open

accessvolume 38 , number 1
published 15 march 2023

original research

Immunomodulating Effect of OM-X Fermented Plant
Extract: A Randomized, Placebo-Controlled, Double-Blind,
Comparative Study
Takeshi Kaneko1; Akinobu Miyata2; Muneaki Takahata3
Japan Clinical Trial Association (JACTA), 5F, Forecast Shinjuku South Bldg. 4-3-17 Shinjuku, Shinjuku-ku, Tokyo, 160-0022, Japan;
Miyata Medical Clinic, 9F, Tokyo Fugetsudo Nihonbshi Bldg. 2-2-8 Nihonbshi, Chuo-ku, Tokyo, 103-0027, Japan; 3BIOBANK Co., Ltd.,388-1 Hirata, Kita-ku, Okayama City, Okayama, 700-0952, Japan1
2

Citation: Kaneko T, Miyata A & Takahata M (2023) Immunomodulating Effect of OM-X Fermented Plant Extract: A Randomized,
Placebo-Controlled, Double-Blind, Comparative Study. J Orthomol Med. 38(1)abstract

The purpose of this study was to verify an immunomodulating effect of OM-X, a plant fermentation extract containing
lactic acid bacteria (LAB) and bifidobacteria in it. The study
was conducted as a randomized, placebo-controlled, double-blind, parallel-group trial. A method of health-related
quality of life (HRQOL), based upon short form-8 healthsurvey (SF-8) along with a questionnaire about the subjects’ physical conditions was employed. The study also
evaluated the safety of the test food during the test period.
After 12-weeks ingestion, there were significant differencesin the SF-8 survey and questionnaire results when compared to baseline. The study suggested that the ingestionof OM-X might be effective in the improvement of physicalconditions and immunomodulating function in healthy
subjects with a feeling of unwellness and/ or predisposition
to colds or cold-like symptoms. The safety of the test foods
was also confirmed.
introduction

In recent years, various environmental adaptations havemanifested in response to local, regional and globalchanges in the climate, such as changes in rainfall patterns, surface and air temperature, winds and ocean
currents. These environmental adaptations are thought
to be a primary contributor to the emergence of newviral variants. These adaptations are predicted to affectviral infections at three levels: change in transmission
patterns, the ecology of the host, and socioeconomicalchanges influencing host populations. Climate change
may influence epidemiological outcome as well as themorbidity and mortality associated with a particularviral infection.
Therefore, the increased risk for those infection diseases
urges us to consider a valid strategy for prevention of
infection, especially for those who have underlying
diseases, or elders in general. As one of the effective
measures for the prevention of infectious diseases,
boosting the immune strength of human biologicalprotections has been thought to be essential. There arecertain known strategies to improve immune strength,
like moderate exercise (Suzuki K, 2004), stress relief(Murakami, Kamoshita, Sawada, & Katsura, 1989), anddietary habits to optimize the intestinal environment.
Fermented foods have been a recent focus of attention
for their effect on the gut immune system (Hosoi, 2003;
Wastyk et al., 2021), antioxidant effect, and anti-inflammation effect (Miyamoto, Noda, Ohya, & Kamada, 2000;
Nakamura & Esaki, 2013; Suzuki S, 2004). Particularly
foods containing lactic acid bacteria (LAB) as anactive ingredient have been reported to enhance
innate and adaptive immunity, prevent gastric mucosal lesion development, and improve defense against
intestinal pathogens (Hachimura, 2007; Miyoshi,
2020; Tategaki, 2019)© 2023 International Society for Orthomolecular Medicine ISSN 0317-0209

Immunomodulating Effect of OM-X Fermented Plant Extract
OM-X,he test product in this research, is a fermented
supplement developed by Dr. Iichiro Ohira. OM-X has
been sold for more than 30 years in 10 countries in theworld including Japan. OM-X contains 12 kinds of lactic acid bacteria, bifidobacteria, oligosaccharide, dietaryfiber, and lipids (short-chain fatty acids). Thus far, OM-X
has been reported to have beneficial effects on boneand oral health (Kawakami et al., 2003; Hashim, Rahman,& Philip, 1999), as well as physical capabilities (Kawakami
et al., 1998). In this report, we deliver the result of ourstudy on OM-X’s effects on human immune modulation
through the randomized, placebo-controlled, double-blind, parallel-group trial run for 12 weeks.
materials and methods

Study Design
A randomized, placebo-controlled, double-blind
paralleled design was implemented from August to
November 2021 at Japan Clinical Trial Association;
JACTA, Tokyo. This trial was registered at UMIN Clinical
Trial Registry as UMIN000045192.

plan for vaccination against COVID-19 within 7 days
before the visit; (11) are judged as unsuitable for the
study by the principal investigator.
Randomization
According to inclusion/exclusion criteria, 40 subjects
were selected and sequentially allocated to two groupsof 20 each using a random number table: Group A andB. Among those, one subject in Group A declined toparticipate in the study, and the remaining 39 subjects
launched allocated intervention. Background factors
such as gender and age were taken into consideration
to avoid biased distribution. The allocation list wassealed and strictly controlled until the end of the study.
Subjects in Group A received the test sample (Active)
and subjects in Group B received Placebo. As shown in
Figure 1.
Figure 1. Flow diagram of subject disposition
Enrollment

Participants
Healthy subjects participated in the present study.
All subjects were public volunteers who enrolled in
the monitor bank of InCROM Inc. (Nishiwaki, Hyogo),
recruited from July through August 2021.
The inclusion criteria were as follows: (1) healthy
Japanese males and females from 40 to 59 years of age;(2) a self-reported feeling of unwellness at the time of
study enrollment and/or predisposition to colds. The
exclusion criteria were as follows: (1) chronic fatigue or
diagnosed chronic fatigue syndrome; (2) serious cerebrovascular disease, heart disease, liver disease, renal
disease, gastrointestinal disease, psychiatric disease,or designated infectious disease; (3) receiving treatment (hormone replacement therapy, drug therapy,
exercise therapy, diet therapy, etc.) or those who are
judged to be in need of treatment at the time of receipt
of informed consent; (4) consistent use of supplements
and/or functional foods affecting immunity, including
food for specified health uses (FOSHU); (5) currently
using drugs for food allergies; (6) have a history of alcohol or drug dependence; (7) a history of recent cigaretteuse within the past year; (8) are pregnant or planningto become pregnant during the study, or breastfeeding;(9) have participated in other clinical trials one monthprior to receipt of informed consent, or those whoplan to enroll in other clinical trials during this trial; (10)Assessed for eligibility
Randomized(n=40) (M:20, F:20)

Group AGroup B
Allocation

Allocated to Active (n=20)(M: 10, F:10)• Received allocatedintervention (n=19)(M:19 F:8)
• Did not receive allocatedintervention (n= 1) [M:1, F:0)
• Declined to participant(n= 1)

Allocated to Placebo (n=20)(M:10, F:10)• Received allocatedintervention (n=20)• Did not receive allocatedintervention (n=0)

Follow-Up
Lost to follow-up (n=0)
Discontinued intervention(n=0)

Lost to follow-up (n=0)
Discontinued intervention(n=0)
AnalysisAnalysed (n=19) (M:9, F:10]• Excluded from analysis (n=0)

Analysed (n=20) (M: 10, F: 10)• Excluded from analysis (n=0)

Experimental Groups and Test Foods
Group A, the active group, received OM-X. Group B
received placebo. OM-X is made of fermented extracts
from several kinds of Japanese plants with 12 kinds oflactic acid bacteria (hereinafter called LAB) and bifidobacteria such as TH10. OM-X also includes fulvic acid,

2 | Journal of Orthomolecular Medicine, Volume 38, Number 1, 2023

Immunomodulating Effect of OM-X Fermented Plant Extract
D-amino acids, L-amino acids, melanoidin, polyphenols,
organic acids, fatty acids, vitamins, minerals, dietaryfibers, and oligosaccharides. The placebo received byGroup B was made primarily from safflower oil. The
amount of daily intake was 3 softgel capsules (1 capsuleweighs 580 mg) for each group. Both active and placebo
foods, prepared by BIOBANK Co., Ltd., were indistinguishable in shape, color, or taste, and were managed
by identification marks. . Table 1 and Table 2 show the
ingredients contained in OM-X production and composition of organic acids and carbohydrates in OM-X.
Table 1. Composition of food materials for making

of OM-X (%)

Fruits;  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 28.6
Prune, Fig, Chinese bayberry, Chinese matrimony,
Blueberry, Yuzu (lomon)
Vegetables;  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   . 8.6
Japanese mugwort, Komatsuna
Mushrooms;   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   . 4.1
Shiitake mushroom, Maitake (dancing mushroom),
Agaricus mushroom
Seaweeds;  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 2.7
Wakame (brown seaweed), Hijiki seaweed, Konbu (Kelp)
Sugar  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  55.4
LAB;  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  0.6Bifidobacterium breve ss. Breve, Bifidobacterium infantis ss.
Infantis, Bifidobacterium longum, Enterococcus faecalis,
Lactobacillus acidophilus, Lactobacillus brevis,
Lactobacillus bulgaricus, Lactobacillus casei ss. casei,
Lactobacillus fermentum, Lactobacillus helvericus ss. jugurti,
Lactobacillus plantarum, Streptococcus thermophillus
Values are expressed as the mean ± SD.
1) ∆0-12w for SF-8 health survey, ∆phase 1- phase 2 for physical condition2) †p<0.1, * p<0.05, ** p<0.01 against baseline3) ‡p<0.1, # p<0.05, ## p<0.01 between-group difference

Experimental Procedures
Subjects in both the placebo and experimental groups
received three oral softgel capsules once a day for 12
weeks. All subjects were instructed to: take the assigned
capsules daily; maintain their usual lifestyle and habits; avoid excessive amounts of food, drink, or alcohol;
avoid any medicine or FOSHU (food for specified healthuses) with an immunomodulating effect; maintaina daily record of their physical condition, sleeping,appetite, and exercise; and send the diary once a week
to the study coordinator.

Table 2. Composition of organic acids and carbohy-

drates in OM-X (g/100g)

Citric acid  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  0.18
Lactic acid  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  . 0.11
Malic acid  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  0.10
Formic acid  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  0.06
Acetic acid   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   . 0.05
Succinic acid  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  0.02
Propionic acid  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  N.D.
Butyric acid  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  N.D.
Glucose   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   . 8.87
Fructose  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  6.46
Galactose  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  0.52
Mannose   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   . 0.38
Isomaltose   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   . 0.21
Panose  .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .   .  0.11

OutcomeThe objective of this study was to explore the potential immunomodulating activity of OM-X in healthy
subjects with a predisposition to cold-like symptoms.
The following assessments were administered to subjects: the health-related quality of life (HRQOL) scale;the Japanese version of SF-8 health survey; and a questionnaire evaluating subjects’ physical condition (Table4). Furthermore, the safety of the test foods (OM-X andplacebo) was evaluated as the secondary outcome. The
SF-8 was administered pre- and post-intervention. The
questionnaires for assessing subjects’ physical condition
and the safety of the test foods were collected as a diaryduring the study.
The Japanese version of the SF-8 (© QualityMetric Inc.,
Fukuhara, S) is a comprehensive scale that is suitable
for the continuous measurement of HRQOL in healthy
individuals. The subscales consist of physical functioning; PF, role physical; RP, body pain; BP, general
health; GH, vitality; VT, social functioning; SF, roleemotional; RE, and mental health; MH (Fukuhara& Suzukamo, 2004, 2019a; Fukuhara & Suzukamo, 2005).
The two summary scores are physical component summary, PCS; and mental component summary, MCS(Fukuhara & Suzukamo, 2004, 2019b). The higher thescore for all 10 items combined, eight subscales plus
two summary scores, the higher the QOL.

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Immunomodulating Effect of OM-X Fermented Plant Extract
Physical Condition
The questionnaire assessing subjects’ physical condition,
included the following symptom inventory: runny nose,
nasal congestion, sore throat, cough, lassitude, articular pain, chill, and the sum of all symptoms (Kokubo
et al., 2020; Kondo, 2021; Shibata, 2016). Subjects were
instructed to report daily symptoms marked with acircle or cross, then the total number of days with symptoms during phase 1 (7 days immediately after the startof the study; 1-7 days later) and phase 2 (7 days immediately before the end of the study; 78-84 days later) werecounted. The fewer days, the better physical condition.
SafetyThe safety of the test food was evaluated utilizing a written questionnaire during the study. Any unexpected
medical occurrence during the study period, definedan adverse event, does not necessarily have to have acausal relationship with the test food. The principal
investigator determined the relations between cause
and consequence of the adverse events.

Table 3. Subject demographics
Item

Subjects *Male: Female *
Age *

Unit

Group AGroup B

numbernumber
year

19
9:10
49.5 ± 4.6

20
10:10
52.0 ± 4.7

Years are expressed as the mean ± SD.
* no significant difference

Result of Subjective Evaluation
Table 4. indicates the results of SF-8 and physical condition. As for SF-8, 5 items (VT, SF, RE, MH, MCS) out of
10 increased significantly in Active, though the Placebo
showed a significant decrease in GH. In addition, intergroup analysis depicted significant differences in 6 items(GH, VT, SF, RE, MH, and MCS). With reference to physical condition, lassitude and sum total of symptoms in
Active, and nasal congestion in Placebo showed significant differences after 12 weeks of ingestion. There weresignificant differences between the two groups in nasal
congestion, lassitude, and the sum total of symptoms.

Data Analysis
An intention-to-treat (ITT) analysis was adopted, andno sample size calculation was applied. All statistics
were expressed as mean ± standard deviation (SD).
Chi-square test and Student’s t-test were used to compare the subject’s backgrounds between groups. As forscores, the paired t-test was used for intragroup analysis,and Student’s t-test was used for intergroup comparisons to quantify the amount of change before andafter the intervention. Multiplicity was not adjusted for.
Statistical analyses were performed using Excel Tokei
3.23 (BellCurve) and Statcel 4 (Yanai, 2015). The level ofsignificance was set to p=0.05 for the two-sided tests.

Table 4. Results of subjective evaluation

results

Physical condition								runny noseday -0.79 ± 1.87 † 0.40 ± 2.39 0.093 ‡nasal congestion day -0.21 ± 0.63
0.65 ± 1.18 * 0.008 ##sore throat
day 0.74 ± 2.23
0.55 ± 2.91 0.824
coughday 0.47 ± 1.47
0.25 ± 3.82 0.813
lassitude
day -2.79 ± 3.60 ** -0.30 ± 2.32		 0.014 #articular pain
day -1.21 ± 4.04
0.00 ± 2.36 0.257
chill
day 0.37 ± 1.61
0.30 ± 1.08 0.876
sum of symptoms day -3.42 ± 7.06 * 1.85 ± 8.80 0.047 #Subjects
Of the 40 subjects who enrolled, 39 completed thestudy. There was a high level of adherence to the study
protocol, with all subjects consuming their assigned test
food. The data obtaine≠d from 39 subjects (Group A; 19,
Group B; 20) were used for efficacy analysis (Figure 1).
The subjects were 50.7 ± 4.8 years of age. There were no
significant differences in gender ratio or age at baseline
between groups (Table 3).

		
OutcomeUnit

Amount of change 1) 2)
Active (n=19) Placebo (n=20) P-value 3)

SF-8								PFscore1.5 ± 7.4		
-0.3 ± 5.7		 0.409
RPscore
0.7 ± 6.5		
0.3 ± 4.5		 0.828
BPscore -0.7 ± 9.0		
-0.5 ± 6.4		 0.942-4.1 ± 6.0** <0.001 ##GH
score
2.4 ± 5.2 †VTscore
2.7 ± 4.8 *-1.0 ± 3.9		 0.011 #SF
score
4.4 ± 5.3 **-0.4 ± 6.1		 0.013 #RE
score
3.9 ± 6.7 *-0.3 ± 4.8		 0.030 #MH
score
4.1 ± 5.5 **-0.7 ± 4.7		 0.006 ##PCS
score -0.5 ± 8.7		
-0.9 ± 5.1
0.846-0.6 ± 5.2		 0.005 ##
MCS
score
5.3 ± 7.2 **Values are expressed as the mean ± SD.
1) 0-12w for SF-8 health survey, phase 1- phase 2 for physical condition2) †p<0.1, * p<0.05, ** p<0.01 against baseline3) ‡p<0.1, # p<0.05, ## p<0.01 between-group difference

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Immunomodulating Effect of OM-X Fermented Plant Extract
Adverse Events
As for Active group, the number of days with a sorethroat, cough, and chills increased slightly after 12
weeks, though the change in individual subjects was
minimal and resolved. Thus the principal investigator
determined that there was likely no causal relationshipwith the test food. No other adverse events occurred,and no clinical side effects were observed.
discussion

The present study demonstrated that the use of OM-X,
containing plant fermentation extract, LAB, and bifidobacterial improves human immune function when usedconsistently for 12 weeks. The ingestion of 3 capsulesof OM-X per day significantly improved 6 items (GH, VT,
SF, RE, MH, and MCS) in the HRQOL questionnaire. In
addition, there was a significant improvement in nasal
congestion, lassitude, and overall physical health subjects receiving OM-X. OM-X appeared to be safe with nosigns of adverse effects.
In this study, we attempted to verify the immunomodulating effect of the ingestion of OM-X. Our metabolome
analysis confirmed that the plant extract made througha multi-year fermentation process using LAB andbifidobacteria contains hundreds of low-molecularcompounds including proteins, peptides, organic acids,
short-chain fatty acids, dietary fiber, and polyphenols in
the food capsules (data not shown). It is reported thatthe ingestion of the OM-X extract by type I allergy mice
had been proven to be effective in inhibition of RBL-2H3
cells degranulation and PCA (the passive cutaneous
anaphylaxis) reaction at the same time (Itoh et al., 2015).
This study indicated that the ingestion of the OM-X had
promoted the production of nitrogen monoxide, IL-6,
and TNF-α within the organism, and activation of macrophage cells (Wakame et al., 2017). The LAB and thebifidobacteria contained in OM-X are representative
examples of probiotics (Fuller, 1989) and are reported
to be effective in the improvement of intestinal florabalance, prevention of virus infection (Yasui, 2010),
and coordination of the immune system (Yasui, Shida,
Matsuzaki, & Yokokura, 1999). LAB are also known for
their positive effects on immunostimulatory activities(Morimoto, 2005; Perdigon, Alvarez, Rachid, Agüero,& Gobbato, 1995), anti-allergic properties (Majamaa& Isolauri, 1997; Suzuki S et al., 2020), balance ability
between Th1 and Th2 (Hachimura, 2007; Sashihara,2013), and antibiotic activities due to activation of pDCs

(Tanaka, 2015). As well, TH10, a prime component of thelactic acid bacteria in OM-X has been reported to help
activation of macrophages (Itoh, 2012). In addition, antioxidative substances such as polyphenol contained in
OM-X has been reported to be effective in suppressing
the oxidative stress which is associated with various
diseases and their progressions (Tanaka et al., 2016). In
this study, the original lactic acid bacterium, TH10, andother bifidobacteria contained in OM-X together were
thought to bring positive effects on immunoregulation
via maintaining a balance between Th1 and Th2 as a
key to immunological responses and activating macrophage cells and dendritic cells..
It is assumed that the long-term fermentation and aging
process of the extract helped produce melanoidin as aresult of a Maillard reaction between sugar and aminoacids. Melanoidin has been shown to suppress thedegranulation of granulocytes (neutrophils, basophils,
and eosinophils) and mast cells and thus reduce allergy-related symptoms such as cough and runny nose
(Itoh, 2015).
conclusion

The results of the study suggested that the OM-X, a plant
fermentation extract containing lactic acid bacteria andbifidobacteria, and its ingestion for 12 weeks might havean immunomodulating effect on healthy subjects with afeeling of unwellness and/ or preposition to colds. OM-X
was found to be safe for consumption.
conflict of interest

All parts of this study were funded by BIOBANK Co.,
Ltd. MT is an executive officer of BIOBANK Co., Ltd. The
other authors declare that the study was conducted in
the absence of any financial relationships that could beinterpreted as a conflict of interest.
ethics statements

The authors ensure that the current clinical trial has
been carried out in accordance with the ethical principles of the declaration of Helsinki and the Ethical
Guidelines for Medical and Health Research Involving
Human Subjects. The protocol was approved by theInstitutional Review Board of Pharmaceutical Law
Wisdoms, Tokyo, and was conducted in compliancewith the protocol. Written informed consent was
obtained from all subjects prior to enrollment.

5 | Journal of Orthomolecular Medicine, Volume 38, Number 1, 2023

Immunomodulating Effect of OM-X Fermented Plant Extract
funding

This work was supported by BIOBANK Co., Ltd., Okayama,
Japan.

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