Safety of beneficial
microbes – are we at the
crossroads yet?
[with quotes]
Jagiellonian University 1364 A.D.
„When the motor conked out, we paddled home.
Boy was I glad I was wearing Rely.”
I will try to explain the safety aspects of
beneficial microbes as straightforward as Albert Einstein did, when asked to comment on the new
technology – the radio:
- You see, wire telegraph is a kind of a very, very long cat. You pull his tail in New York
and his head is meowing in Los Angeles.
Do you understand this? And radio
operates exactly the same way: you send signals here, they receive them there. The
only difference is that there is no cat.
— Albert Einstein
Current international definition:
„Probiotics are live microorganisms, which when administered in adequate amount confer a health benefit on the host.”
„Probiotyki to żywe drobnoustroje, które podane
w odpowiedniej ilości wywierają korzystny
wpływ na zdrowie gospodarza.” – Polish Society for Probiotics and Prebiotics
Adverse reactions:
According to FAO/WHO guidelines from 2001 and 2006, probiotics may be (no longer)
theoretically responsible for different types of adverse reactions:
1. Systemic infections
2. Deleterious metabolic effects
3. Excessive immune stimulation in susceptible individuals
4. Gene transfer
No man's life, liberty, or
property are safe while the legislature is in
session.
— Mark Twain
Safety
• Parameters, that should be taken into account when analyzing beneficial microbes’ safety are:
- pathogenicity,
- potential for causing infections,
- virulence, including toxin production, - metabolic activity and
- inherent characteristics of a given genus and species (and recently also the strain) of the microbe.
Safety (continued)
Summing up, the studies recommended by
FAO/WHO regarding probiotic safety encompass:
1. Determination of antibiotic resistance patterns
2. Assessment of certain metabolic activities
(e.g., D-lactate production, bile salt deconjugation) 3. Assessment of side-effects during human studies
4. If the strain under evaluation belongs to a species that is a known mammalian toxin producer, it must be
tested for toxin production. One possible scheme for testing toxin production has been recommended by the EU Scientific Committee on Animal Nutrition (SCAN, 2000)
5. If the strain under evaluation belongs to a species with known hemolytic potential, determination of
hemolytic activity is required
Safety (continued)
6. Epidemiological surveillance of adverse incidents in consumers (post-market)
Furthermore, in the light of recent developments, and in agreement with ISAPP – evaluation showing no infectivity and no adverse events of the probiotic strain, performed on immunocompromised animal models, will increase the safety profile of the tested strain.
Safety (continued)
Drug vs. Dietary Supplement or Food
In countries outside the USA, beneficial microbes and preparations containing such strains have various
designations:
- In some countries, incl. those in the EU, probiotics
were registered as drugs previously and automatically stayed drugs when legislation changed.
- In other countries beneficial microbes are contained in preparations which qualify as food supplements or
food containing beneficial strains, e.g. dairy products.
They are considered to have GRAS status.
Health claims control = EFSA.
Still, in some countries there is no legislature.
Get your facts first, then you can distort
them as you please.
— Mark Twain
Dutch PROPATRIA study
(PRObiotics in PAncreatitis TRIAl) as a catalyst
• Multicenter, randomized, double-blinded, placebo controlled clinical trial on 298 patients with severe acute pancreatitis.
• Aim: to show less complications with multispecies probiotic preparation use
• Composition: Ecologic 641 - Lactobacillus acidophilus, L. casei, L. salivarius, Lactococcus lactis, Bifidobacterium bifidum and B.
lactis in a dose 1010 of bacteria.
• Dosing: twice daily via nasojejunal tube for 28 days
• Unexpected result: higher mortality in the probiotic group.
• Groups were similar as to the patient type, severity of symptoms and course of the disease.
• Mortality upon completion of the study: 24 persons died in the probiotic group vs. 9 persons in the placebo
group.
• Nine patients in the probiotic group suffered from bowel ischemia (8 died), none in the placebo group (p=0.004).
PROPATRIA (continued)
There are three kinds of lies: lies, damned lies,
and statistics.
— Mark Twain
Case from the USA (post transplant)
• 56 year old HIV+ patient undergoing lung transplant.
• Aim: prevention of C. difficile associated diarrhea
• Standard regimen used in that institution was to administer Lactobacillus GG the day after the surgical procedure.
• Unexpected result: A week post discharge from the hospital the patient was diagnosed with empyema and the same probiotic
strain that was administered earlier on was isolated from the sample. The patient had to undergo decortication (removal of
pleura) because of relapsing empyema and was given a two week IV ampicillin with sulbactam. Patient’s status is currently
satisfactory.
Case from Poland (cardiosurgical)
• 24 year old female patient after aortic valve replacement.
• Cel: supplementary probiotic rx with perioperative antimicrobial prophylaxis
• Lactobacillus rhamnosus Pen, E/N, Oxy before and after surgery.
• Unexpected result: Sepsis. Molecular confirmation that the isolated strains were the same as the probiotic ones used.
Antimicrobial treatment was successful.
German study in the prevention of atopic dermatitis
• Randomized, double-blinded, placebo controlled clinical study on 94 patients.
• Aim: primary prevention of atopic dermatits by administering a probiotic
• Lactobacillus GG (ATCC 53103) 5x109 CFU 2 x daily per os.
• Unexpected result: supplementation of pregnant women and
newborns did not lower the number of cases and had no influence on the course of atopic dermatitis. Unfortunately it was also
associated with relapsing episodes of wheezing. The German team does not recommend the use of Lactobacillus GG for the prevention of atopic dermatitis.
Australian study on atopic dermatitis
• Randomized, double-blinded, placebo controlled on 178 patients.
• Aim: lower the incidence risk of atopic dermatitis by administering a probiotic
• Lactobacillus acidophilus LAVRI-A1 3x109 daily per os.
• Unexpected result: probiotic supplementation in the first 6 months of life not only did not lower the incidence of atopic
dermatitis but even increased the likelihood of allergic disorders in the studied group.
Review study of Lactobacillus infections:
over 200 cases analyzed
• Retrospective.
• Aim: evaluation of cases, treatment and its efficacy
• Lactobacillus was most often isolated in endocarditis, bacteriemia, peritonitis, abscesses and meningitis cases.
• Results: isolates were shown to be most sensitive to erythromycin and clindamycin, and most resistant to vancomycin. The strain
most sensitive to vanco: L. acidophilus.
Mortality ~30%, most often due to inapropriate rx and mixed infections.
Postulated mechanisms of severe adverse events (SAE)
related to probiotic use
1. Intestinal hypoxia, e.g.:
(a) administration of 10 billion probiotic bacteria daily,
including nasojejunal feeding, could have put additional local oxygen demand, worsening the already hypoxic state of the G.I. tract.
(b) excessive number of (probiotic) bacteria, resulting in a
Postulated mechanisms of
SAE related to probiotic use (continued)
2. Microaspiration of G.I. tract flora.
3. Damage to the intestinal barrier (mentioned in point no.
1), including toxic action of drugs on the mucosa, leading to bacterial translocation.
4. Ineffective treatment when using ”salvage
antimicrobials”, owing to resistance of many probiotic strains.
Analyzing the current literature one may come to a conclusion that probiotic use may be
riskyrisky even dangerous for the following:
- persons severely immunocompromised, - persons with organ failure,
- persons with severe chronic conditions, - persons undergoing complex surgical
RISK GROUPS FOR PROBIOTIC USE
• PLEASE NOTE! Statistics and generalizations are deceitful (papers on probiotics very often talk of
”probiotics being safe owing to their long history of use by many millions of people…”).
• Good example are airlines: millions of passengers
travel by plane every year, it’s considered to be one of the safest means to travel, but disasters do happen.
CONCLUSION 1
If my neighbour beats his wife everyday, and I never
do, then in the light of
statistics we both beat our women every second day.
— George Bernard Shaw
• People love sensational news.
• That is the reason why adverse events related to probiotics receive so much more publicity than their beneficial effects.
CONCLUSION 2
A scientist is a mimosa
when he himself has made a mistake, and a roaring lion when he discovers a
mistake of others.
— Albert Einstein
• Current situation regarding probiotics and adverse events is plain ignorance. It’s similar to hospital infections 20 years ago in communist Poland – if you’d ask a physician back then he would tell you there is no such thing as a hospital infection!
• The time has come to realise that probiotics like any drugs, medicinal products or supplements may be
responsible for adverse events, also SAE, in selected groups of people. Maybe it’s also time for the
producers to place warnings and such info in product information leaflets?
CONCLUSION 3
Errors are a path to the truth.
— Fyodor Dostoyevsky
There is no bad tobacco, as there are no ugly
women.
— Albert Einstein There are no bad
probiotics, as there are no
ugly women.
Final conclusion:
New definition of probiotics should be proposed:
„Probiotics are live microorganisms, which when administered in adequate amount confer a health benefit on the host but should be avoided in certain
risk groups.”
Science becomes
dangerous only when it imagines that it has
reached its goal.
— George Bernard Shaw
References
• Besselink M.G., Dutch Acute Pancreatitis Study Group i wsp.: Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial.
Lancet 371:651–659 (2008)
• Borriello S.P., Hammes W.P., Holzapfel W. i wsp.: Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis 36, 775–780 (2003)
• Deshpande G., Rao S., Patole S.: Probiotics for prevention of necrotising enterocolitis in preterm neonates with very low birthweight: a systematic review of randomised controlled trials. Lancet 369, 1614–1620 (2007)
• Ishibashi N., Yamazaki S.: Probiotics and safety. Am J Clin Nutr 73, 465S–470S (2001)
• Luong M.-L., Sareyyupoglu B., Nguyen M.H. i wsp.: Lactobacillus probiotic use in cardiothoracic transplant recipients: a link to invasive Lactobacillus infection. Trans Infect Dis 12, 561–564 (2010)
• Cannon J.P., Lee T.A., Bolanos J.T., Danziger L.H.: Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases. Eur J Clin Microbiol Infect Dis 24, 31-40 (2005)
• Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria. Córdoba, Argentina, 1-4 October 2001, s. 1–34.
• Joint FAO/WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. London, Ontario, Canada, April 30 and May 1, 2002, s. 1–11.
• Kalliomäki M., Salminen S., Poussa T., Isolauri E.: Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial. J Allergy Clin Immunol 119, 1019–1021 (2007)
• Kopp M.V., Hennemuth I., Heinzmann A., Urbanek R.: Randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of Lactobacillus GG supplementation. Pediatrics 121, e850–e856 (2008)
• Lilly D.M., Stillwell R.H.: Probiotics: growth promoting factors produced by microorganisms. Science 147, 747–748 (1965)
• Liong M.T.: Safety of probiotics: translocation and infection. Nutr Rev 66, 192–202 (2008)
• MacFie J., O'Boyle C., Mitchell C.J., Buckley P.M., Johnstone D., Sudworth P.: Gut origin of sepsis: a prospective study investigating associations between bacterial translocation, gastric microflora, and septic morbidity. Gut 45, 223–228 (1999)
• Naidu A.S., Bidlack W.R., Clemens R.A.: Probiotic spectra of lactic acid bacteria (LAB). Crit Rev Food Sci Nutr 38, 13–126 (1999)
• Osborn D.A., Sinn J.K.: Probiotics in infants for prevention of allergic disease and food hypersensitivity. Cochrane Database Syst Rev 4:CD006475 (2007)
• Salminen M.K., Rautelin H., Tynkkynen S., Poussa T., Saxelin M., Valtonen V., Järvinen A.: Lactobacillus bacteremia, species identification, and antimicrobial susceptibility of 85 blood isolates. Clin Infect Dis 42, e35–e44 (2006)
• Salminen M.K., Tynkkynen S., Rautelin H. i wsp.: Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin Infect Dis 35, 1155–1160 (2002)
• Saxelin M., Chuang N.H., Chassy B. i wsp.: Lactobacilli and bacteremia in southern Finland, 1989-1992. Clin Infect Dis 22, 564–566 (1996)
• Światowa Organizacja Zdrowia, Organizacja Narodów Zjednoczonych ds. Wyżywienia i Rolnictwa. Probiotyki w żywności. Właściwości zdrowotne i żywieniowe oraz wytyczne do ich oceny, red. P. Kochan, Polskie Towarzystwo Probiotyczne i Prebiotyczne, Kraków, 2007.
• Taylor A.L., Dunstan J.A., Prescott S.L.: Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial. J Allergy Clin Immunol 119, 184–191 (2007)
• Tissier H.: Traitement des infections intestinales par la méthode de la flore bactérienne de l'intestin. CR Soc Biol 60, 359–361 (1906)
• Tuohy K.M., Probert H.M., Smejkal C.W., Gibson G.R.: Using probiotics and prebiotics to improve gut health. Drug Discov Today 8, 692–700 (2003)
• Wang X., Andersson R., Soltesz V., Leveau P., Ihse I.: Gut origin sepsis, macrophage function, and oxygen extraction associated with acute pancreatitis in the rat. World J Surg 20, 299–307 (1996)
• Wykorzystano stronę internetową The Noble Foundation.
• Pozostałe obrazki i zdjęcia pochodzą z domeny publicznej, Wikipedii oraz zbiorów własnych autora.
