Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial
BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7298.1327 (Published 02 June 2001) Cite this as: BMJ 2001;322:1327
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Dr's Cremonini and Gasbarrini raised the question on the effective
dose of the probiotics. It is an important and relevant question and we
agree that when probiotic bacteria are given in dry form (in capsules,
sachets etc), daily doses of billions may be needed. However, we have seen
that milk (and maybe other buffering food substances) protect the bacteria
very effectively in the intestine. In 1991 (1) we showed that about ten
billion Lactobacillus GG bacteria (in powder form) were needed daily to be
able to recover the strain in stools. Then we showed that when
administered in fermented milk, one billion was high enough for faecal
recovery (2). We did not study lower doses with fermented milk but later
we studied the faecal recovery of LGG when administered in fresh milk. We
found that 100 million cfu/day was high enough for faecal recovery (3).
Another excellent vehicle is e.g. a ripened cheese. And the LGG level in
faecal samples is higher when 10^8 cfu is administered in milk or cheese,
compared to 10^10 in powder form (1, 3, 4).
The compliance of the LGG administration was evaluated also in our
study published recently in BMJ (5). It can be read in the electronic form
of the article, unfortunately the printed version was shortened quite a
lot. "Compliance was also measured by the faecal recovery of Lactobacillus
(from 100 child before, in the middle and at the end the intervention).
Initially 12% of children in the Lactobacillus group and 4% in the control
group carried Lactobacillus GG type bacteria (P = 0.29). Recovery figures
from the same children were 97% v 9% (P <0.0001), respectively, in the
middle of the study and 91% v 15% (P <0.0001) at the end." There are
still many open questions about probiotics and an effective dose is one of
those. In our opinion there is not only one right answer to that, but it
depends on the form of application. Recovery from faecal or biopsy samples
(5) of the living probiotic strain is one tool to evaluate the effective
dose, but the human intervention studies like our day care centre study
are needed to confirm the health benefits.
References
1. SAXELIN, M., ELO, S., SALMINEN, S., and VAPAATALO, H. 1991. Dose
response colonization of faeces after oral administration of Lactobacillus
casei strain GG. Microb. Ecol. Health Dis. 4: 209-214.
2. SAXELIN, M., AHOKAS, M., and SALMINEN, S. 1993. Dose response on the
faecal colonization of Lactobacillus strain GG administered in two
different formulations. Microb. Ecol. Health Dis. 6: 119-122.
3. SAXELIN, M. 1996. Colonization of the human gastrointestinal tract by
probiotic bacteria. Nutrition Today 31 (6), Supplement 1: 5S-8S.
4. SAXELIN, M., PESSI, T., and SALMINEN, S. 1995. Fecal recovery following
oral administration of Lactobacillus strain GG (ATCC 53103) in gelatine
capsules to healthy volunteers. Int. J. Food Microb. 25: 199-203.
5. HATAKKA, K., SAVILAHTI, E., PÖNKÄ, A., MEURMAN, J.H., POUSSA, T., NÄSE,
L., SAXELIN, M., and KORPELA, R. 2001. Effect of long term consumption of
probiotic milk on infections in children attending day care centres:
double blind, randomised trial. Br. Med. J. 322: 1327-1329.
6. ALANDER, M., SATOKARI, R., KORPELA, R., SAXELIN, M., VILPPONEN-SALMELA,
T., MATTILA-SANDHOLM, T., and VON WRIGHT, A. 1999. Persistence of
colonization of human colonic mucosa by a probiotic strain, Lactobacillus
rhamnosus GG, after oral consumption. Appl. Environm. Microbiol. 65 (1):
351-354.
Competing interests: No competing interests
Dear Readers,
Dr Campbell, Thorley, and Myr raised a question concerning breast
feeding and infections. We agree that breast milk is ideal food for
infants, and also in Finland it is recommended that exclusive breast
feeding should last 4-6 months and after that partial breast feeding until
6-12 months of age. Breast milk is known to contain different kinds of
antibodies (1), and is known to support the growth of bifidobacteria in
the intestine (2,3).
In the beginning of our study we collected very extensive background
data on children’s nutrition, including breast feeding. None of the
children (aged 1-6 years) received breast milk during the study. There
was no differences between the probiotic group and the placebo group in
the mean duration of exclusive (2.8 vs 2.9 months; p=0.41) or total breast
feeding (6.8 vs. 7.1 months; p=0.43). The mean time without breast
feeding before the study was 47.7 months in the LGG group and 45.3 months
in the placebo group (p=0.11), and the minimum time respectively was 2.5
vs. 3.1 months. We have now also adjusted the results by the duration of
breast feeding, but this adjustment did not affect the results; the effect
of probiotic milk was still apparent. Actually the duration of breast
feeding seemed to have quite a small impact on the infections. Only
gastrointestinal symptoms seemed to be negatively, but not significantly
associated with breast feeding.
We’d also like to stress, that milk containing probiotic
Lactobacillus GG is cow’s milk and thus not a substitute for breast milk.
Actually in Finland cow’s milk is not recommended to children under 12
months of age.
What comes to raw milk, it may contain some beneficial bacteria but
also many harmful bacteria. The safety aspects (4), in addition to ability
to survive in the GI-tract and colonisation, are important characteristics
of probiotic bacteria (5).
To conclude, none of the children in our study were breast fed and
breast feeding had been finished at least 2.5 months before the study, the
mean time from the weaning being 3.9 years. Therefore we do not think that
breast feeding has been a confounding factor or affected the incidence of
infections in this intervention. Breast feeding is a very important factor
in promoting children’s health. Colonic microflora also plays an important
role in the development of immune response, and probiotics may be one
possibility in enhancing immunity (6).
Yours sincerely.
Katja Hatakka
References
1. Hanson LA. Breastfeeding provides passive and likely long-lasting
active immunity. Ann Allergy Asthma Immunol 1998;81:523-533.
2. Wharton BA, Balmer SE, Scott PH. Faecal flora in the newborn. Effect of
lactoferrin and related nutrients. Adv Exp Med Biol 1994;357:91-98.
3. Goldman AS. Modulation of the gastrointestinal tract of infants by
human milk. Interfaces and interactions. An evolutionary perspectives. J
Nutr 2000;130:426S-431S.
4. Salminen S, von Wright A, Morelli L, Marteau P, Brassart D, de Vos WM,
Fonden R, Saxelin M, Collins K, Mogensen G, Birkeland SE, Mattila-Sandholm
T. Demonstration of safety of probiotics - a review. Int J Food Microbiol
1998;44:93-106.
5. Tuomola E, Crittenden R, Playne M, Isolauri E, Salminen S. Quality
assurance criteria for probiotic bacteria. Am J Clin Nutr 2001;73:393S-
398S.
6. Isolauri E, Sutas Y, Kankaanpaa P, Arvilommi H, Salminen S. Probiotics:
effects on immunity.
Am J Clin Nutr 2001;73:444S-450S.
Competing interests: No competing interests
Hatakka et al mention only in passing what is potentially one of the
most interesting outcomes of this study, namely the effect of the
treatment on the development of allergies.
The hygiene hypothesis attributes the dramatic increase in the
prevalence of asthma and other allergic diseases in recent years to a more
sterile environment and a reduced incidence of childhood infections [1].
If it is true that infections in childhood protect against the development
of allergy, then we might expect to see more of the children in the
probiotic group going on to develop allergic diseases. On the other hand,
high levels of gut lactobacilli are associated with a decreased prevalence
of allergy [2]. Since the probiotic milk promotes colonisation of the gut
with lactobacilli, we might therefore expect reduced incidence of allergy
in the treated group.
Unfortunately, the statement ‘There was no difference between the
groups in abdominal pain or allergic symptoms’ does not really address
this question. Was incident allergic disease specifically looked for? Was
the sample size adequate to detect any effect on allergies? I am sure that
the follow-up was not long enough to collect useful information on
allergies. If Hatakka et al are planning any long-term follow-up of these
children, I hope they will look at this question in more detail.
If a simple intervention such as this can prevent the development of
asthma, a disease with lifelong symptoms, need for medication, and effects
on quality of life, I would consider this far more impressive than a small
reduction in the incidence of some mild, self-limiting infections.
References:
1. von Hertzen LC. The hygiene hypothesis in the development of atopy and
asthma — still a matter of controversy? Q J Med 1998;91:767–771
2. Björkstén B, Naaber P, Sepp E, Mikelsaar M. The intestinal microflora
in allergic Estonian and Swedish 2-year-old children. Clin Exp Allergy
1999;29:342–346
Competing interests: No competing interests
Dear Editor,
Dr. Hatakka’s paper on the effect of probiotic milk supplementation on
childhood respiratory tract infections is of great interest.(1) However,
some concern is raised by the real amount of Lactobacillus GG actually
delivered to the young patients. Lactobacillus GG has well-known positive
effects on rotavirus diarrhoea, antibiotic-associated dirrhoea and several
other conditions, and has been succesfully used specially in pediatric
populations. (2,3)
Rationale for probiotic effectiveness is based on the requirement of bowel
wall colonisation. This may allow the local and systemic enhancement of
the immune system which could explain the reduction of the incidence of
infections at follow-up. Lactobacillus GG has, indeed, good properties of
adhesion to the bowel wall, but supplementation should be performed with
very high concentrations of bacterial Colony Forming Units (CFU). In
almost all study performed CFU is in the range of billions. (4)
In contrast, calculation of Lactobacillus GG supplemented by Hatakka and
colleagues does not reach these figures, but is in terms of millions of
CFU. This would not be adequate to achieve a colonization and a balancing
effect over resident flora, whose entity is enormously much bigger. In
this case a significant immunostimulation by relatively few Lactobacilli
would be almost impossible.
Moreover, the fecal assessment of Lactobacillus GG recovery, which is a
possible tool to ascertain delivery of the probiotic to the colon, should
have been performed before and after probiotic supplementation in the same
subjects, to establish that recovery was really due to supplementation.
The placebo design helps to indicate significant benefits between groups,
but does not provide any direct evidence for a benefit specifically
derived from the probiotic. This, despite producing interesting results,
adds confusion to the debate on the optimum dose of probiotic (and the
type of probiotic) needed to achieve a measurable effect.
References
1. Hatakka K, Savilahti E, Ponka A, Meurman JH, Poussa T, Nase L, et
al. Effect of long term consumption of probiotic milk on infections in
children attending day care centres : double blind, randomised trial. BMJ
2001;322:1-5
2. Vanderhoof JA, Young RJ. Use of probiotics in childhood gastrointetinal
disorders. J Pediatr Gastroenterol Nutr 1998;27:323-32
3. Rolfe RD. The role of probiotic cultures in the control of
gastrointestinal health. J Nutr 2000;130(suppl):S396-S402
4. Tuomola E, Crittenden R, Playne M, Isolauri E, Salminen S. Qualità
assirance criteria for probiotic bacteria. Am J Clin Nutr
2001;73(suppl):S393-8
Filippo Cremonini, MD
Antonio Gasbarrini, MD
Medicina Interna, UCSC, Rome, Italy
Policlinico Gemelli, Largo Gemelli 8
00168 Roma, Italia
e-mail: angiologia@rm.unicatt.it
Competing interests: No competing interests
I note that other respondents have mentioned that breastfeeding might
give these children the same benefits as the probiotic used. In the
article it is stated under the description of methods, that other
probiotic-containing foods (than the milk with added probiotic) were
'forbidden'.
Would the authors care to comment on whether that included breastmilk, and
if so, whether there were any children who were weaned for the purpose of
participating in this study?
Again, it seems that we need to be reminded that breastfeeding is not
something which is beneficial to the babes-in-arms and without impact once
the child is over a year, or two, or three or more. Why, then, are we so
stingy with this natural resource?
For all we know, one reason we have two breasts can be to be able to
continue to feed an older child even after the next baby is born. We
really have no idea what is optimal breastfeeding duration. This study
shows that at least one component of breastmilk has benefits for the child
whose contact with surroundings has expanded. We already know that
specific antibodies are distributed throughout the day's production of
milk, so that a child getting breastmilk even once a day is getting a full
quota of antibodies if the mother is only breastfeeding that child.
Competing interests: No competing interests
The paper by Hatakka et al(1) on effects of long-term consumption of
probiotic milk of bovine origin on infections and days absent from day
care is interesting, insofar as it goes. From a close reading of the
paper, the study, involving day care children aged 1-6 years, makes no
mention of a further relevant question, whether any of the younger
children were continuing to receive breastmilk, a source of protective
bacilli that costs nothing. I note that three of the study’s authors were
either current or past employees of the manufacturer of the probiotic
product, or had a past relationship. Health authorities are increasingly
recommending that breastfeeding continue beyond the first year of
extrauterine life,(2) yet the authors fail to state whether they had
ascertained if any of the children were receiving breastfeeds, or whether
all were non-breastfeeders.
This is relevant because of the protective effects of breastmilk on
the intestinal mucosa, a scenario in which Lactobacillus bifidus plays a
role.(3) Indeed, breastmilk is protective against a wide range of
digestive, respiratory and other ailments through a number of
mechanisms.(4, 5) It is thus no wonder that in an earlier Peruvian
study cited in the editorial by Wanke in the same issue,(6) it was the
non-breasteeding children who showed the most improvement on the probiotic
food. Perhaps we shall some day see the results of a study of the effects
of breastfeeding into the second year on intestinal health and days absent
from child care.
Virginia Thorley, OAM, MA, IBCLC
Brisbane, Queensland,
Australia
REFERENCES
(1) Hatakka K, Erkki S, Ponka A, et al. Effect of long term consumption of
probiotic milk on infections in children attending day care centres:
double blind, randomised trial. Br Med J 2001;322(7298):1327-29.
(2) American Academy of Pediatrics. Breastfeeding and the use of human
milk. Pediatrics 1999;100(6):1035-39.
(3)Riordan J, Auerbach KG. Breastfeeding and human lactation. Boston:
Jones & Bartlett, 2nd edn., 1999, p. 141.
(4) ibid, chapter 5.
(5) Lawrence RA, Lawrence RM. Breastfeeding: a guide for the medical
profession. St Louis: Mosby, 5th edn., 1999, chapter 5.
(6)Wanke CA. Mr Med. J 2001;322(7298):1318.
Competing interests: No competing interests
Editor,
Breastfed infants have high intestinal levels of Lactobacillus
bifidus, which promotes intestinal acidity and reduces growth of
enteropathogens(1). Breastfed infants have been found to have, relative
to artificially fed infants, a lower incidence of gastroenteritis,
respiratory infection and otitis media(2).
The children studied by Hatakka et al(3) included many who had been
breastfed for long periods. This may account for the small differences
they found: probiotic therapy is known to be more effective in non-
breastfed children(4), who are deprived of the natural probiotic content
of human milk.
A more appropriate study design might compare groups of children with
the duration and exclusivity of their breastfeeding (if any) carefully
described. This could yield useful information both on optimum
breastfeeding practice and on the true clinical usefulness of probiotic
therapy.
Meanwhile, perhaps we should simply encourage and support mothers to
breastfeed their toddlers for longer, rather than devising yet another
commercial substitute for breastmilk.
Yours sincerely,
Carol Campbell
References
1. Riordan J, Auerbach KG (eds). Breastfeeding and human lactation. 2nd ed. Jones and Bartlett: Sudbury, 1999.
2. Campbell CMA. Breastfeeding and health in the
western world. Brit J Gen Pract 1996;46:613-617.
3. Hatakka K et al. Effect of long term consumption of
probiotic milk on infections in children attending day
care centres: double blind, randomised trial. BMJ
2001;322:1327-9.
4. Oberhelman RA et al. A placebo-controlled trial of
Lactobacillus GG to prevent diarrhoea in
undernourished Peruvian children. J Pediatr
1999;134:15-20.
Competing interests: No competing interests
If non-pathogenic bacteria added to milk consumed by infants confers
benefits, then might not "raw" or unpastuerized milk provide a similar
benefit? Of course, fortification with certain deficient nutrients would
most likely be warranted, especially if this were the primary source of
nourishment for an infant.
Does anyone have any information or thoughts about this? Would the
risks be too great? Is there any published evidence, either positive or
negative, on this subject?
Competing interests: No competing interests
This is fascinating academic news, the stuff of which grants are made
(by food companies?) and of interest to those who cannot keep their
children at home or breastfeed them.
Competing interests: No competing interests
Let's be Realistic
I note the flurry of responses this paper has generated, and was
impressed with how unrealistic several of them are with regard to the
practicality of extending breastfeeding beyond 12 months of age. Apart
from the response the authors provided showing no difference between the
breast & non-breast fed children in this study, it is also worth
noting the practical reality that children are generally in childcare
because their mothers are in paid work. Moreover, the majority of mothers
do not have the luxury of on-site or co-located childcare facilities,
which thus largely precludes ongoing breast feeding. Balancing work and
childcare responsibilities are difficult enough for many mothers without
an additional burden of guilt for failing to breastfeed beyond 12 months
being applied without definite proof of its benefit.
Declaration of competing interests:
I am a mother of 3 children, who were breast fed to ~12 months of age, and
have maintained work (and used childcare during this time).
Competing interests: No competing interests