Patent Application
20240000869
The present disclosure relates to synbiotic composition, comprising probiotic bacterial strains and prebiotic fibres or oligosaccharides, for use in the amelioration, treatment, reductions of symptoms of a neuropsychiatric disorder and/or the reduction of side effects of a pharmacological treatment of a neuropsychiatric disorder.
During the last decades the importance of the gut microbiota for wellbeing and health has been intensively studied. New knowledge has resulted in a suggestion to view the gut microbiota as a new organ. Molecular genetic methods have revolutionized the insight into the composition of the microbiota and microbiota analysis has made it possible to include studies of the microbiota as part of many human intervention studies. One example where the microbiota has been shown to play an important role is on the gut-brain axis. The gut-brain axis is the bidirectional interaction between the gut and the central nervous system. Molecules of importance for this interaction are e.g. short chain fatty acids which can be produced by the gut microbiota.
Recent studies have reported that inflammatory condition often is linked to different diseases e.g. the metabolic syndrome and also to different neuropsychiatric conditions. Prevalence of inflammation in psychiatric disorders is estimated to 20-40%. Studies of the gut microbiota in humans with different neuropsychological conditions have been conducted recently and the studies shown that the microbiota is less diverse in those groups of individuals than in healthy individuals.
Currently, many neuropsychiatric conditions are treated with pharmacological substances. Such pharmacological treatments are often accompanied by several adverse effects. Thus, there is a need for alternative or complementary treatments of neuropsychiatric disorders/conditions.
According to a first aspect, the above and other objects of the invention are achieved, in full or at least in part by a composition as defined by claim 1. According to this claim, the above object is achieved by a synbiotic composition for use in the treatment of a neuropsychiatric disorder or for use in the amelioration and/or reduction of symptoms of a neuropsychiatric disorder and/or for use in the reduction of side effects of a pharmacological treatment of a neuropsychiatric disorder, wherein the synbiotic composition comprises at least two bacterial strains chosen from the group consisting of Lactobacillus plantarum, Lactobacillus paracasei, Pediococcus pentosaceus, Leuconostoc mesenteroides, and Bifidobacterium breve; and at least one dietary fiber chosen from the group consisting of inulin, pectin, beta-glucan, resistant starch, a galacto-oligosaccharide, an isomalto-oligosaccharide, and a rice fiber.
According to one embodiment, the Lactobacillus plantarum strain is Lactobacillus plantarum (LMG P-20606).
According to a second embodiment, the Lactobacillus paracasei strain is chosen from the group consisting of Lactobacillus paracasei (LMG P-17806), and Lactobacillus paracasei (LMG P-26118).
According to a further embodiment, the Pediococcus pentosaceus strain is Pediococcus pentosaceus (LMG P-20608); and/or the Leuconostoc mesenteroides strain is Leuconostoc mesenteroides (LMG P-20607); and/or the Bifidobacterium breve strain is Bifidobacterium breve (LMG-P-26117).
According to another embodiment, the composition comprises at least one Lactobacillus plantarum strain, preferably Lactobacillus plantarum (LMG P-20606), and at least one Lactobacillus paracasei strain, preferably Lactobacillus paracasei (LMG P-17806) or Lactobacillus paracasei (LMG P-26118).
According to one embodiment, the composition further comprises at least one Pediococcus pentosaceus strain, preferably Pediococcus pentosaceus (LMG P-20608).
According to another embodiment, the composition further comprises at least one Leuconostoc mesenteroides strain, preferably Leuconostoc mesenteroides (LMG P-20607).
According to a further embodiment, the composition further comprises at least one Bifidobacterium breve strain, preferably Bifidobacterium breve (LMG-P-26117).
According to yet another embodiment, the composition comprises Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806) or Lactobacillus paracasei (LMG P-26118), and Pediococcus pentosaceus (LMG P-20608).
According to one embodiment, the composition comprises inulin, pectin, beta-glucan and/or resistant starch.
According to another embodiment, the composition comprises resistant starch, a galacto-oligosaccharide, and/or an isomalto-oligosaccharide.
The composition may comprise a rice fiber.
The composition may comprises inulin, pectin, beta-glucan resistant starch and/or rice fibers.
According to one embodiment, the total amount of bacteria in one dose is 1×106 to 1×1013, such as 5×106 to 1×1013, such as 1×107 to 1×1013, such as 5×107 to 1×1013, such as 1×108 to 1×1013, such as 5×108 to 5×1012, especially 1×109 to 1×1012, such as 5×109 to 9×1011, such as 1×1010 to 8×1011, such as 5×1010 to 7×1011, such as 1×1011 to 6×1011, such as 3×1011 to 5×1011, such as 4×1011 CFUs.
According to a further embodiment, the total amount of fibers in one dose is between 0.1 to 20 g, such as 0.5 to 20 g, such as 1 to 20 g, such as 2 to 15 g, such as 2.5 to 12.5 g, such as 5 to 10 g, such as 6 to 8.5 g, such as 7.5 g.
According to one embodiment, the neuropsychiatric disorder is chosen from the group consisting of ADHD, ADD, Asperger's syndrome, autism, OCD, and borderline personality disorder.
According to another embodiment, the neuropsychiatric disorder is chosen from the group consisting of schizophrenia, depressive disorders, generalized anxiety disorder (GAD), and bipolar disorder.
According to yet another embodiment, the depressive disorder is chosen from the group consisting of major depression, persistent depressive disorder and seasonal affective disorder (SAD).
According to one embodiment, the synbiotic composition is administered orally or rectally or by tube feeding.
According to another embodiment, the synbiotic composition is administered 1 to 3 times a day, 1 to 7 times a week.
According to a further embodiment, the synbiotic composition is in the form of a powder, a capsule, a tablet, a lozenge, a liquid, an emulsion, an enema, a suppository, or a tube feeding.
According to another embodiment, the synbiotic composition is a food supplement, a food product, a nutritional supplement, a natural remedy or a pharmaceutical product.
The food product may be a biscuit, a cracker, a bar, a liquid, e.g. a shot.
The bacterial strains disclosed here in have previously been deposited with the Belgian Coordinated Collections of Micro-organisms (BCCM), Laboratorium voor Microbiologie Bacteriënverzameling (LMG), Universiteit Gent, K. L. Ledenganckstraat 35, 9000 Gent, Belgium (Web site: http://bccm.belspo.be).
Pediococcus pentosaceus (LMG P-20608), Lactobacillus plantarum (LMG P-20606), and Leuconostoc mesenteroides (LMG P-20607) were deposited on Jun. 19, 2001.
Lactobacillus paracasei (LMG P-17806) has been deposited with the Belgian Coordinated Collection of Microorganisms.
Lactobacillus paracasei (LMG P-26118) and Bifidobacterium breve (LMG P-26117) were deposited on Nov. 24, 2010.
Pediococcus pentosaceus (LMG P-20608), Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806) and Leuconostoc mesenteroides (LMG P-20607) have previously been published in EP 1 624 762 B1
Lactobacillus paracasei (LMG P-26118) and Bifidobacterium breve (LMG P-26117) have previously been published in EP 2 672 980 B1.
Other objectives, features and advantages of the present disclosure will appear from the following detailed description, from the experimental data, as well as from the attached claims. It is noted that the disclosure relates to all possible combinations of features.
Generally, all terms used in the claims are to be interpreted according to their ordinary meaning in the technical field, unless explicitly defined otherwise herein. All references to “a/an/the [component, means, step, etc.]” are to be interpreted openly as referring to at least one instance of said component, means, step, etc., unless explicitly stated otherwise. The steps of any method disclosed herein do not have to be performed in the exact order disclosed, unless explicitly stated.
As used herein, the term “comprising” and variations of that term are not intended to exclude other additives, components, integers or steps.
The gut with its microbiota has a key function to maintain immune homeostasis and approximately 70% of the immune system is estimated to be located in the gut.
Probiotics are defined as “a live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” (FAO/WHO 2002).
Fibres are an essential part of our diet. Fibres can be divided into different groups and the group called soluble fibre are important for the gut microbiota. A group of the soluble fibres and oligosaccharides are called prebiotics.
Prebiotics are defined as “a substrate that is selectively utilized by host microorganisms conferring a health benefit” (International Scientific Association for Probiotics and Prebiotics 2017). When prebiotics are fermented in the gut, short chain fatty acids can be produced. Examples of the short chain fatty acids are acetic acid, butyric acid, propionic acid, and formic acid. It is known that short chain fay acids influence health, e.g. butyric acid nourishes the gut mucosa and propionic acid influences fat metabolism.
Synbiotics is defined as “an ingredient or dietary supplement combining probiotics and prebiotics for a synergy between the compounds”.
The combination of strains presented herein and used in the studies and experiments were carefully selected to be optimal combination of strains for efficacy including bacterial survival and favourable influence on each other.
Different combinations of bacterial strains and fibers may be used in a composition according to the present disclosure. Different combinations of bacterial strains and different combinations of fibers are described below. Specific combinations of bacterial strains and fibers are shown in Table 1. However, the following is not to be interpreted as excluding other combinations of bacterial strains and fibers.
Throughout the present disclosure, specific bacterial strains are identified by their deposition number. Thus, “Lactobacillus plantarum (LMG P-20606)” can be denoted as “Lactobacillus plantarum (deposit no: LMG P-20606)” or “Lactobacillus plantarum LMG P-20606”, all meaning a strain of Lactobacillus plantarum having the deposition number “LMG P-20606”.
Compositions according to the present disclosure comprise at least two bacterial strains chosen from the group consisting of Lactobacillus plantarum, Lactobacillus paracasei, Pediococcus pentosaceus, Leuconostoc mesenteroides, Bifidobacterium breve.
The composition may comprise one Lactobacillus plantarum strain and one Lactobacillus paracasei strain.
The composition may comprise Lactobacillus plantarum (LMG P-20606) and Lactobacillus paracasei (LMG P-17806).
The composition may comprise Lactobacillus plantarum (LMG P-20606) and Lactobacillus paracasei (LMG P-26118).
The composition may comprise one Lactobacillus plantarum strain, one Lactobacillus paracasei strain and one Pediococcus pentosaceus strain.
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), and Pediococcus pentosaceus (LMG P-20608).
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-26118), and Pediococcus pentosaceus (LMG P-20608).
The composition may comprise one Lactobacillus plantarum strain, one Lactobacillus paracasei strain, one Pediococcus pentosaceus strain, and one Leuconostoc mesenteroides strain.
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608) and Leuconostoc mesenteroides (LMG P-20607).
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-26118), Pediococcus pentosaceus (LMG P-20608) and Leuconostoc mesenteroides (LMG P-20607).
The composition may comprise one Lactobacillus plantarum strain, one Lactobacillus paracasei strain, one Pediococcus pentosaceus strain, and one Bifidobacterium breve strain.
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608) and Bifidobacterium breve (LMG-P-26117).
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-26118), Pediococcus pentosaceus (LMG P-20608) and Bifidobacterium breve (LMG-P-26117).
The composition may comprise one Lactobacillus plantarum strain, one Lactobacillus paracasei strain, one Pediococcus pentosaceus strain, one Leuconostoc mesenteroides strain and one Bifidobacterium breve strain.
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608), Leuconostoc mesenteroides (LMG P-20607) and Bifidobacterium breve (LMG-P-26117).
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-26118), Pediococcus pentosaceus (LMG P-20608), Leuconostoc mesenteroides (LMG P-20607) and Bifidobacterium breve (LMG-P-26117).
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608). Preferably, the composition also comprises Leuconostoc mesenteroides (LMG P-20607) and/or Bifidobacterium breve (LMG-P-26117).
The composition may comprise Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-26118), Pediococcus pentosaceus (LMG P-20608). Preferably, the composition also comprises Leuconostoc mesenteroides (LMG P-20607) and/or Bifidobacterium breve (LMG-P-26117).
The composition may comprise Lactobacillus plantarum (LMG P-20606); Lactobacillus paracasei (LMG P-17806); Pediococcus pentosacceus (LMG P-20608); Leuconostoc mesenterioides (LMG P-20607); and Bifidobacterium breve (LMG P-26117).
The composition may comprise Lactobacillus plantarum (LMG P-20606); Lactobacillus paracasei (LMG P-26118); Pediococcus pentosacceus (LMG P-20608); Leuconostoc mesenterioides (LMG P-20607); and Bifidobacterium breve (LMG P-26117).
The composition may comprise Lactobacillus plantarum (LMG P-20606) and Lactobacillus paracasei (LMG P-17806).
The composition may comprise Lactobacillus plantarum (LMG P-20606) and Bifidobacterium breve (LMG P-26117).
Compositions according to the present disclosure comprise at least one fiber chosen from the group consisting of inulin, pectin, beta-glucan, resistant starch, a galacto-oligosaccharide, an isomalto-oligosaccharide, and a rice fiber.
The composition may comprise resistant starch.
The composition may comprise inulin, pectin, beta-glucan and resistant starch.
The composition may comprise inulin, pectin, beta-glucan, rice fiber and resistant starch.
The composition may comprise resistant starch and a galacto-oligosaccharide.
The composition may comprise resistant starch and an isomalto-oligosaccharide.
The composition may comprise resistant starch, galacto-oligosaccharide and isomalto-oligosaccharide.
A composition according to the present invention may be administered one to three times a day.
Some examples of compositions according to the present disclosure are shown in Table 1 below.
L.
L.
L.
P.
L.
plantarum
paracasei
paracasei
pentosaceus
mesenteroides
B. breve
A composition according to the present invention may be administered one to seven days a week.
Preferably, a composition according to the present invention is administered once a day as a single dose.
The total amount of bacteria in one dose of a composition according to the present disclosure is between 1×106 to 1×1013, such as 5×106 to 1×1013, such as 1×107 to 1×1013, such as 5×107 to 1×1013, such as 1×108 to 1×1013, such as 5×108 to 5×1012, especially 1×109 to 1×1012, such as 5×109 to 9×1011, such as 1×1010 to 8×1011, such as 5×1010 to 7×1011, such as 1×1011 to 6×1011, such as 3×1011 to 5×1011, such as 4×1011 CFUs (colony forming units).
The total amount of fibers in one dose of a composition according to the present disclosure is between 0.1 to 20 g, such as 0.5 to 20 g, such as 1 to 20 g, such as 2 to 15 g, such as 2.5 to 12.5 g, such as 5 to 10 g, such as 6 to 8.5 g, such as 7.5 g.
A composition according to the present disclosure may be in the form of a dry powder intended to be mixed with a liquid, preferably water, before intake.
A composition according to the present disclosure may be in the form of a capsule, a tablet, a lozenge, a liquid, an emulsion, an enema, a suppository, or a tube feeding.
Patients suffering from a neuropsychiatric disorder such as ADHD, ADD, Asperger's syndrome, autism, OCD, and borderline personality disorder, may be administered a composition according to the present disclosure in the form of a powder suspended in a liquid, preferably water, or in the form of a capsule, a tablet, a lozenge, a liquid, an emulsion, an enema, a suppository, or by tube feeding.
Patients suffering from a neuropsychiatric disorder such as schizophrenia, depressive disorders, generalized anxiety disorder (GAD), and bipolar disorder, may be administered a composition according to the present disclosure in the form of a powder suspended in a liquid, preferably water, or in the form of a capsule, a tablet, a lozenge, a liquid, an emulsion, an enema, a suppository, or by tube feeding.
ADHD (attention deficit hyperactivity disorder) usually debuts in childhood and the worldwide prevalence of ADHD is 3-5%. Core symptoms are inattention and hyperactivity impulsivity. The disorder shows a great heterogeneity regarding manifestation and successful treatment. A large proportion of ADHD patients have psychiatric conditions e.g. mood, anxiety, learning, tic, disorders, and also somatic disorders related to the immune disorders such as asthma, eczema, rhinitis and celiac disease.
The symptom(s) of ADHD that may be treated, ameliorated or reduced may be one or more of symptoms chosen from the group consisting of inattention, hyperactivity, difficulties in emotion regulation, perceived stress and obsessive compulsive disorder. Specifically, the symptom is inattention and/or hyperactivity.
ADD (attention deficit disorder) usually also debuts in childhood. The core symptom is inattention. The disorder shows a great heterogeneity regarding manifestation and successful treatment. A large proportion of ADD patients have psychiatric conditions e.g. mood, anxiety, learning, tic, disorders, and also somatic disorders related to the immune disorders such as asthma, eczema, rhinitis and celiac disease.
The symptom(s) of ADD that may be treated, ameliorated or reduced may be one or more of symptoms chosen from the group consisting of inattention, difficulties in emotion regulation, perceived stress and obsessive compulsive disorder. Specifically, the symptom is inattention.
OCD (obsessive compulsive disorder) is a chronic mental health condition characterized by obsessions (repetitive, unwanted thoughts) which lead to compulsive behaviors (irrational, excessive urges to do certain actions).
The symptom(s) of OCD that may be treated, ameliorated or reduced may be obsessions and/or compulsions.
The symptom(s) of Asperger's syndrome/autism that may be treated, ameliorated or reduced may be one or more of symptoms chosen from the group consisting of inattention, perceived stress and obsessive compulsive symptoms.
The symptom(s) of borderline personality disorder that may be treated, ameliorated or reduced may be one or more of symptoms chosen from the group consisting of difficulties in emotion regulation, perceived stress and obsessive compulsive symptoms.
The symptom(s) of schizophrenia that may be treated, ameliorated or reduced may be one or more of symptoms chosen from the group consisting of inattention, hyperactivity, difficulties in emotion regulation, perceived stress and obsessive compulsive.
The symptom(s) of depressive disorders that may be treated, ameliorated or reduced may be one or more of symptoms chosen from the group consisting of inattention, difficulties in emotion regulation and perceived stress.
The symptom(s) of generalized anxiety disorder that may be treated, ameliorated or reduced may be one or more of symptoms chosen from the group consisting of difficulties in emotion regulation and perceived stress.
The symptom(s) of bipolar disorder that may be treated, ameliorated or reduced may be one or more of symptoms chosen from the group consisting of hyperactivity, difficulties in emotion regulation and perceived stress.
One composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of ADHD, ADD, Asperger's syndrome, autism and/or borderline personality disorder comprises Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608). Preferably, the composition also comprises Leuconostoc mesenteroides (LMG P-20607) and/or Bifidobacterium breve (LMG-P-26117).
Another composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of ADHD, ADD, Asperger's syndrome, autism and/or borderline personality disorder comprises Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-26118), Pediococcus pentosaceus (LMG P-20608). Preferably, the composition also comprises Leuconostoc mesenteroides (LMG P-20607) and/or Bifidobacterium breve (LMG-P-26117).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of ADHD, ADD, Asperger's syndrome, autism and/or borderline personality disorder comprises Lactobacillus plantarum (LMG P-20606); Lactobacillus paracasei (LMG P-17806); Pediococcus pentosacceus (LMG P-20608); Leuconostoc mesenterioides (LMG P-20607); and Bifidobacterium breve (LMG P-26117).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of ADHD, ADD, Asperger's syndrome, autism and/or borderline personality disorder comprises Lactobacillus plantarum (LMG P-20606); Lactobacillus paracasei (LMG P-26118); Pediococcus pentosacceus (LMG P-20608); Leuconostoc mesenterioides (LMG P-20607); and Bifidobacterium breve (LMG P-26117).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of ADHD, ADD, Asperger's syndrome, autism and/or borderline personality disorder comprises Lactobacillus plantarum (LMG P-20606) and Lactobacillus paracasei (LMG P-17806).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of ADHD, ADD, Asperger's syndrome, autism and/or borderline personality disorder comprises Lactobacillus plantarum (LMG P-20606) and Bifidobacterium breve (LMG P-26117).
Compositions that are specifically suitable for the treatment, amelioration or reduction of symptoms of ADHD, ADD, Asperger's syndrome, autism and/or borderline personality disorder are Composition Nos. 19, 22, 37, 40, 47, 50 and 56 in Table 1.
One composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of depressive disorder and/or generalized anxiety disorder comprises Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608). Preferably, the composition also comprises Leuconostoc mesenteroides (LMG P-20607) and/or Bifidobacterium breve (LMG-P-26117).
Another composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of depressive disorder and/or generalized anxiety disorder comprises Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-26118), Pediococcus pentosaceus (LMG P-20608). Preferably, the composition also comprises Leuconostoc mesenteroides (LMG P-20607) and/or Bifidobacterium breve (LMG-P-26117).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of depressive disorder and/or generalized anxiety disorder comprises Lactobacillus plantarum (LMG P-20606); Lactobacillus paracasei (LMG P-17806); Pediococcus pentosacceus (LMG P-20608); Leuconostoc mesenterioides (LMG P-20607); and Bifidobacterium breve (LMG P-26117).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of depressive disorder and/or generalized anxiety disorder comprises Lactobacillus plantarum (LMG P-20606); Lactobacillus paracasei (LMG P-26118); Pediococcus pentosacceus
(LMG P-20608); Leuconostoc mesenterioides (LMG P-20607); and Bifidobacterium breve (LMG P-26117).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of ADHD, ADD, Asperger's syndrome, autism and/or borderline personality disorder comprises Lactobacillus plantarum (LMG P-20606) and Lactobacillus paracasei (LMG P-17806).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of depressive disorder and/or generalized anxiety disorder comprises Lactobacillus plantarum (LMG P-20606) and Bifidobacterium breve (LMG P-26117).
Compositions that are specifically suitable for the treatment, amelioration or reduction of symptoms of depressive disorder and/or generalized anxiety disorder are Composition Nos. 19, 22, 37, 40, 47, 50 and 56 in Table 1.
One composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of schizophrenia and/or bipolar disorder comprises Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608). Preferably, the composition also comprises Leuconostoc mesenteroides (LMG P-20607) and/or Bifidobacterium breve (LMG-P-26117).
Another composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of schizophrenia and/or bipolar disorder comprises Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-26118), Pediococcus pentosaceus (LMG P-20608). Preferably, the composition also comprises Leuconostoc mesenteroides (LMG P-20607) and/or Bifidobacterium breve (LMG-P-26117).
A further composition that is specifically suitable for the treatment of symptoms of schizophrenia and/or bipolar disorder comprises Lactobacillus plantarum (LMG P-20606); Lactobacillus paracasei (LMG P-17806); Pediococcus pentosacceus (LMG P-20608); Leuconostoc mesenterioides (LMG P-20607); and Bifidobacterium breve (LMG P-26117).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of schizophrenia and/or bipolar disorder comprises Lactobacillus plantarum (LMG P-20606); Lactobacillus paracasei (LMG P-26118); Pediococcus pentosacceus (LMG P-20608); Leuconostoc mesenterioides (LMG P-20607); and Bifidobacterium breve (LMG P-26117).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of schizophrenia and/or bipolar disorder comprises Lactobacillus plantarum (LMG P-20606) and Lactobacillus paracasei (LMG P-17806).
A further composition that is specifically suitable for the treatment, amelioration or reduction of symptoms of schizophrenia and/or bipolar disorder comprises Lactobacillus plantarum (LMG P-20606) and Bifidobacterium breve (LMG P-26117).
Compositions that are specifically suitable for the treatment, amelioration or reduction of symptoms of schizophrenia and/or bipolar disorder are Composition Nos. 19, 22, 37, 40, 47, 50 and 56 in Table 1.
Examples of areas where the microbiota has been shown to play an important role is on various immune functions including inflammation and on the gut-brain axis. The gut-brain axis is the bidirectional interaction between the gut and the central nervus system. Molecules of importance for this interaction are e.g. short chain fatty acids (SCFAs) which can be produced by the gut microbiota if a suitable substrate is available e.g. soluble fibres or oligosaccharides. The most abundant short chain fatty acids (SCFAs) in stool and body fluids are formic acid, acetic acid, propionic acid and butyric acid. SCFAs are multifunctional molecules, being e.g. an essential energy source for local intestinal cells, but also influencing barrier function, neurotransmitter release, microglial maturation and activation, neural proliferation, mitochondrial function, oxidative stress, immune-modulation, and anti-inflammatory processes. SCFAs can regulate brain function and behavior via a number of potential mechanisms and dysregulation of these pathways may contribute to autism and related disorders. Butyric acid, formic acid, acetic acid and propionic acid have previously been reported to have anti-inflammatory effects. SCFAs regulate several leukocyte functions including production of cytokines eicosanoids and chemokines.
Different immune markers have previously been studied in neuropsychiatric disorders. IL-12/IL-23p40 has been shown to be elevated in patients with schizophrenia. Thus, reducing the expression of IL-12/IL-23p40 is anticipated to have an effect on the clinical manifestation of this disease.
VCAM-1 is a cell surface glycoprotein expressed on e.g. endothelial cells and immune cells such as macrophages and dendritic cells. VCAM-1 was originally identified as a cell adhesion molecule that helps to regulate inflammation-associated vascular adhesion and the transendothelial migration of leukocytes, such as macrophages and T cells. Recent evidence suggests that VCAM-1 is closely associated with the progression of various immunological disorders.
ICAM-1 has been shown to be elevated in several neuropsychiatric disorders, e.g. ADHD, autism, Asperger's syndrome and borderline personality disorder, schizophrenia, depressive disorders, generalized anxiety disorder (GAD), and bipolar disorder. Thus, reducing the expression of ICAM-1 is anticipated to have an effect on the clinical manifestation of these diseases.
In the experiments described below, the effect of a composition (corresponding to Composition No. 4) on the leves of i.a. IL-12/IL-23p40, ICAM-1, and SCFAs has been studied.
The levels of selected immunological markers and short chain fatty acids were measured in blood samples from healthy individuals (n=57) and individuals diagnosed with ADHD (n=154, 8-55 years old, both men and women). A variety of immune activity markers of which some also are virus receptors were analysed.
As can be seen in Table 2, individuals diagnosed with ADHD have significantly (p<0.005) lower expression of IL-10 (an anti-inflammatory marker) and significantly (p<0.005) higher expression of the inflammatory markers sICAM-1 and sVACM-1.
This clearly demonstrate that individuals diagnosed with ADHD express an inflammatory pattern regarding immune markers, and especially ICAM-1, which previously has been shown to be elevated in several neuropsychiatric disorders, e.g. ADHD, autism, Asperger's syndrome and borderline personality disorder, schizophrenia, depressive disorders, generalized anxiety disorder (GAD), and bipolar disorder.
Formic and propionic acids (short chain fatty acids) were lower in the individuals diagnosed with ADHD compared to the control group of 57 healthy individuals. Short chain fatty acids in plasma correlated positively with IL-10, i.e. individuals with a low level of short chain fatty acids also had a low level of the anti-inflammatory cytokine IL-10. This was seen both in children and in adults (data not shown).
A human intervention study was performed in a group of individuals (n=49, children, both boys and girls) diagnosed with ADHD. The effect of a synbiotic composition according to the present disclosure on plasma levels of immune markers and short fatty acids in children diagnosed with ADHD was investigated. The synbiotic composition included Lactobacillus plantarum LMG P-20606, Lactobacillus paracasei LMG P-26118, Pediococcus pentosaceus LMG P-20608 and the fibres inulin, pectin, resistant starch and beta-glucan. The total amount of bacteria was 4×1011 and the total amount of fibres was 10 g. The individuals diagnosed with ADHD were randomized into one group (n=28) receiving the synbiotic composition according to the present disclosure and one group (n=21) receiving a maltodextrin placebo. The synbiotic composition according to the present disclosure was consumed once daily for nine weeks. Immune markers were analysed in plasma at start of the study (T=0) and after nine weeks of intervention (T=9).
After 9 weeks, children receiving the synbiotic composition according to the present disclosure had a significantly (p<0.05) reduced level of the inflammatory marker IL-12/IL-23p40, sICAM and transforming growth factor β3 (TGF-β3) in plasma compared to the levels at start of the intervention study (Table 3).
The results clearly show that the synbiotic composition according to the present disclosure lowered the expression of IL-12/IL-23p40, sICAM and TGF-β3 which all are inflammatory marker. IL-12/IL-23p40 is a target for drugs against inflammatory diseases, such as Crohn's disease and ICAM has been shown to be to be elevated in several neuropsychiatric disorders, e.g. ADHD, autism, Asperger's syndrome and borderline personality disorder, schizophrenia, depressive disorders, generalized anxiety disorder (GAD), and bipolar disorder.
A human intervention study was performed in a group of individuals (n=49, children, both boys and girls) diagnosed with ADHD as described above. The synbiotic composition increased the levels of propionic and acetic acid, which correlated negatively to the levels of sICAM-1 and sVCAM-1, i.e. the proinflammatory markers were high when the short chain fatty acid level was low (data not shown). Thus, treatment with the synbiotic composition according to the present disclosure is associated with lower vascular inflammation. The results clearly show that the level of short chain fatty acids is associated to the level of immune markers, and with low levels of short chain fatty acids associated to a pro-inflammatory pattern of the immune markers. In the study it was also clear that the synbiotic composition increased the plasma level of short chain fatty acids which will stimulate a low inflammation. A low degree of inflammation is important for a healthy functioning of the gut-brain axis including neuropsychological conditions such as ADHD.
To investigate the effect of a synbiotic composition according to the present disclosure (corresponding to Composition No. 19) on reducing impulsive, compulsive, and aggressive behaviors in a sample of highly impulsive adults with a diagnosis of attention-deficit/hyperactivity disorder (ADHD) and/or borderline personality disorder (BPD), a 10-week multicenter, prospective, randomized, double-blind, placebo-controlled, parallel design study was performed. The composition comprised Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608), and Leuconostoc mesenteroides (LMG P-20607) (total amount of bacteria 4×1011 CFU/dose). Each dose further comprised inulin, pectin, resistant starch, betaglucan (total amount of fibers per dose: 10 g). The study was performed in close cooperation between three European clinical centers: Goethe University Hospital Frankfurt, Frankfurt, Germany; Vall d'Hebron Research Institute, Barcelona, Spain; and Semmelweis University, Budapest, Hungary.
Participants: Participants were eligible for participation in the study if they met all the inclusion criteria and none of the exclusion criteria listed below. Participants were randomized to the experimental (EG) or the control (CG) group in a 1:1 allocation ratio (60 to 90 participants per group) using an independent web-based computerized service (www.randomization.com). Each individual received a “treatment kit” containing all required daily synbiotic or placebo envelope for the 10-week trial prepared in advance by sequentially numbering and labeled as “A” or “B.” To secure bacterial viability, participants were asked to the envelopes at +4-6° C. Participants were asked to continue with their previous medications and/or usual treatments and add the synbiotic or placebo once daily on top of cold foods such as yogurt, muesli, or salad.
Inclusion criteria: Both males and females aged 18-65 years; A high level of multidimensional impulsivity based on both a Clinical Global Impression-Severity Scale; (CGI-S) score ≥4 and an Affective Reactivity Index (ARI) ≥5; DSM-5 criteria for attention deficit/hyperactivity disorder (ADHD) and/or borderline personality disorder (BPD) confirmed by a structured diagnostic interview (ADHD: Diagnostic Interview for Adult ADHD [DIVA 2.0]; BPD: Structured Clinical Interview for DSM-IV [SCID-II]); Deemed reliable and compliant with the protocol by the investigator; Ability to speak and comprehend the native language of the country in which the assessments take place; Informed consent signed.
Exclusion criteria: Antibiotherapy within the last 6 weeks prior to study; Currently taking probiotics; Presence of a major psychiatric disorder with psychotic symptoms or other major psychiatric conditions requiring hospitalization (e.g., significant mood disorders); Neurological disorders involving central functions (e.g., epilepsy, multiple sclerosis, narcolepsy); Intelligence quotient (IQ) <70 (measured by WAIS, if available); Major physical illnesses of the cardiovascular, endocrine, pulmonal, immune, or gastrointestinal system or undergoing immunosuppression; History of/present clinically relevant somatic acute or chronic disorders that, in the opinion of the investigator, might confound the results of tolerability/safety assessments or prohibit the patient from completing the study or would not be in the best interest of the patient; Documented allergy, hypersensitivity, or intolerance to any of the ingredients of the intervention; Subject has taken another investigational product or taken part in a clinical study within 30 days prior to entering the study.
Synbiotic composition: Each dose (powder-containing sachet) of the synbiotic composition contained 100 billion of each of Pediococcus pentosaceus (LMG P-20608), Lactobacillus paracasei (LMG P-17806), Lactobacillus plantarum (LMG P-20606), and Leuconostoc mesenteroides (LMG P-20607), in combination with four bioactive fermentable fibers (2.5 g each of β-glucan, inulin, pectin, and resistant starch). This composition corresponds to composition No. 19 in Table 1.
Placebo composition: The placebo was composed of the polysaccharide maltodextrin and had a texture and flavor similar to the synbiotic composition.
Outcomes were assessed at the start of the study (TS), after 5 weeks (T1) and after 10 weeks (T2).
Repeated measures ANCOVA with the factors Diagnosis (ADHD/BPD/ADHD+BPD) and Treatment group (Active/Placebo) and their interaction.
The results of this study is shown in
ADHD RS (Attention-Deficit/Hyperactivity Disorder Rating Scale): The ADHD-RS provides not only a total ADHD score (
Total score: There was a dramatic decrease of ADHD symptoms [total score] (see
Inattention: There was also a decrease of inattention (see
Hyperactivity: There was also a decrease of hyperactivity (see
Impulsivity: No statistically significant decrease of impulsivity was observed in the group receiving the synbiotic composition (open circles; N=90 [56 ADHD; 23 BPD; 11 ADHD+BPD]) compared to the placebo group (filled circles; N=88 [56 ADHD; 20 BPD, 12 ADHD+BPD]). (Data not shown.)
Conclusion: Taken together, these results demonstrate that a synbiotic composition according to the present disclosure decreases at least inattention and hyperactivity. These symptoms are present in ADHD, but also in borderline personality disorder. ADHD or BDPD are often seen in patients with other disorders such as Asperger's syndrome, autism, borderline personality disorder, schizophrenia, depressive disorders, generalized anxiety disorder (GAD), and bipolar disorder.
DERS (Difficulties in Emotion Regulation Scale): DERS is a widely used self-report measure of subjective emotion ability, and is often used in treatment and research settings for adults with emotional (i.e., anxiety, mood, obsessive-compulsive, or trauma-related) disorders. Difficulties with emotion regulation are central to borderline personality disorder (BPD) and these difficulties are generally considered as difficult to treat with conventional medication,
Total score: There was a decrease of DERS [total score] (see
Conclusion: These results demonstrate that a synbiotic composition according to the present disclosure decreases at least inattention and hyperactivity. These symptoms are present in ADHD, but also in borderline personality disorder and in autism, ADHD or BDPD are often seen in patients with other disorders such as Asperger's syndrome, autism, borderline personality disorder, schizophrenia, depressive disorders, generalized anxiety disorder (GAD), and bipolar disorder.
PSS (Perceived stress scale): The Perceived Stress Scale (PSS) is the most widely used psychological instrument for measuring the perception of stress. It is a measure of the degree to which situations in one's life are appraised as stressful.
Total score: There was also a decrease of perceived stress (see
Y-BOCS (Yale-Brown Obsessive Compulsive Scale): Y-BOCS is a 10-item scale designed to measure the severity and type of symptoms in people with obsessive-compulsive disorder (OCD) over the past seven days. The symptoms assessed are obsessions and compulsions. Y-BOCS is regarded as the “gold standard” in assessing the severity of OCD symptoms and is widely used when tracking OCD symptoms at intake and during/after treatment.
ADHD/ADD: As shown above, symptoms associated ADHD, such as inattention, hyperactivity, difficulties in emotion regulation, perceived stress and obsessive compulsive behavior, can be affected by the intake of a composition according to the present disclosure. Thus, it is plausible that a synbiotic composition according to the present disclosure can be used in the treatment of ADHD, although more research is needed for confirmation. As stated above, no statistically significant effect was seen on impulsivity. Thus, a composition according to the present disclosure may particularly successfully used in the treatment of ADHD focusing on treatment of inattention. Specifically, a composition according to the present disclosure may find use in the treatment of ADD.
Asperger's syndrome/Autism: As shown above, symptoms associated Asperger's syndrome/autism, such as inattention, perceived stress and obsessive compulsive symptoms, can be affected by the intake of a composition according to the present disclosure. Thus, a synbiotic composition according to the present disclosure can be used in reducing symptoms of Asperger's syndrome/autism.
Borderline personality disorder: As shown above, symptoms associated with borderline personality disorder, such as difficulties in emotion regulation, perceived stress and obsessive compulsive symptoms, can be affected by the intake of a composition according to the present disclosure. Thus, a synbiotic composition according to the present disclosure can be used in reducing symptoms in a patient suffering from borderline personality disorder.
Obsessive compulsive disorder (OCD): A synbiotic composition according to the present disclosure seems to reduce obsessions and compulsions. Thus, a synbiotic composition according to the present disclosure can be used in reducing obsessive compulsive symptoms in a patient suffering from obsessive compulsive disorder (OCD).
Depressive disorders: As shown above, symptoms associated with depressive disorders, such as inattention, difficulties in emotion regulation and perceived stress, can be affected by the intake of a composition according to the present disclosure. Thus, a synbiotic composition according to the present disclosure can be used in reducing symptoms in a patient suffering from depressive disorders.
Generalized anxiety disorder: As shown above, symptoms associated with generalized anxiety disorder, such as difficulties in emotion regulation and perceived stress, can be affected by the intake of a composition according to the present disclosure. Thus, a synbiotic composition according to the present disclosure can be used in reducing symptoms in a patient suffering from generalized anxiety disorder.
Bipolar disorder: As shown above, symptoms associated with bipolar disorder, such as hyperactivity, difficulties in emotion regulation and perceived stress, can be affected by the intake of a composition according to the present disclosure. Thus, a synbiotic composition according to the present disclosure can be used in reducing symptoms in a patient suffering from bipolar disorder.
Comorbidity: Comorbidity with two or more of the above syndromes and disorders are common, partly due to overlapping symptoms. Thus, a synbiotic composition according to the present disclosure can be used in the treatment, amelioration and reduction of symptoms also in patients suffering from two or more of the syndromes and disorders above.
895 individuals (both men and women, from 18 years old) who had used a synbiotic composition according to the present disclosure (corresponding to Composition No. 19 in Table 1) for 1 week up to 2 years, sporadically up to every day, were questioned about their experiences and perceived effects of intake of the composition. The composition comprised Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608), and Leuconostoc mesenteroides (LMG P-20607) (total amount of of bacteria was 1.5×1010 CFU/dose). Each dose further comprised inulin, pectin, resistant starch and betaglucan (total amount of fibers 4 g). Each individual independently reported any experienced positive effect(s) as well as any negative effects. None reported severe adverse effect or that medical treatment was needed. 132 individuals reported that one purpose of using synbiotic composition was “for a good mental health”. 109 of these respondents had used the synbiotic composition daily or a couple of times per week. Responses to the question whether they felt that the synbiotic composition had helped them with problems with depression/fatigue are shown in Table 4a and in
Notably, already after 1-4 weeks, 24% of the respondents reported that they had less problems with depression/fatigue and after 1-6 months, 48% of the respondents reported that they had less problems with depression/fatigue. After 1-2 years of regular intake, 61% of the respondents reported that they had less problems with depression/fatigue. The group “6-12 months” included 12 individuals, i.e. the smallest group in this survey and smaller than the groups “1-4 weeks”, “1-6 months” and 1-2 ears”. Thus, in this group, a single individual's response will contribute to a larger extent to the percentage of reported effect of the synbiotic composition. Even though the percentage of responders reporting an effect on depression/fatigue is lower in the “more than 2 years”-group than in the “1-2 years”-group, still 42% of the respondents reported less problems with depression/fatigue. Thus, the results indicate that a synbiotic composition according to the present disclosure may reduce problems with depression/fatigue and can be used in the treatment of depressive disorders.
93 individuals (both men and women, from 18 years old) who had used a synbiotic composition according to the present disclosure (corresponding to Composition No. 19 in Table 1) for 4 weeks, sporadically up to every day, were questioned about their experiences and perceived effects of intake of the composition on effects concerning problems related to mental health. The composition comprised Lactobacillus plantarum (LMG P-20606), Lactobacillus paracasei (LMG P-17806), Pediococcus pentosaceus (LMG P-20608), and Leuconostoc mesenteroides (LMG P-20607) (total amount of of bacteria was 1.5×1010 CFU/dose). Each dose further comprised inulin, pectin, resistant starch and betaglucan (total amount of fibers 4 g). Each individual independently reported any experienced positive effect(s) as well as any negative effects. None reported severe adverse effect or that medical treatment was needed.13 individuals reported that they suffered from anxiety or other mental problems. 12 of these respondents had used the synbiotic composition daily, almost every day or about half of the days. Responses to the question whether they felt that the synbiotic composition had helped them with problems related to mental health are shown in Table 4b.
As can be seen in Table 4b, already when the time period of regular intake of a synbiotic composition according to the present disclosure is as short as 4 weeks, respondents reported an improvement in symptoms such as focus/concentration, moodswings, depression, anxiety and fatigue. Thus, the results indicate that a synbiotic composition according to the present disclosure may reduce problems with these symptoms and can be used in the treatment of disorders such as depressive disorders, anxiety, such as generalized anxiety disorder and biopolar disorder.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2051326-3 | Nov 2020 | SE | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/SE2021/051137 | 11/12/2021 | WO |
