WO2006048446A1

WO2006048446A1 - Lactobacillus for preventing and/or treating chronique fatigue syndrome and associated diseases

Info

Publication number: WO2006048446A1
Application number: PCT/EP2005/055750
Authority: WO
Inventors: Karl Anders Olof Henriksson; Robert Llewellyn Clancy
Original assignee: Dsm Ip Assets B.V.
Priority date: 2004-11-05
Filing date: 2005-11-04
Publication date: 2006-05-11

Abstract

The present invention describes a probiotic product comprising as active ingredient a Lactobacillus acidophilus strain and/or a Lactobacillus helveticus strain having the following properties of: - restoring immunological competence and/or, - limiting the pro-inflammatory response and/or, - reducing abnormal shedding of an herpes type virus in human, and hence reducing the clinical outcomes of fatigue, cognitive defects, and impaired performance. Preferably the probiotic product comprises the Lactobacillus acidophilus strain CBS 116411, which can be used as a medicament for preventing and/or treating CFS and associated diseases in a human being in a need thereof. This strain can also be formulated in a food product. The invention further relates to the use of said strain for manufacturing said medicament or said food product.

Description

DSM IP Assets B.V. 24475WO

LACTOBACILLUS FOR PREVENTING AND/OR TREATING CHRONIQUE FATIGUE SYNDROME AND ASSOCIATED DISEASES

Field of the invention

The present invention relates to the field of chronique fatigue syndrome (CFS) and associated diseases, and in particular to Lactobacillus strains, which have the capacity to prevent and/or treat CFS and associated diseases.

Background of the invention

Many people are affected by CFS. CFS is characterized by a chronic, debilitating fatigue, which lasts for longer than 6 months. Frequent and recurrent findings include fewer, pharyngitis, difficulties in cognition and disorders of the mood. In a majority of patients, the illness is initiated suddenly with an acute "flue like" illness. Abnormalities like lymphocystosis, atypical lymphocystosis, monocytosis, elevation of hepatocellular enzymes, low levels of antinuclear antibodies, varying levels of antithyroid antibodies, elevated CD4:CD8 ratio, decreased cystolytic activity of natural killer cells and low levels of immune complexes. Clinical and serological studies suggest an association of CFS with all of the herpesviruses, particularly Epstein-Barr virus (EBV) (Komaroff & Goldenberg 1989, The chronic fatigue syndrome: definition, current studies and lessons for fibromyalgia research. Journal of Reumatology - Supplement. 10:23-27). In addition, other infectious agents such as Hepatitis, Ross River virus, Q fever could also in some cases be associated with CFS after illness or stress. It is likely that, depending both on the genetic and environment background of each person, several combinations of factors can result in CFS.

US 2003/0180260 alleged that a probiotic composition, which could comprise any probiotic could be used in human for immunotherapy and/or for preventing or treating bacterial or viral infections.

There is still a need for improved probiotic formulation having an established clinical effect on CFS and associated diseases in human. Detailed description of the invention

For the first time, the efficacy of a probiotic product has been directly established on human for preventing and/or treating CFS and associated diseases.

The present invention relates to a probiotic product comprising as active ingredient a

Lactobacillus acidophilus strain and/or a Lactobacillus helveticus strain, which has the capacity to prevent and/or treat CFS and associated diseases in a human being in a need thereof. According to a preferred embodiment, the probiotic product of the invention comprises as active ingredient any Lactobacillus acidophilus strain or Lactobacillus helveiicus strain having the foiiowing properties of:

- restoring immunoiogicai competence and/or,

- limiting the proinflammatory response in response to a stress and/or - reducing abnormal shedding of an herpes type virus in human, and hence reducing the clinical outcomes of fatigue, cognitive defects, and impaired performance, These effects (reducing, restoring, iimiting) are preferabiy measured in humans suffering from CFS after daiiy oral administration of at least 10⁸ cfu (coiony forming units) per day during at ieast 1 day. More preferably, during at least 5 days, even more preferably during at least 10 days, even more preferabiy at least 30 days, even more preferably at ieast 80 days, even more preferabiy at ieast four month and most preferabiy during at least one year. The number of cfu is preferably estimated by enumeration of Lactobacillus coiony formed on Mann Ragosa Sharp (MRS) (Oxoid, UK) agar, after incubation of inocuiated agar plates at 37⁰C for at ieast 48 hours under anaerobic conditions. Humans suffering from CFS and which can be used to assess the efficacy of probiotic strains are preferably individuals that have been subjected to physicai stress, e.g. athletes or other individuals that are susceptibie to EBV or other virai infections that

Restoring immunoiogicai competence means restoring normal ievei of mucosal immunity. This is preferably evaluated by measuring the ievei of interferon gamma (IFN-" ^; saiivary immunogiobuline A (IgA) and/or of interleukine 12 (IL12) in CFS subjec .fter probiotic treatment and compared to the corresponding Ievei found in a normai subject. Normai subject in this context is a subject not suffering from CFS. The leveS of SgA and IFMy is preferabiy measured as described in the exampie. According preferred embodiment, IFKh/ is used as the indicator of restoration of imrnunoiogicai competence. We expect that when norma! subjects are treated as described in the exampie (after dasly orai administration of a composition given in the exampie during one month), their IFNy ievei may increase from about 20% to about 150%. We further expect that when humans suffering from CFS are given the same treatment, their SFNy ievei may increase from about 150% to about 400%. According to a preferred embodiment, restoring imrnunoiogicai competence in human suffering from GFS means that after at ieast ten days of daiiy administration of at ieast 10⁸ cf u (coiony forming units) of GBS 1 1841 1 , the ievei of i FNy as detected using the assay used in the exampie is increased of at ieast 150%, Even more preferabiy, the ievei of iFNγas detected using the assay used in the exampie is increased of at ieast 200%, even more preferabiy at ieast 300%, and most preferabiy at ieast 400%. More preferabiy, the treatment is continued during at ieast 30 days or one month to obtain this effect, even more preferabiy during at ieast two months, even more preferabiy during at ieast four months, even more preferabiy at ieast six months, and most preferabiy during at ieast

Limiting the proinflammatory response after a stress means having an as Sow as possibie proinflammatory response after a stress (such as maxima! exercise as exemplified in the example), by comparison to the absence of a pro-inflammatory response in a normal subject. A normai subject in this context is a subject not suffering from CFS. Preferabiy, the pro-inflammatory response is evaluated by measuring the level of NO formed. This is preferabiy performed using the method described in the exampie. According to a preferred embodiment, limiting the pro-inflammatory response after a stress in human means that after treatment after daiiy orai administration of at ieast 10⁸ cfu fcoiony forming units) per day during at ieast 5 day, a normai ievei of NO is detected using the assay used in the exampie. More preferabiy, the treatment is continued during at least 10 days to obtain this effect, even more preferably during at least 30 days, even more preferabiy at ieast 80 days, even more preferably at least four month and most preferabiy during at ieast one year.

Reducing abnormal shedding of a herpes type virus in human is preferabiy determined with EBV as herpes type virus. More preferabiy, the presence of EBV is detected by PGR as described in the exampie. According to a preferred embodiment, reducing abnormal -A-

shedding of EBV in human means that after treatment after daiiy oral administration of at ieast 10⁸ cfu (colony forming units) per day during at least 5 day, no shedding of EBV is detected using PCR. More preferabiy, the treatment is continued during at least 10 days to obtain this effect, even more preferably during at ieast 30 days, even more preferably at ieast 80 days, even more preferabiy at ieast four month and most preferabiy during at ieast one year. According to another preferred embodiment, the herpes type virus is a herpes type 1 and type 2 virus or a cytomegalovirus.

According to another preferred embodiment, the probiotic product of the invention comprises as active ingredient a Lactobacillus acidophilus strain and/or a Lactobacillus helveticus strain, which has the capacity to prevent CFS and associated diseases in a human being in a need thereof. In this case, the probiotic product is abie to prevent:

- the deterioration of the irnmunologicai competence and/or,

- the induction of an pro-inflammatory response in response to a stress and/or

- the abnormal shedding of an herpes type virus in human, and hence preventing the clinical outcomes of fatigue, cognitive defects, and impaired performance.

To check whether or not a new identified Lactobacillus strain could be used in the probiotic product of the invention, this strain is preferably tested in the triai presented in the example. Lactobacillus acidophilus and Lactobacillus helveϊicus are defined by their ability to utilize range of carbohydrates, as described in table 1. The ability of strain GBS 118411 is also given, in addition, the strain should have at least 70% DNA-DNA homology with L helveticus DSM 20075^T as determined by spectroscopic DNA-DNA hybridisation as described briefly in the section experimental before the examples. More preferably, the strain shouid have at least 75% DNA-DNA homology with said strain using the same program, most preferably at least 79% DNA-DNA homology. All strains of Lactobacillus acidophilus or Lactobacillus heleveticus having these properties are encompassed by the present invention. Tabie 1 Carbohydrate utilization of Lactobacillus strains

According to an even more preferred embodiment, the probiotic product of the invention comprises as active ingredient at least the following probiotic: Lactobacillus acidophilus strain LAFTI® L10 deposited at the CBS under accession number CBS 1 1641 1 on 15/10/04.

According to a preferred embodiment, the probiotic product of the invention consists of a biologically pure culture of said deposited strain. According to a more preferred embodiment, the product consists of a biologically pure culture of said deposited strain in combination with any other valuable probiotic strain. A probiotic strain is defined herein as a live microbial strain, which beneficially affects the human host cell by improving its microbial balance. Preferred probiotica are isolated strains of Bifidobacterium, Lactobacillus, Propionibacterium, and Enterococcus. More preferred probiotic species are Bifidobacterium infantis, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus paracasei and Lactobacillus helveticus.

In the context of the invention, CFS is defined as follows: any type of fatigue associated with a viral infection.

In the context of the invention, associated disease is defined as being preferably a herpes type viral disease. Preferably, the associated disease is: EBV infections, herpes type 1 and type 2 infections, cytomegalovirus infections.

In the context of the invention, a human being in the need of the probiotic product of the invention is defined as follows: human subjects that experience some form of fatigue and/or stress. Stress and fatigue can have any origin but has preferably a professional origin: shiftwork, international travel, academic stress in students, over-training in sport (athletes). Alternatively and/or in combination with stress having a professional origin, stress has preferably a domestic origin: family stress, stress caused by children. Alternatively and/or in combination with previous origin of stress, stress is caused by mid¬ life crisis and/or diet-related stress. More preferably, the stress and/or fatigue causes impaired physical performance in human over-training in sport such as athletes.

For the first time, it has been directly demonstrated that the administration of a probiotic product (Lactobacillus acidophilus strain CBS 1 1641 1 ) has the capacity to prevent and/or treat CFS and associated diseases in human. This effect has been demonstrated by the fact that probiotic treatment leads to a

- restoration of immunological competence and

- limitation of the proinflammatory response and - reduction of abnormal shedding of EBV in human, and hence a diminution of the clinical outcomes of fatigue, cognitive defects, and impaired performance, This probiotic product reduces shedding of EBV in saliva. This effect was associated with a normalisation of mucosal level of INF-γ as well as a reduced mucosal level of Nitric Oxide, which demonstrates that oral administration of the probiotic product leads to a restoration of mucosal immunity and a limitation of mucosal inflammation. Inhibition of reactivation of EBV by the probiotic product, should reduce fatigue in athletes with impaired performance.

In a preferred embodiment, the probiotic product of the invention is a medicament or a food product.

The invention also relates to the use of a Lactobacillus acidophilus strain and/or a Lactobacllius helveϊicus strain, preferably the Lactobacillus acidophilus strain is CBS1 1641 1 , having the properties of:

- restoring immunological competence and/or,

- iimiting the proinflammatory response and/or,

- reducing abnormal shedding of an herpes type virus in human, and hence reducing the clinical outcomes of fatigue, cognitive defects, and impaired performance, for preventing and/or treating CFS and associated diseases in a human being in a need thereof.

According to a preferred embodiment, said Lactobacillus strain is used for the manufacture of said medicament or food product. The medicament of the invention may comprise any physiologically or pharmacologically acceptable excipient and/or diluent.

According to another preferred embodiment, the probiotic product is a food product or part thereof. If the probiotic product is part of a food product, the probiotic product can be present as a granule, powder or the like. The food product of the invention comprising the probiotic product of the invention may comprise any physiologically or acceptable excipient and/or diluent. Preferred food products are cultured milk, yoghurt, cheese, milk drink, milk powder, sport drink, coveratures (defined as mixtures of oil, sugar(s) and milk protein (whey)), infant formulas and fermented meat products.

Alternatively and according to another preferred aspect of the invention, a Lactobacillus strain as defined before, preferably the Lactobacillus acidophilus strain

CBS 1 1641 1 is used in the preparation of a food product for preventing and/or combating CFS and associated diseases in a human being in a need thereof. The product (medicament or food product) of the invention comprises a Lactobacillus strain as defined earlier, preferably the Lactobacillus acidophilus strain CBS 1 1641 1 in an effective amount to prevent and or treat CFS and associated diseases. According to a more preferred embodiment, the food product or medicament comprises at least 10⁶ (cfu)/g product, which is consumed to give at least 10⁸ cfu as the daily dose, or preferentially from 10⁹ to 10¹¹ cfu/day.

According to another preferred embodiment, the probiotic product (medicament and food product) of the invention is in the form of tablet, capsule, powder or granule, orally liquid administered liquid preparations, suppositories, dry preparations. More preferably, the probiotic product is in the form of an enteric tablet, capsule, powder or granule, meaning it will survive the stomach and arrive intact in the intestine. All these forms can be prepared by known means, using food grade, respectively pharmaceutically acceptable carriers, excipients, solvents or adjuvants. For the preparation of the medicament, standard ingredients and method of preparation as already described in Remington: The science and practice of pharmacy, 1995, Mack Publishing, Co Easton, PA 18042, USA) can be used. Remington is herewith incorporated by reference.

The invention therefore also relates to a method wherein a Lactobacillus strain as defined earlier, preferably the Lactobacillus acidophilus strain CBS 1 1641 1 is formulated in a food product or in a medicament, and said food product or medicament is administered to a given human being in an amount effective for preventing and/or treating CFS and associated diseases. Therefore, the invention further relates to a method for preventing and/or treating CFS and associated diseases in a given human being. This method comprises the step of administering the medicament or food product of the invention to said human being. It will be appreciated that the exact dosage of the essential active ingredient which is said strain, preferably the Lactobacillus acidophilus strain CBS 1 1641 1 constituting an amount effective for preventing and/or treating CFS and associated diseases in a human being in a need thereof may vary depending on the specific nature of the clinical conditions being treated, severity of the condition, age of human being treated, weight and condition of the human being treated, mode of administration of the dosage form, and the specific formulation being administered. Preferably, administrating the product of the invention preferably means ingesting said product to give a daily dose of at least 10⁸ cfu per day. More preferably, an amount of the product that corresponds to 10¹⁰ cfu in said product per day.

According to another preferred embodiment, the product of the invention consist of the strain as defined earlier, preferably the strain Lactobacillus acidophilus CBS 1 1641 1 in combination with at least one of the following ingredients in order to get a synergetic combination on the human being treated. Preferred ingredients are: vitamin A, vitamin C, vitamin D3, vitamin E, vitamin B1 , vitamin B2, vitamin B6, vitamin B12, vitamin C, nicotinamide, folic acid, beta carotene, lutein, Zinc, Copper, selenium, polyphenol, and prebiotics. According to a more preferred embodiment, the probiotic product of the invention consist of the strain as defined earlier, preferably the strain Lactobacillus acidophilus CBS 1 1641 1 in combination with a polyphenol. Even more preferably, the polyphenol is a green tea extract. Even more preferably, the major compound present in the green tea extract is epigallocatechin gallate (EGCG). Most preferably, the probiotic product of the invention consist of the strain as defined earlier, preferably the strain Lactobacillus acidophilus CBS 1 1641 1 in combination with Teavigo™ According to another preferred embodiment, the prebiotic is at least one of the prebiotic defined in US 6,180,099: inulin, and/or fructoligosaccharides.

The invention will now be illustrated by the following example, which should not be construed as limiting the scope of the invention.

Experimental: Briefly, a method is given to determine DNA-DNA homology by spectroscopic DNA-DNA hybridisation. DNA is isolated using a French pressure cell (Thermo Spectronic) and is subsequently purified by chromatography on hydroxy apatite as described by Cashion et al (Cashion et al, (1977), A rapid method for base ratio determination of bacterial DNA. Anal. Biochem. 81 , 461 -466). DNA-DNA hybridisation is carried out as described by De Ley et al (De Ley et al, (1970) The quantitative measurement of DNA hybridisation from renaturation rate. Eur. J. Biochem. 12, 133-142) with the modification apported by Huss et al (Huss et al, (1983), Studies on the spectrophotometric determination of DNA hybridization from renaturation rate, Syst. Appl. Microbiol., 4, 184-192) and Escara and Hutton (Escara and Hutton, (1980), Thermal stability and renaturation of DNA in dimethylsulphoxide solutions: acceleration of renaturation rate. Biopolymers, 19:1315- 1327), using a model 2600 spectrophotometer equipped with a model 2527-R thermoprogrammer and plotter (Gilford Instrument Laboratories). Renaturation rates are computed with the TRANSFER. BAS program of Jahnke, 1992 (Jahnke K.D. (1992), Basic computer program for evaluation of spectroscopic DNA renaturation data from Gilford System 2600 spectrometer on a PC/XT/AT type personal computer. J. Microbiol. Methods, 15:61 -73).

Example

In this example, a clinical trial is reported which demonstrates that Lactobacillus acidophilus CBS 1 1641 1 : - restores the immunological competence and limits the pro-inflammatory host response and - reduces abnormal shedding of EBV in man suffering from CFS, and hence reduces the clinical outcomes of fatigue, cognitive defects, and impaired performance. Nine subjects were recruited because of complaints of impaired sporting performance. The clinical characteristics were of reduced energy, cognitive defects (variable) and fall- off in athletic performance. Often this was episodic with episodes initiated by 'sore throats', and exercise and training would exacerbate. This group was selected as a defined selection within the broader context of 'chronic fatigue syndrome (CFS)'. In table 2 below, several parameters are indicated, which were measured in the CFS group as well as in the control group (normal). Of the nine CFS subjects, eight were seropositive for EBV (a similar proportion to the general public) as tested by Polymerase Chain Reaction (PCR) as already described ("Valtrex therapy for EBV reactivation and upper respiratory symptoms in elite runners". Med Sci Sports Exerc 36 No.7 1 104-1 1 10. Cox A, Gleeson M, Pyne D, Saunders P, Clancy R, Fricker P).

Table 2: Charaterisation of Normal and CFS groups

The study was planned as follows:

The eight seropositive persons, so called "CFS" and 18 "normal" subjects were followed.

The effect of the probiotica product or of a placebo was tested on both groups before and after a physical exercise (one hour running on a trade mill). Several parameters were measured: EBV shedding, IFNγ, saliva IgA, NO.

The placebo used was AviceM OO™ (microcristalline cellulose). The probiotica product tested was a daily dose of 10^{1 o}cfu of Lactobacillus acidophilus CBS 1 1641 1 formulated in

AviceM OO TM

1 .1 . Effect of probiotica on EBV excretion within CFS group The excretion of EBV within the eight seropositive subjects (CFS subjects) was determined by PCR (as defined in the former paragraph) and was followed as explained below. Three samples were taken for each subject (24 samples in total). EBV excretion was measured four times within the same eight subjects:

- at the beginning of the study: three samples were found positive (3/24)

- after one month of placebo: 3/24 - after one month of no treatment (washout period): 6/24 - after one month of treatment with the probiotic product: 1/24 The results are given again in table 3 below:

1 month

Placebo: EBV positive by PCR 3/24 3/24

/-.acidophilus: EBV positive by PCR 6/24 1/24

Table 3: effect of probiotica on EBV excretion within CFS subjects

We conclude EBV excretion was reduced from six to one positive sample after treatment with Lactobacillus acidophilus CBS 1 1641 1 , compared to no change (ie 3 & 3) with placebo.

1 .2. Probiotica restores mucosal immunity towards normal within CFS group

As indicators of mucosal immunity level, saliva immunoglobuline A (IgA) and interferon gamma (IFN-γ) levels were measured within CFS group and normal group before and after treatment with either Lactobacillus acidophilus CBS1 1641 1 or placebo. Saliva immunoglobuline A (IgA) was measured as described in the example of WO01 /97836. INF-γfrom whole blood culture was measured according to the following publication ("Circulating T cell response to Helicobacter pylori infection in chronic gastritis". Helicobacter 5;3:135-141 (2000)). The results are presented below:

(i) Saliva IgA (median levels mg/l)

Normals Before probiotic 59mg/l (25-129)

After probiotic 51 mg/l (27-103)

CFS Before probiotic 56mg/l (38-185) After probiotic 70mg/l (20-85)

(ii) INF-γ (from whole blood culture) Normals Before probiotic 1 1 .9 pg/ml

After probiotic 26.8 pg/ml

CFS Before probiotic 7.8 pg/ml After probiotic 32.1 pg/ml

P = 0.04

(Before means before treatment with probiotics, after means after treatment with probiotics)

Three samples were taken from each subject at each time point (ie 24 samples in total). We conclude:

- The placebo did not have any detectable effect on both Normal and CFS subjects before and after physical exercise (data not shown).

- The CFS group is characterized by a lowered IFN-γ level as compared to the one of the normal group (p<0.02), indicating an impaired mucosal immune competence. - Treatment with Lactobacillus acidophilus restores mucosal immunity level towards a normal level: the level of mucosal immunity is comparable within CFS group after probiotic treatment and normal subjects before or after probiotic treatment as indicated by IFN-γ levels.

1 .3. Limitation of nitric oxide production

In CFS group, the stress of maximal exercise (ie VO2 max) caused an increase and uncontained level of NO (one hour post physical exercise as defined before) as measured in saliva by measuring nitrite accumulation, a stable metabolic product of NO with oxygen. This is determined by the Griess reaction. Briefly, equal volumes of saliva and Griess reagent (0.5% sulfanilamide and 0.05% N-1 napththylethelenediamide hydrochloride in 2.5% phosphoric acid) were mixed at room temperature. After 5 mins, the absorbance was measured at 550 nm using an ELISA microplate reader. The concentration of nitrite was determined by a standard curve prepared with sodium nitrite (1 - 10O mM). After one month of treatment with Lactobacillus acidophilus CBS 1 1641 1 , the NO response to exercise was contained and 'normalised' to pattern found in normal control group as demonstrated below: Nitric Oxide (recovery levels one hour after exercise challenge)

Normals Before probiotic 16OuM After probiotic 175uM

CFS Before probiotic 215uM

After probiotic 145uM

The placebo did not have any detectable effect on both Normal and CFS subjects before and after physical exercise (data not shown).

We conclude probiotica treatment of CFS subject limits the inflammatory response of the subject, which should lead to a reduction of the symptoms associated with CFS.

Therefore for the first time, it is demonstrated that probiotica treatment of CFS subjects leads to the 'normalisation' of immune marker (IFN-γ) and parameter of inflammation (NO).

M IP Assets B.V. 15 24475WO

I Applicant's or agent's file reference number 24475WO I International application No.

INDICATIONS RELATING TO A DEPOSITED MICROORGANISM

(PCT Rule 13bis)

The indications made below relate to the microorganism referred to in the description Firstly mentioned on page 4 line 17 in the word document

B. IDENTIFICATION OF DEPOSIT Further deposits are identified on an additional sheet

Name of depositary institution

CENTRAALBUREAUVOORSCHIMMELCULTURES

Address of depositary institution (including postal code and country) Uppsalalaan 8 P.O. Box 85167 NL-3508 AD Utrecht The Netherlands

Date of deposit 15 October 2004 Accession Number CBS 116411

ADDITIONAL INDICATIONS (leave blank if not applicable) This information is continued on an additional sheet

We inform you that the availability of the microorganism identified above, referred to Rule 13bis PCT, shall be effected only by issue of a sample to an expert nominated by the requester until the publication of the mention of grant of the national patent or, where applicable, for twenty years from the date of filing if the application has been refused, withdrawn or deemed to be withdrawn.

D. DESIGNATED STATES FOR WHICH INDICATIONS AKE MADE (if the indications are not for all designated States)

E. SEPARATE FURNISHING OF INDICATIONS (leave blank if not applicable)

The indications listed below will be submitted to the International Bureau later (specify the general nature of the indications e.g., "Accession Number of Deposit")

For receiving Office use only ^■""^• For International Bureau use only — —

This sheet was received with the international This sheet was received by the International Bureau application on:

Authorized officer Authorized officer

r. A .1 & PASCHE

Form PCT/RO/134 (July 1992)

Claims

1 . Probiotic product comprising as active ingredient a Lactobacillus acidophilus strain and/or a Lactobacillus helvetlcus strain, which have the capacity to prevent and/or treat CFS and associated diseases in a human being in a need thereof.

2, Probiotic product according to ciaim 1 having the properties of:

- restoring immunoiogicai competence and/or, - limiting the pro-infiammatory response and/or,

- reducing abnormal shedding of an herpes type virus in human, and hence reducing the clinical outcomes of fatigue, cognitive defects, and impaired performance,

3. Probiotic product according to claim 1 or 2, wherein the Lactobacillus acidophilus strain is CBS1 1641 1 .

4. Probiotic product according to any one of claim 1 to 3, wherein the product is a medicament or a food product.

5. Probiotic product according to claim 4, wherein the product is for preventing and/or treating CFS and associated diseases in a human being in a need thereof.

6. Probiotic product according to claim 5, wherein the associated disease is a herpes type viral disease selected from the group consisting of: EBV infections, herpes type 1 and type 2 infections, cytomegalovirus infections.

7. Probiotic product according to claim 5 or 6, wherein the human being in a need of the medicament is selected from the group consisting of: human subjects that experience some form of fatigue and/or stress.

8. Use of a Lactobaciilus acidophilus strain and/or a Lactobacillus helveticus strain, preferably the Lactobacillus acidophilus strain is CBS1 1641 1 , having the properties of: - restoring immunoiogicai competence and/or,

- limiting the pro-infiamrnatory response and/or

9. Use of a Lactobacillus strain as defined in claim 8 for the preparation of a medicament.

10. Use of a Lactobacillus strain as defined in claim 8 for the preparation of a food product or a medicament for preventing and/or treating CFS and associated diseases in a human being in a need thereof.

11. Use according to any one of claim 8 to 10, wherein the associated disease is a herpes type viral disease selected from the group consisting of: EBV infections, herpes type 1 and type 2 infections, cytomegalovirus infections.

12. Use according to any one of claim 8 to 11 , wherein the human being in a need of said food product of medicament is selected from the group consisting of: human subjects that experience some form of fatigue and/or stress.