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Hiroyuki Fukami
Central Research Institute Mizkan Group Corporation
2-6, Nakamura-cho, Handa, Aichi, 475-8585, Japan
Tel: +81-569-24-5128 / Fax: +81-569-24-5029 / E-mail: h-fukami@mizkan.co.jp
Anti-Aging Medicine 6 (7) : 60-65, 2009
(c) Japanese Society of Anti-Aging Medicine
Original Article
Continuous Ingestion of Acetic Acid Bacteria
:Effect on Cognitive Function in Healthy Middle-Aged and Elderly Persons
60
Acetic acid bacteria, the fermentative microorganisms of traditional foods, have unique and highly pure membrane lipid
components such as sphingolipids (dihydroceramide). Sphingolipids are important components of brain tissue and many indirect
studies demonstrated that ingestion of ceramide or its sphingolipid-derivatives might have beneficial effects on cognitive function.
In a double-blind experiment, we tested whether continuous ingestion of the acetic acid bacterium, Acetobacter malorum NCI
1683 (S24) derived from fermented milk, could improve cognitive function in healthy middle-aged and elderly persons.
Cognitive function was evaluated using the CogHealth battery of tasks that can detect slight variations. A 12-week supplement of
Acetobacter malorum significantly shortened the response times of the working memory, the primary outcome of this study,
compared to the placebo supplement (P<0.05). The working memory and delayed recall tasks in the low-dosage group (111
mg/day), and the choice reaction and delayed recall tasks in the high-dosage group (400 mg/day) were also improved at 8 or 12
weeks when compared to those observed before treatment (P<0.05). These results suggest that the continuous ingestion of
Acetobacter malorum has a beneficial effect on cognitive function. No clinical problems were observed in the physical and
medical examinations of any of the groups. These results and the historic experiences with eating fermented foods indicate that
an intake of acetic acid bacteria is safe and beneficial for the life of elderly persons through the maintenance of cognitive
function from the early stages of aging.
Abstract
Hiroyuki Fukami
1)
, Hideki Tachimoto
1)
, Mikiya Kishi
1)
, Takayuki Kaga
1)
, Yasukazu Tanaka
2)
,
Yoshihiko Koga
3)
, Takuji Shirasawa
4)
1) Central Research Institute, Mizkan Group Corporation
2) Research Team for Functional Genomics, Tokyo Metropolitan Institute of Gerontology
3) Department of Neuropsychiatry, Kyorin University School of Medicine
4) Department of Aging Control, Graduate School of Medicine, Juntendo University
KEY WORDS: acetic acid bacteria, sphingolipids, cognitive function, aging
Received: Jun. 19, 2009
Accepted: Aug. 14, 2009
Published online: Sep. 24, 2009
Introduction
Acetic acid bacteria, the traditional vinegar-brewing bacteria,
are responsible for the fermentation processes resulting in vinegar,
nata de coco
1)
and fermented milk such as kefir
2)
and Caspian Sea
yogurt
3)
, among others. They have characteristic membrane lipid
components limited to some gram-negative bacteria, containing
phospholipids (e.g., phosphatidylcholine), hopanoids (terpenoid
compounds), sphingolipids, amino lipids and coenzyme Q
4-7)
.
There are only a few reports characterizing the sphingolipids
present in bacteria associated with fermented foods. All of the
sphingolipids in acetic acid bacteria have sphinganine as the sphingoid
base and 2-hydroxypalmitoyl-sphinganine (dihydroceramide)
as the main compound
5,7)
. On the other hand, higher organisms,
such as animals and plants, contain a large variety of sphingolipids,
and dihydroceramide-containing sphingolipids are only minor
component
8)
. Therefore, acetic acid bacteria are unique in
accumulating dihydroceramide in such a high purity.
In animals, dihydroceramide is converted to ceramide, which
is then metabolized into various sphingolipids. Many studies have
demonstrated that sphingolipids are important lipid components of
brain tissue. For example, gangliosides, composed of sialic acid
and oligosaccharides conjugated to ceramide, have been reported
to improve the symptoms of Alzheimer’s disease patients by
subcutaneous injection
9)
. In vitro studies have been demonstrated
that gangliosides participate in the formation of synapses, and are
related to the action of nerve growth factor
10,11)
. Furthermore,
ceramide and sphingomyelin, a derivative of ceramide, have been
reported to have the function of nerve growth factors and affect the
development and survival of nerve cells
12-15)
. These indirect
evidences suggest that ingestion of ceramide, or its derivatives,
might have a beneficial effect on cognitive function.
It is widely accepted that cognitive function deteriorates with
advancing age in experimental animals and humans. In humans,
functions such as working memory and space orientation deteriorate
following the maturation period
16)
. It is thought that such
deterioration is caused by disorders in synaptic communication
17)
.
powder was enclosed in a capsule with cornstarch and sucrose
esters of fatty acids. The composition of the supplements in the
three different capsules is shown in Table 2. The content of
dihydroceramide was analyzed in such a way that the alkali-stable
lipid was extracted from the bacteria according to the previously
reported method
7)
and the UV absorption at 230 nm of the
benzoylated derivative of dihydroceramide in the alkali-stable
lipid was detected with HPLC
27)
.
Experimental design and procedures
The experiment was set up as a double-blind test that assumed
a placebo contrast and comparison between parallel groups of
three different supplements. A flow diagram of the experimental
design and procedure is shown in Figure 1. The subjects ingested
two capsules a day for 12 weeks. After 4, 8, and 12 weeks of
supplementation, the subjects’ response times on the CogHealth
battery of tasks were analyzed.
Methods of examination
Cognitive function analyses. CogHealth is a laboratory procedure
to analyze higher brain functions based on a task-switching test
using cards displayed on a computer screen
22,23,28)
. Culture,
language and course of study are reported to have no influences on
the test results
22,29-31)
. The Japanese version of CogHealth was
provided by Health Solution, Inc., Tokyo. The following five tasks
were conducted for a total of about 30 min. The simple reaction
task required the subject to respond as quickly as possible when a
playing card was flipped over; and thus measured psychomotor
function (speed of processing). The choice reaction task required
the subject to respond as quickly as possible when a playing card
In attempts to improve such declines in cognitive function,
nutritional supplements, such as polyunsaturated fatty acids
including docosahexaenoic acid
18,19)
, ginkgo biloba
20)
and
phosphatidylserine
21)
, have been tested. However, the effects of
ingested ceramide or its derivatives on cognitive function have not
been reported.
Therefore, we focused on the possibility that acetic acid
bacteria, containing high concentrations of dihydroceramide, a
precursor of the various sphingolipids in the brain, might improve
cognitive function in aging. There are historic experiences with
ingesting acetic acid bacteria and they are likely to be safe as a
food substance. In this study, we tested whether the continuous
ingestion of the acetic acid bacterium, Acetobacter malorum
derived from traditional fermented food, could improve cognitive
function in healthy middle-aged and elderly persons. Cognitive
function was evaluated using the CogHealth battery of tasks,
which can detect slight variations in cognitive function
22,23)
. We
regarded the response time of the working memory task as the
primary outcome, which is impaired in individuals with mild
cognitive impairment (MCI) compared to healthy controls and
correlates with the ages of individuals with MCI
22)
.
Methods
Subjects
Healthy male and female subjects (50-69 years old), who
lived in Tokyo and Gunma, Japan, were recruited and screened for
the study. Persons whose Hasegawa dementia scale-revised
(HDS-R)
24)
scores were 20 or less points, who habitually ate foods
containing acetic acid bacteria, and who used health supplements,
medicines, or game instrumentations and books designed to
improve cognitive function were excluded from this study.
Eligibility was further confirmed based on a physical examination,
hematology and urine tests, and on medical history. Persons with
health problems such as food allergy, gastrointestinal disease,
diabetes, liver disease, renal disease, heart disease, alcoholism or
other serious diseases were excluded.
A total of 66 participants (40 women, 26 men; 58.8 ± 0.7
years old) were selected and randomly assigned to three groups
(placebo group, acetic acid bacteria low-dosage group, and
high-dosage group). The background data of the three groups are
shown in Table 1. There were no significant differences in the
mean response times of CogHealth, age, or sex among the three
groups.
The experimental protocol was approved by the Ethics
Committee of Anti-Aging Science, Inc. (Minato-ku, Tokyo) and
conformed to the ethical principles set forth in the Declaration of
Helsinki. Voluntary written informed consent was obtained from
all participants. The experiment was conducted under the
management of medical doctors at Shirasawa Hospital (Director
Minoru Shirasawa, Midori-cho, Tatebayashi-shi, Gunma) and
Kowa Clinic (Kowa Medical Corporation, Director Tsuyoshi
Yamato, Komagome, Toshima-ku, Tokyo).
Acetic acid bacteria supplement
Acetic acid bacteria were isolated from fermented milk by the
method of Entani and Masai
25,26)
. The strain was classified by the
sequence of its 16S rRNA and by DNA-DNA hybridization as
Acetobacter malorum NCI 1683 (S24). The bacteria were
homogenized at high pressure and powdered by spray drying. This
61
HDS-R; Hasegawa dementia scale-revised
Table 1 Characteristics of study participants
(Mean values with their standard errors)
Mean SE
Placebo group
Characteristic
No. of participants
No. of males/females
Age (years)
Response times for CogHealth tasks (sec)
Simple reaction
Choice reaction
Working memory
Delayed recall
Divided attention
HDS-R (score)
22
9/13
59
389
619
913
1347
594
28
1.3
20
19
37
94
23
0.3
Mean SE
Acetic acid bacteria
low-dosage group
22
9/13
59.1
385
614
917
1330
586
28.4
1
13
26
27
61
30
0.3
Mean SE
Acetic acid bacteria
high-dosage group
22
8/14
58.2
387
624
922
1357
572
28.8
1.2
20
19
26
76
34
0.4
Subjects ingested two capsules per day.
The capsule was composed of pullulan, an eatable coat made from plant material.
Table 2 Composition of the supplements
PlaceboComponent (per one capsule)
Acetic acid bacteria (mg)
Corn starch (mg)
Sucrose esters of fatty acids (mg)
Total weight (mg)
0
250
10
260
Acetic acid
bacteria
low-dosage
55.5
194.5
10
260
Acetic acid
bacteria
high-dosage
200
50
10
260
of the CogHealth tasks were compared among the three groups
with the Kruskal Wallis test. Multiple comparisons were
performed using the Steel test. HDS-R scores at post-12 weeks
were compared with those at pre-supplementation using paired
t-tests (two-sided).
Results
CogHealth test
Table 3 shows the mean response times for the five tasks of
the CogHealth test battery in each group at pre-supplementation
and at 4, 8, and 12 weeks during supplementation. The mean
response times for all five tasks were shorter at each succeeding
time point throughout the experiments in all three groups. This
may be accounted for by the effects of learning due to repetition of
the tasks. In the low-dosage group, the mean response times in the
working memory task tended to be shorter than those in the
placebo group at each supplementation time point and a significant
difference was identified at 12 weeks after supplementation
compared to the placebo group. However, no significant
differences were found between those of the high-dosage group
and the placebo group at any time in any of the tasks.
In the acetic acid bacteria low-dosage group, the response
times in the working memory and delayed recall tasks tended to be
shorter at 8 weeks and were significantly shorter at 12 weeks than
at pre-supplementation. In the high-dosage group, the response
times at 12 weeks for the choice reaction task and at 8 weeks for
the delayed recall task were significantly shorter than at
pre-supplementation. The high-dosage of acetic acid bacteria also
tended to improve the results of the working memory and delayed
recall tasks at 12 weeks compared to pre-supplementation. In the
placebo group, there were no significant differences or tendencies
between the pre- and post-supplementation times in any of the
tasks.
was flipped over and to answer whether it was red or not by
pressing YES or NO. In the working memory task, the subject was
required to decide whether the newly flipped card exactly matched
the previous card. The delayed recall task required the subject to
decide whether or not the same card had been seen before in the
same task and measured visual learning and memory. In the
divided attention task, the subject had to respond as quickly as
possible when any one of the five cards moving up and down
touched a white line above or below the cards. In all cases the
participants were instructed to perform the tasks quickly and
precisely. The reaction times of each task were evaluated.
Physical and medical examinations. Physical examinations
consisted of height, body weight, BMI, blood pressure, and pulse
rate measurements. Blood samples were analyzed for aspartate
transaminase (AST/GOT), alanine transaminase (ALT/GPT),
alkaline phosphatase (ALP), lactate dehydrogenase (LDH), γ
-glutamyl transpeptidase (γ-GTP), total bilirubin, total protein,
albumin, A/G ratio, acylglycerol, total cholesterol, HDL-C,
LDL-C, urea nitrogen, creatinine, uric acid, Na
+
, K
+
, Cl
–
, blood
glucose, HbA1c, red blood cell count, hemoglobinometry,
hematocrit, mean corpuscular hemoglobin (MCH), mean
corpuscular volume (MCV), mean corpuscular hemoglobin
concentration (MCHC), platelet count, and white blood-cell count.
Urine samples were analyzed for pH, specific gravity, protein,
glucose, occult blood, and urobilinogen. In addition, a medical
doctor interviewed participants concerning their subjective
symptoms and objective responses.
Diary reports. All participants were asked to keep diaries. Here
they recorded checkmarks when they consumed the supplements,
as well as subjective comments concerning any symptoms, the
intake of medicines and other health supplements, body
temperature in case of fever, and whether they had loose bowels,
diarrhoea, or constipation.
Statistical analysis
One-way repeated measures ANOVA was used to compare the
response times of the CogHealth tasks from the pre- and post-4, 8,
and 12 weeks supplementation periods and multiple comparisons
were performed using a Bonferroni correction. The response times
62
Fig. 1.
Flow diagram of the experimental design and procedure
Acetic Acid Bacteria and Cognitive Function
Screening for eligibility
CogHealth, HDS-R, physical examination, hematology test, urine test, and medical history
66 participants randomly assigned
Daily supplementation and diary report
After 4 weeks, 8 weeks, 12 weeks of food supplementation
CogHealth, HDS-R, physical examination, hematology test, urine test, and medical history
22 participants
Placebo group
2 dropouts 1 dropout
22 participants
Acetic acid bacteria
Low-dosage group
22 participants
Acetic acid bacteria
High-dosage group
CogHealth (response time), age, and sex are equally distributed
63
Table 3 Response times in five tasks of the CogHealth test battery in each group
(Mean values with their standard errors and P values)
MeanPhysical symptoms
Pre-supplement 4 weeks 8 weeks 12 weeksGroup / Task
Placebo group (n=20)
Simple reaction
Choice reaction
Working memory
Delayed recall
Divided attention
Acetic acid bacteria low-dosage group (n=21)
Simple reaction
Choice reaction
Working memory
Delayed recall
Divided attention
Acetic acid bacteria high-dosage group (n=22)
Simple reaction
Choice reaction
Working memory
Delayed recall
Divided attention
394
620
914
1342
593
381
599
908
1314
579
387
624
922
1357
572
SE
21
20
41
102
23
13
22
27
61
31
20
19
26
76
35
Mean
406
599
889
1250
528
404
565
814
1189
570
395
587
847
1279
535
SE
17
16
41
75
17
14
12
27
40
21
14
15
26
92
18
P (vs.pre-)
1.000
1.000
1.000
1.000
0.117
1.000
1.000
0.150
0.206
1.000
1.000
0.422
0.162
1.000
1.000
Mean
387
597
856
1214
545
388
551
797
1095
544
360
568
855
1152
527
SE
18
19
34
58
27
8
14
29
30
27
11
14
34
75
22
P (vs.pre-)
1.000
1.000
0.813
0.763
1.000
1.000
0.310
0.053
0.031∗
1.000
1.000
0.016∗
0.263
0.008∗∗
0.914
Mean
367
578
866
1130
522
368
558
778
1057
519
356
563
834
1152
553
SE
16
15
34
49
23
9
13
29
37
24
10
16
32
63
32
P (vs.pre-)
1.000
0.679
0.857
0.220
0.156
1.000
0.512
0.041∗,¶
0.017∗
0.587
0.616
0.011∗
0.096
0.063
1.000
Response time (sec)
Dropouts were excluded from the data analyses.
*P<0.05, **P<0.01 (vs. pre-supplementation);
Data were analyzed by one-way repeated measures ANOVA.
Multiple comparisons of 4, 8, and 12 weeks with pre-supplementation were carried out using a Bonferroni correction.
¶P=0.047 (vs. placebo group);
Data were analyzed with the Kruscal Wallis test.
Multiple comparisons were made of the low-dosage and high-dosage groups with the placebo group using the Steel test.
n=20, 21, and 22 for the placebo, low-dosage, and high-dosage groups, respectively;
Dropouts were excluded from the analyses.
Table 4 Values of the HDS-R scores and physical
measurements before (pre-) and after (12 weeks)
the supplementation in each group.
(Mean values with their standard errors)
GroupTest
HDS-R
(score)
Body weight
(kg)
BMI
Systolic
blood pressure
（mmHg）
Diastolic
blood pressure
（mmHg）
Pulse rate
（beats/min)
Placebo
Low-dosage
High-dosage
Placebo
Low-dosage
High-dosage
Placebo
Low-dosage
High-dosage
Placebo
Low-dosage
High-dosage
Placebo
Low-dosage
High-dosage
Placebo
Low-dosage
High-dosage
Mean SE
Pre-supplement
27.8
28.4
28.8
62
59.9
58.6
23.3
22.8
23
13
130
138
82.3
84.4
84.9
72.1
69.2
71.3
0.5
0.4
0.3
2.3
2.1
2.4
0.4
0.5
0.7
3
4
5
2
2.1
2.6
2
1.9
1.8
Mean SE
12 weeks
28.9
29.1
29
62.1
60
57.8
23.4
23.4
22.7
126
124
133
78.6
79.1
83.1
73.1
71.6
74.6
0.3
0.2
0.3
2.3
2
2.4
0.5
0.5
0.7
3
3
4
2.1
2.1
2.5
2.4
1.9
2.1
Safety evaluation
The results of the HDS-R test and the physical data for each
group before and after supplementation are shown in Table 4.
HDS-R scores at the pre- and post-supplementation periods in
each group were not significantly different from one another, and
the individual variations were within the normal range.
Several variations of other values were shown after
supplementation. However, the variations of the systolic and
diastolic blood pressures were small and that of the hematology
examinations were within the normal range. Clinically morbid
manifestations and obvious contributions by the supplements were
not identified for all the variations in the individual subjects.
As to adverse events experienced by the subjects during the
course of the experiment, except for one case of habitual pollinosis
in the placebo group and one case of urticaria in the high-dosage
group, subjects recovered from all events within one to ten days.
No obvious correlation between the events and the supplements
was identified.
malorum consists of approximately 1% dry weight of
dihydroceramide, approximately 0.8 mg and 2.9 mg of
dihydroceramide were consumed per day in the low-dosage and
high-dosage supplements, respectively. In addition to sphingolipid,
Acetobacter malorum also contain about 5% dry weight of
phosphatidylcholine, which is reported to be a nutritional
supplement for improving cognitive function
39)
, but the amount of
phosphatidylcholine ingested in the current study was less than the
reported effective dose (1200 mg/day). Gangliosides are reported
to act on in vitro neurons at concentrations in the nM range
40,41)
,
which is markedly lower than other functional lipids. The
dihydroceramide from Acetobacter malorum is thought to be
utilized by the human body, and that some of its metabolites, such
as gangliosides, may actively affect cognitive function in
middle-aged and elderly persons.
In this study, we also confirmed the safety of consuming 111
mg/day and 400 mg/day Acetobacter malorum for 12 weeks. The
results of the HDS-R confirmed that there were no serious
impairments to cognitive function (Table 4). There were no
abnormal variations, clinically morbid manifestations, and specific
adverse events in any of the groups after the supplementation in
the safety evaluation. These results indicate that an intake of
Acetobacter malorum is both safe and beneficial.
In conclusion, the results of this study suggest that the
continuous ingestion of acetic acid bacteria derived from
traditional fermented food is effective at improving cognitive
function in healthy middle-aged and elderly persons, and is safe at
the concentrations consumed. Foods containing acetic acid
bacteria are expected to contribute to better aging through the
maintenance of cognitive function in middle-aged and elderly
persons.
It is necessary, however, to obtain further evidence of the
effect of acetic acid bacteria on cognitive improvement in subjects
with more serious cognitive impairment. It is also important to
elucidate the pharmacokinetics of acetic acid bacteria and their
mode of action to confirm the relationship of sphingolipids as
active ingredients.
64
Acknowledement
H. F., H. T., M. K. and T. K. were responsible for performing
this study. T. S. was responsible for the experimental design and
the interpretation of the clinical data. Y. T. was also responsible for
the interpretation of the data and manuscript writing. Y. K. advised
on the cognitive function analyses. We are grateful to Mikiyuki
Katagiri, Ryota Sakurai and Terumichi Tawara of Anti-Aging
Science, Inc. for recruiting volunteers and performing the clinical
tests. Shin Ogawa of Mizkan Group Corporation contributed to
supplying the Acetobacter malorum. We thank Atsushi Ishikawa,
Takashi Fushimi, Takahiro Oda and Kenichi Sugiyama of Mizkan
Group Corporation for advising on the data analysis and reviewing
the manuscript. The authors report no conflict of interest in the
preparation of this paper. This research received no specific grant
from any funding agency in the public, commercial or
not-for-profit sectors.
Discussion
In this double-blind experiment, we examined whether
continuous ingestion of the acetic acid bacterium, Acetobacter
malorum NCI 1683 (S24) derived from traditional fermented food,
could improve cognitive function in healthy middle-aged and
elderly persons. Acetic acid bacteria are included in nata de coco
1)
,
fermented milk such as kefir
2)
and Caspian Sea yogurt
3)
and tea
mushrooms (kombucha)
32)
, among others
1)
. We analysed the
content of dihydroceramide in nata de coco; the total dry weight in
a 100 g can of nata de coco (Dole Japan, Ltd.) includes 0.8 mg of
dihydroceramide. In the low-dosage group, 111.1 mg of
Acetobacter malorum corresponding to 0.8 mg of dihydroceramide
was supplemented per day. In addition, we had confirmed the
safety of consuming 1200 mg/day of Acetobacter malorum for 14
days in a pilot study and 400 mg/day was supplemented in the
high-dosage group of this study.
The CogHealth battery of tasks used in this study is reported
to be able to detect slight variations in cognitive function
22,23,33)
.
The tasks assess short-term memory (instantaneous memory,
working memory) and attention (sustained attention, selective
attention, divided attention), which reflect the function of the
frontal lobes
22,23,28)
. We found that the response times of several
tasks in the CogHealth battery related to short-term memory
(working memory and delayed recall), were significantly
improved after the supplementation of Acetobacter malorum
(Table 3). The response times for the working memory task, which
were the primary outcome of this study, was significantly
shortened in the low-dosage group compared to the placebo group.
This finding demonstrates that the ingestion of Acetobacter
malorum has a beneficial effect on cognitive function in healthy
middle-aged and elderly persons. In this study, low-dosage group
and high-dosage group showed different effects on the response
times of several tasks. To provide stronger evidence for the benefit
of Acetobacter malorum on cognitive function, it is desirable to
ascertain the correlation between the dosage and the effect on each
task.
The levels of gangliosides, which are representative derivatives
of ceramide in the brain, decrease with age from the juvenile and
reach a level of about one-third at 85 years of age
34)
. Clinically,
gangliosides have been reported to improve the symptoms of
stroke patients by intraveneous injection and those of patients with
Alzheimer’s disease by subcutaneous injection
9)
. Gangliosides are
known by in vitro studies to accelerate the release of acetylcholine
from synapses and to enhance the activity of neurotrophic factors
in events such as neuronal dendritic elongation
11,17)
. Ceramide is
reported to affect dendrite and axon elongation in in-vitro
hippocampal neurons and cerebellar Purkinje cells and the survival
of these neurons in rats
13,14,35,36)
, to inhibit cytotoxicity by
reactive oxygen or amyloid β-peptide
37)
, and to participate in the
actions of nerve growth factor
12,15)
. These clinical and in vitro
studies support the concept that ingested ceramide and its
derivatives might have beneficial effects on the decline in
cognitive function associated with aging.
Acetic acid bacteria contain dihydroceramide. Dihydroceramide
is synthesized from serine and palmitoyl-CoA and has sphinganine
as its sphingoid base, which does not contain a double bond in the
molecule. On the other hand, in animal tissues, the main sphingoid
base is sphingosine, which is an unsaturated molecule. When
radiolabeled sphinganine or sphingosine was administered orally
to rats, the amounts of sphinganine detected in the intestinal tract
lymph were remarkably higher than those of sphingosine
38)
,
suggesting that the ingested sphinganine-based lipids are more
available for absorption and utilization in animal tissues
compared with other sphingoid base structures. As Acetobacter
Acetic Acid Bacteria and Cognitive Function
65
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