's syndrome, may also be causally related to a chronic
intestinal carrier state, as may other syndromes with an immune
mediated component such as glomerulonephritis, haemolytic uraemic
syndrome, juvenile diabetes mellitus, Behcet's syndrome, coeliac
disease and dermatitis herpetiformis. Similarly, syndromes with an
immune complex mediated component, such as scleroderma, systemic
lupus erythematosus, mixed cryoglobulinaemia, polyarteritis,
familial Mediterranean fever, amyloidosis, and the various
presentations of such syndromes, together with such "idiopathic"
states as chronic urticaria, may be manifestations of variations of
immune regulated responses to related bowel-origin pathogens
chronically shedding their antigen(s), toxins or biological
response modifiers into the circulation. Other chronic conditions
such as acne, and chronic idiopathic pseudo-obstructive syndrome,
may well be influenced by similar mechanisms.
[0022] For many of these syndromes present therapy offers only
palliation of symptoms and/or the induction of remission of the
disease process but not cure. The present inventor therefore
recognised the need to find a curative therapy for these wide
ranging disease processes associated with considerable
morbidity.
[0023] By judicious selection of the microorganisms of the
invention it has been surprisingly found by the present inventor
that lasting recolonisation of the gut microflora does not require
pretreatment to remove a portion of the host's existing enteric
microflora. Thus, by incorporation of Clostridia spp. in the
therapy, it has been surprisingly found that the prior art
requirement for removal of at least a portion of the existing
enteric microflora before administration of the substitute
microflora is rendered unnecessary. Without the addition
specifically of Clostridia species, the use of probiotic mixtures,
eg such as those of bacteroides and Escherichia coli failed to have
the necessary impact on the above-mentioned clinical disorders for
the treatment to be clinically useful.
[0024] It required a prior purging of the gut of its presumably
infected and abnormal bowel flora, re colonisation with bacteroides
and Escherichia coli--the main components of lower intestinal
tract, and ongoing feeding of patients with such bacteria until
colonisation was established. The use of Clostridia appears to be
the mainstay of this new therapy and the Clostridia appear to have
power of themselves to remove offending bacterial species which may
be responsible for the underlying condition (presumably pathogenic
clostridia--yet to be identified scientifically). Hence, the
combination of non-pathogenic clostridia together with the crucial
major colonic bacterial components of bacteroides and Escherichia
coli can now be used as oral therapy to crowd out/destroy/replace
and recolonise the dysbiotic flora of patients with various
gastrointestinal conditions which are caused by abnormal bowel
flora. In fact, such a therapy becoming available has permitted or
allowed greater understanding of the pathogenesis of many other
conditions which hitherto were thought to be caused by
degenerative, inflammatory, or auto immune mechanisms.
[0025] Thus according to a first embodiment of the invention there
is provided a pharmaceutical composition useful for the treatment
and/or prophylaxis of chronic disorders associated with the
presence in the gastrointestinal tract of a mammalian host of
abnormal or an abnormal distribution of microflora, which
composition comprises viable non-pathogenic or attenuated
pathogenic Clostridia.
[0026] Typically the composition includes Clostridia selected from
the group consisting of Clostridium absonum, Clostridium
argentinense, Clostridium baratii, Clostridium bifermentans,
Clostridium botulinum, Clostridium butyricum, Clostridium
cadaveris, Clostridium camis, Clostridium celatum, Clostridium
chauvoei, Clostridium clostridioforme, Clostridium cochlearium,
Clostridium difficile, Clostridium fallax, Clostridium felsineum,
Clostridium ghonii, Clostridium glycolicum, Clostridium
haemolyticum, Clostridium hastiforme, Clostridium histolyticum,
Clostridium indolis, Clostridium innocuum, Clostridium irregulare,
Clostridium limosum, Clostridium malenominatum, Clostridium novyi,
Clostridium oroticum, Clostridium paraputrificum, Clostridium
perfringens, Clostridium piliforme, Clostridium putrefaciens,
Clostridium putrificum, Clostridium ramosum, Clostridium
sardiniense, Clostridium sartagoforme, Clostridium scindens,
Clostridium septicum, Clostridium sordellii, Clostridium
sphenoides, Clostridium spiroforme, Clostridium sporogenes,
Clostridium subterminale, Clostridium symbiosum, Clostridium
tedium, Clostridium tetani, Clostridium welchii, Clostridium
villosum.
[0027] In a preferred form the composition further comprises one or
more additional viable non-pathogenic or attenuated pathogenic
microorganisms selected from the group consisting of Bacteroides,
Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic
cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas,
Peptostreptococcus, species and, more specifically, bacteria
selected from Table 1. Preferably fungi are also present such as
Monilia.
[0028] In a preferred form the composition comprises Clostridia,
Bacteroides, Peptostreptococcus, Escherichia coli, Bifidobacterium,
and Lactobacillus.
[0029] In a more preferred form the composition comprises
Clostridium innocuum, Clostridium bifermentans, Clostridium
butyricum, Bacteroides fragilis, Bacteroides thetaiotaomicron,
Bacteroides uniformis, one or more strains of Escherichia cog, and
one or more strains of Lactobacillus.
[0030] Alternatively, in a preferred form the composition comprises
Clostridium bifermentans, Clostridium innocuum, and Clostridium
butyricum in combination one or more strains of Escherichia coli,
one or more strains of bacteroides and Peptostreptococcus
productus.
[0031] According to a second embodiment of the invention there is
provided a pharmaceutical composition useful for the treatment
and/or prophylaxis of chronic disorders associated with the
presence in the gastrointestinal tract of a mammalian host of
abnormal or an abnormal distribution of microflora, which
composition comprises viable non-pathogenic or attenuated
pathogenic Escherichia coli, at least one strain of viable
non-pathogenic or attenuated pathogenic Bacteroides, and at least
one other viable non-pathogenic or attenuated pathogenic
microorganism.
[0032] In a preferred form the other viable non-pathogenic or
attenuated pathogenic microorganism is selected from the group
consisting of Clostridia, Peptostreptococcus, Bifidobacterium, and
Lactobacillus.
[0033] Typically the composition of the first or second embodiments
of the invention is derived from disease screened fresh homologous
faeces, equivalent freeze-dried and reconstituted faeces or a
"synthetic" faecal composition. The fresh homologous faeces does
not include an antibiotic resistant population.
[0034] Typically, the composition of the first or second
embodiments of the invention is a synthetic faecal composition.
[0035] In a preferred form the synthetic faecal composition
comprises a preparation of viable flora which preferably in
proportional content, resembles normal healthy human faecal flora
which does not include antibiotic resistant populations. Suitable
microorganisms may be selected from the following: Bacteroides,
Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic
cocci, Ruminococcus, Escherichia coli, Gemmiger, Clostridium,
Desulfomonas, Peptostreptococcus, Bifidobacterium, species and,
more specifically, bacteria selected from Table 1. Preferably fungi
are also present such as Monilia.
[0036] In a preferred form the composition of the first or second
embodiments of the invention comprises a liquid culture.
[0037] Preferably, the composition of the first or the second
embodiments of the present invention is lyophilised, pulverised and
powdered. It may then be infused, dissolved such as in saline, as
an enema.
[0038] Alternatively the powder may be encapsulated as
enteric-coated capsules for oral administration. These capsules may
take the form of enteric-coated microcapsules. As a powder it can
preferably be provided in a palatable form for reconstitution for
drinking or for reconstitution as a food additive. The composition
can be provided as a powder for sale in combination with a food or
drink. Typically, the food or drink is a dairy-based product or a
soy-based product. The invention therefore also includes a food or
food supplement containing a composition according to the first or
second embodiment. In a preferred form the food or food supplement
contains enteric-coated microcapsules of the composition of the
invention. In a preferred form the food is yogurt.
[0039] The powder may be reconstituted also to be infused via
naso-duodenal infusion.
[0040] The composition can be combined with other adjuvants such as
antacids to dampen bacterial inactivation in the stomach., eg
Mylanta, Mucaine, Gastrogel. Acid secretion in the stomach could
also be pharmacologically suppressed using H2-antagonists or proton
pump inhibitors. Typically, the H2-antagonist is ranitidine.
Typically the proton pump inhibitor is omeprazole.
[0041] The composition of the first or second embodiments of the
invention is therefore preferably in the form of: [0042] an enema
composition which can be reconstituted with an appropriate diluent,
or [0043] enteric-coated capsules, or [0044] enteric-coated
microcapsules, or [0045] powder for reconstitution with an
appropriate diluent for naso-enteric infusion or colonoscopic
infusion, or [0046] powder for reconstitution with appropriate
diluent, flavouring and gastric acid suppression agent for oral
ingestion, or [0047] powder for reconstitution with food or drink,
or [0048] food or food supplement comprising enteric-coated
microcapsules of the composition, powder, jelly, or liquid.
[0049] According to a third embodiment of the invention there is
provided a method for the treatment and/or prophylaxis of a chronic
disorder associated with the presence in the gastrointestinal tract
of a mammalian host of abnormal or an abnormal distribution of
microflora, which method comprises administering an effective
amount of a composition according to the first or second embodiment
of the invention.
[0050] In its preferred form the treatment should effect a cure of
the symptoms of such disorders. The change of flora is preferably
as "near-complete" as possible and the flora is replaced by viable
organisms which will crowd out any remaining, original flora.
[0051] The method of the present invention is applicable to animals
in general, in particular humans and economically significant
domestic animals.
[0052] In the case of humans, the present invention encompasses
methods of treatment of chronic disorders associated with the
presence of abnormal enteric microflora. Such disorders include but
are not limited to those conditions in the following categories:
[0053] gastro-intestinal disorders including irritable bowel
syndrome or spastic colon, functional bowel disease (FBD),
including constipation predominant FBD, pain predominant FBD, upper
abdominal FBD, non-ulcer dyspepsia (NUD), gastro-oesophageal
reflux, inflammatory bowel disease including Crohn's disease,
ulcerative colitis, indeterminate colitis, collagenous colitis,
microscopic colitis, chronic Clostridium difficile infection,
pseudomembranous colitis, mucous colitis, antibiotic associated
colitis, idiopathic or simple constipation, diverticular disease,
AIDS enteropathy, small bowel bacterial overgrowth, coeliac
disease, polyposis coli, colonic polyps, chronic idiopathic pseudo
obstructive syndrome; [0054] chronic gut infections with specific
pathogens including bacteria, viruses, fungi and protozoa; [0055]
viral gastrointestinal disorders, including viral gastroenteritis,
Norwalk viral gastroenteritis, rotavirus gastroenteritis, AIDS
related gastroenteritis; [0056] liver disorders such as primary
biliary cirrhosis, primary sclerosing cholangitis, fatty liver or
cryptogenic cirrhosis; [0057] rheumatic disorders such as
rheumatoid arthritis, non-rheumatoid arthritidies, non rheumatoid
factor positive arthritis, ankylosing spondylitis, Lyme disease,
and Reiter's syndrome; [0058] immune mediated disorders such as
glomerulonephritis, haemolytic uraemic syndrome, juvenile diabetes
mellitus, mixed cryoglobulinaemia, polyarteritis, familial
Mediterranean fever, amyloidosis, scleroderma, systemic lupus
erythematosus, and Behcets syndrome; [0059] autoimmune disorders
including systemic lupus, idiopathic thrombocytopenic purpura,
Sjogren's syndrome, haemolytic uremic syndrome or scleroderma;
[0060] neurological syndromes such as chronic fatigue syndrome,
migraine, multiple sclerosis, amyotrophic lateral sclerosis,
myasthenia gravis, Gillain-Barre syndrome, Parkinson's disease,
Alzheimer's disease, Chronic Inflammatory Demyelinating
Polyneuropathy, and other degenerative disorders; [0061]
psychiatric disorders including chronic depression, schizophrenia,
psychotic disorders, manic depressive illness; [0062] regressive
disorders including Asbergers syndrome, Rett syndrome, attention
deficit hyperactivity disorder (ADHD), and attention deficit
disorder (ADD); [0063] the regressive disorder, autism; [0064]
sudden infant death syndrome (SIDS), anorexia nervosa; [0065]
dermatological conditions such as, chronic urticaria, acne,
dermatitis herpetiformis and vasculitic disorders.
[0066] The above disorders are all characterised by their response
to treatment with the method of the present invention.
[0067] Typically the change in enteric flora comprises introduction
of an array of predetermined flora into the gastro-intestinal
system, and thus in a preferred form the method of treatment
comprises substantially completely displacing pathogenic enteric
flora in patients requiring such treatment.
[0068] Furthermore, in some of these disorders a short course of
antibiotics prior to probiotic treatment may be preferred to rid
tissue-invasive pathogens originating in the bowel lumen. For
example, in Crohn's disease, anti-tuberculosis therapy may be
required for six to twelve weeks before the bowel is cleared out
and the flora content exchanged for a predetermined flora.
[0069] Typically the antibiotic is an anti-Clostridial antibiotic
such as vancomycin, rifampicin, and nitroimidazole or
chloramphenicol. Typically the nitroimidazole is metronidazole.
[0070] In a preferred form of the invention, the method of
treatment or prophylaxis further includes administration of at
least one acid suppressant prior to administering, or in
co-administration with, the composition of the invention.
[0071] In a preferred form of the invention the method of treatment
or prophylaxis further includes nasogastric and/or nasoduodenal
washout prior to administering said composition.
[0072] The introduction of the composition into the
gastro-intestinal system can be effected by enema or
per-colonoscope, via intubation of the small bowel using for
example a large bore catheter equipped with distal balloon to
effect rapid passage down the jejunum, or via the oral route with
enteric-coated capsules, including enteric-coated microcapsules, or
via the oral route with a supplemented food or drink.
[0073] In a preferred form the supplemented food or drink is a
dairy-based or soy-based product. Typically the supplemented food
product is yogurt.
[0074] According to the method of the invention each dose of the
composition is in the range of about 10.sup.3 cells to about
10.sup.13 cells. Preferably each dose is in the range of about
10.sup.5 cells to about 10.sup.11 cells. More preferably each dose
is in the range of about 10.sup.9 cells to about 10.sup.11 cells.
In a preferred form of the invention an initial treatment regimen
consisting of about 10.sup.10 cells per dose is administered about
3 to 6 times per day for a period sufficient to stabilise the gut
flora. According to the method of the invention the treatment
regimen may then comprise a maintenance dose of about 10.sup.10
cells per day.
[0075] Furthermore the present invention also relates to the
treatment of animals, in particular to the treatment of
gastrointestinal disorders in economically important domestic
animals, such as cattle, sheep, horses, pigs, goats etc. The method
of the present invention has been found to be especially useful in
the treatment of the various forms of necrotising enterocolitis
which can be a major problem in animal stocks.
[0076] Obviously in the treatment of animals the appropriate
composition of microflora will vary according to the species being
treated and the constituent normal flora known to inhabit the gut.
Thus the composition according to the invention would comprise, a
preparation of viable flora which preferably in proportional
content, resembles the normal healthy faecal flora of the species
involved. The compositions may be prepared in any of the forms
already described and administered accordingly.
Best Method of Performing the Invention
[0077] In the practice of the invention a synthetic faecal
composition of predetermined flora in the form of a liquid or dry
powdered culture of Clostridia, Bacteroides, Peptostreptococcus,
Escherichia coil, Bifidobacterium, and Lactobacillus, which
composition does not include antibiotic resistant populations, is
prepared as a liquid culture.
[0078] Typically the method of the invention is applicable to a
patient suffering from a chronic disorder associated with the
presence of abnormal microflora in the gastrointestinal tract such
as irritable bowel syndrome.
[0079] In the practice of the invention a composition of
predetermined flora in the form of a liquid culture of Clostridia,
Bacteroides, Peptostreptococcus, Escherichia coli, Bifidobacterium,
and Lactobacillus is ingested by the patient in an amount
sufficient to replace and recolonise the dysbiotic flora of the
gastrointestinal tract, and reverse the disease process.
Alternatively fresh homologous faeces obtained from a disease
screened donor are liquefied and mixed with unprocessed bran. The
mixture is then homogenised anaerobically under CO.sub.2 cover and
infused into the patient per colonoscope.
[0080] Cure or remission of symptoms is then monitored subjectively
and by assessment of stool frequency or other appropriate
criteria.
[0081] Using liquid cultures of Clostridia, Bacteroides,
Peptostreptococcus, Escherichia coli, Bifidobacterium, and
Lactobacillus the inventor has achieved total reversal of colitis,
irritable bowel syndrome and constipation.
[0082] As indicated in the method of treatment aspect of the
invention, a preparatory course of appropriate antibiotics may be
used. For example, Septrin for chronic yersiniasis, Metronidazole
for ulcerative colitis, anti-TB therapy in Crohn's disease, or
Vancomycin in chronic Clostridium difficile infestations.
TABLE-US-00001 TABLE 1 % of flora.sup.b Organism(s) 11.8(0.90)
Bacteroides fragilis ss. Vulgatus 9.9(0.83) Eubacterium aerofaciens
8.9(0.78) Bacteroides fragilis ss. Thetaiotaomicron 6.6(0.68)
Peptostreptococcus productus II 6.0(0.64) Bacteroides fragilis ss.
Distasonis 4.4(0.55) Fusobacterium prausnitzii 3.5(0.49)
Coprococcus eutactus 3.0(0.45) Eubacterium aerofaciens III
2.8(0.44) Peptostreptococcus productus I 2.7(0.43) Ruminococcus
bronii 2.6(0.43) Bifidobacterium adolescentis 2.2(0.39) Gemmiger
formicilis, Bifidobacterium longum 2.1(0.38) Eubacterium siraeum
1.8(0.35) Ruminococcus torques 1.7(0.34) Eubacterium rectale III-H
1.6(0.33) Eubacterium rectale IV, Eubacterium eligens 1.5(0.32)
Bacteroides eggerthii 1.4(0.31) Clostridium leptum 1.3(0.29)
Bacteroides fragilis ss. A 1.2(0.29) Eubacterium biforme 0.91(0.25)
Bifidobacterium infantis 0.84(0.24) Eubacterium rectale III-F
0.57(0.20) Coprococcus comes, Bacteroides capillosus 0.50(0.18)
Ruminococcus albus, Eubacterium formicigenerans, Eubacterium
hallii, Eubacterium ventriosum I, Fusobacterium russii 0.43(0.17)
Ruminococcus obeum, Eubacterium rectale II, Clostridium ramosum I,
Lactobacillus leichmanfi 0.36(0.16) Ruminococcus cailidus,
Butyrivibrio crossotus 0.30(0.14) Acidaminococcus fermentans,
Eubacterium ventriosum, Bacteroides fragilis ss. fragilis,
Bacteroides AR 0.23(0.12) Coprococcus catus, Eubacterium hadrum,
Eubacterium cylindroides, Eubacterium ruminantium, Eubacterium
CH-1, Staphylococcus epidermidis 0.17(0.10) Peptostreptococcus BL,
Eubacterium limosum, Bacteroides praeacutus, Bacteroides L,
Fusobacterium mortiferum I, Fusobacterium naviforme, Clostridium
innocuum, Clostridium ramosum, Propionibacterium acnes,
Ruminococcus flavefaciens 0.10(0.08) Ruminococcus AT, Peptococcus
AU-1, Eubacterium AG, -AK, -AL, -AL-1, -AN; Bacteroides fragilis
ss. ovatus, -ss. d, -ss. f; Bacteroides L-1, L-5; Fusobacterium
nucleatum, Fusobacterium mortiferum, Escherichia coli,
Streptococcus morbiliorum 0.05(0.05) Peptococcus magnus,
Peptococcus G, -AU-2; Streptococcus intermedius, Ruminococcus
lactaris, Ruminococcus CO Gemmiger X, Coprococcus BH, -CC;
Eubacterium tenue, Eubacterium ramulus, Eubacterium AE, -AG-H,
-AG-M, -AJ, -BN-1; Bacteroides clostridfiformis ss.
clostridliformis, Bacteroides coagulans, Bacteroides orails,
Bacteroides ruminicola ss. brevis, -ss. ruminicola, Bacteroides
splanchnlcus, Desuifomonas pigra, Bacteroides L-4, -N-i;
Fusobacterium H, Lactobacillus G, Succinivibrio A .sup.bThe
percentage of the faecal population (the standard deviation of the
estimate is given in parentheses).
[0083] The invention will now be further described with reference
to the following non-limiting examples.
EXAMPLES
Formulations
[0084] The probiotic therapeutic agents may be prepared in liquid
culture anaerobically or aerobically (depending on bacterium
cultured) in pure form. Alternatively the probiotics may be
cultured on solid media and scraped into a liquid carrier. The
resulting product may be spray-dried into a powder form and
encapsulated or combined with excipients to be delivered in
sachets.
[0085] Combinations of Clostridia, Escherichia coli, Bacteroides,
and Peptostreptococcus with or without Lactobacilli, Bifidobacteria
and Eubacteria may be used in varying disorders.
Example No 1
43 Year Old Female
[0086] Patient with long standing constipation not responsive to
high-dose fibre usage together with prokinetics and standard
anti-constipation treatments, was treated with increasing doses of
orally administered bacterial mix (mixture composition included
Clostridium innocuum, bifermentans, butyricum, together with
Bacteroides fragilis, thetaiotaomicron and uniformis. Three strains
of Escherichia coli were also included, as was Lactobacillus). This
was ingested twice daily in the first two weeks and then daily
thereafter. The patient was not given any pre-treatment purgative
nor any antibiotics. However, she did take Ranitidine (an acid
suppressant) three hours prior to ingestion of the bacterial mix.
Two weeks after commencing the treatment the patient's
constipation--which would prevent her from defecating for up to
four days--reversed to increased frequency with reduction of
bloating. Initially, gas production increased and there was
burbulance and gurgling in the abdomen but after four weeks of
treatment the patient was defecating on a daily basis with no
sensation of incomplete emptying and an almost total absence of
bloating. Following the treatment she remained virtually normal,
defecating on a daily basis with 3 month follow up.
Example No 2
41/2 Year Old Male
[0087] Patient with 3 year history of diagnosis of autism
associated with Irritable Bowel Syndrome characterised by
constipation alternating with diarrhoea and flatulence, with foul
motions, was treated with oral administration of bacterial mix
consisting of Clostridium bifermentans, Clostridium innocuum, and
Clostridium butyricum in combination with three strains of
Escherichia coli, three strains of bacteroides and
Peptostreptococcus productus. These were ingested following acid
suppression with Ranitidine and were at first taken 3 times daily,
reducing to twice daily and then once daily maintenance for eight
weeks. The patient's autistic symptoms were reversed quite
dramatically with word power increasing from 20 to 200 words
(counted by teacher at special `autistic` school), he began to
sleep through the night, and his IBS-type symptoms reverted to
near-normality with less constipation, less diarrhoea and less foul
flatulence. He developed eye contact, was able to speak sentences
up to six words constructed to commands and he began to look, to
the untrained eye, as a relatively normal child by about week
10.
Example 3
Male Child, 51/2Years Old
[0088] Male child, 51/2 years of age with autism symptoms dating
back to age of around 15 months--but diagnosed significantly later.
The patient presented initially with gastrointestinal symptoms in
association with classical autism--for treatment of the bowel
symptoms. Although stool test did not indicate any specific
pathogen the bowel symptoms resembled those of a chronic infection
or adult Irritable Bowel Syndrome (IBS), ie intermittent diarrhoea,
constipation, cramping, colicky pain, inability to sleep at night,
occasional explosive diarrhoea and incontinence. The patient was
treated with orthostatic lavage using sodium pico-sulfate followed
by water to produce voluminous diarrhoea and to flush out the
enteric contents. He was then given 125 mg Vancomycin three times
daily orally followed by oral re-colonisation with bacteria at a
concentration of 10.sup.9 through to 10.sup.10, suspended in
yoghurt--of strains which included bacteroides, Escherichia coli,
and non pathogenic Clostridia--including Clostridium innocuum,
bifermentans and ramosum. The response was quite noticeable, in the
reversal of the abnormal stool function towards normality. The
patient was also able to sleep through the night without any
explosive diarrhoea and produced formed stools within five days of
commencing the bacterial therapy. While the bacteriotherapy was
continued the bowel symptoms were well controlled. Within 3-4 weeks
of missing out the treatment for a week or two some of the symptoms
would begin to recur. This suggested that the abnormal bacterial
flora was suppressed rather than being cured with this treatment in
this patient. The unexpected finding however, was a noticeable and
marked reversal of symptoms of autism. Whereas previously
repetitive movements were present with lack of eye contact, eye
contact returned fairly rapidly together with cessation of
repetitive movement and progressive increase of word power from
around 20 words to around 600 words by the sixth month of
treatment. The therapy continues now for more than 12 months with
sustained reversal of autism and IBS symptoms.
Example 4
Male Child, 7 Years Old
[0089] A seven year old male patient was referred for treatment
initially of bowel problems. He had developed autism between age 1
and 2 years characterised by lack of eye contact, repetitive
movements, poorly developed cognitive abilities, vocabulary of
fewer than 20 words The marked bowel symptoms were characterised by
either constipation or large voluminous motions, sometimes
diarrhoea and explosive stools. Stool examination was negative.
[0090] The patient was given a pre-treatment of Vancomycin 125 mg
twice daily and at one week he was given an orthostatic lavage
consisting of picosulfate preparation which flushed out his bowel.
He was then given twice daily oral bacteriotherapy consisting of
cultures containing living probiotics. These included several
bacteroides species, Escherichia coli and non-pathogenic Clostridia
such as Clostridium butyricum, Clostridium bifermentans and
Clostridium innocuum. Within two weeks the bowel symptoms reversed
to normal defecation with soft, formed stool--once or twice per
day. Constipation disappeared, eye contact returned over the next
six weeks and vocabulary and word use quite dramatically improved,
to everyone's surprise. When followed for eight months over 600
words could be counted in the vocabulary with sentences of up to
eight words being constructed where previously this was not
possible. Some abstract thinking was noted by teachers at the
special autism school. Parents in particular noted reduced
aggression, greater co-operation, and general increasing ability to
develop a more normal relationship with the child. Repetitive
action also disappeared.
Example 5
Male Child, 6 Years Old
[0091] A male patient aged 6 was referred to the clinic for
treatment of chronic diarrhoea and at times incontinence. The child
had been autistic since the age of one year and three months. The
diagnosis however was delayed. He had slow cognitive development
and very limited vocabulary. There was virtually absent eye contact
and at times violent and explosive behaviour. The greatest problem
with management was that of control of defecation as the child
developed a fascination with the stools which would then be spread
over furniture and walls. This brought severe pressure upon the
family with respect to difficulty with management. Stool test was
collected and again was negative for any pathogen. The patient was
given Vancomycin 250 mg twice daily for 10 days after which a
polyethylene glycol orthostatic lavage achieved a large volume
flush of the bowel. He was then given twice daily oral
bacteriotherapy in a neutral yogurt as a carrier. Within one week
the bowel function returned to virtual normality. However, the
behavioural changes were just as rapid in reversing again
characterised by fairly rapid reduction in aggressiveness and
uncontrollable behaviour, sleeping through the night, increased eye
contact, and progressively increased word power. The behaviour of
spreading stools also disappeared, more as a behavioural change
than learnt phenomenon. The patient was continued on medications
for over a year and progressively improved in all parameters--at
times fluctuating in severity.
* * * * *