Special Section: Intestinal Microflora and Health

Prevention of Travellers’ Diarrhoea by Lactobacillus GG

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Pekka J. Oksanen’, Seppo Salminen2, Maija Saxelin2, Pirjo Hamatainenz, Arja Ihantola-Vormistoz, Leena Muurasniemi-lsoviita2,Seppo Nikkari2, Tertit Oksanenz, llkka PorstP, Eeva Salminen2, Simo Siitonen2, Helene Stuckey2, Antti Toppila2 and Heikki Vapaatalo’ A placebo-controlled double-blind study was conducted on the efficacy of Lactobacil/us GG in preventing travellers’ diarrhoea. Altogether 820 persons travelling on holiday to southern Turkey to two destinations were randomized into two groups receiving either Lactobacillus GG or placebo in identical sachets. On the return flight each participant completed a questionnaire indicating the incidence of diarrhoea and related symptoms during the trip. Of the original group 756 (92 “/o) subjects completed the study acceptably. The overall incidence of diarrhoea was 43.8 OO/ (331 cases). The total incidence of diarrhoea in the placebo group was 46.5 OO/ and in the LacfobacillusGG 41.0 OO/ indicating an overall protection of 11.8 %. Protection rates varied between two different destinations with the maximum protection rate reported as 39.5 %.Among older age groups there was significantly less diarrhoea when compared to younger travellers. Lacfobacillus GG appeared to be effective in reducing the occurrence of travellers’ diarrhoea in one of the two destinations with no side effects. Key words: Lactobacillus GG; travellers’ diarrhoea. (Annals of Medicine 22: 53-56,


Introduction Traveller’s diarrhoea (TD) is a common syndrome affecting healthy travellers not only to developing countries but also to many European destinations. The incidence of TD varies between 20 to 50 O h (1, 2) depending on the origin and the destination of the traveller as well as the mode of travel. In 1987 we conducted a questionnaire study among 1464 Finnish tourists on the incidence of TD (Oksanen PJ, Vapaatalo H, Salminen s. The incidence of travellers’ diarrhoea among Finnish t ou ri st s in different cou nt ries. Un publ ished o bservations.) It was found to be 7 O h in Spain and Greece, 21 O/O in Tunisia, 40 O h in Turkey and 59 % in Thailand. Various infectious agents have been described as the cause of TD. Toxin-producing strains of E. coli are the most common organisms colonising the upper intestine, although other microbial agents have been isolated as well. Depending on the laboratory methods an aetiological agent cannot be isolated from 15-37 OO/ of cases (1, 3). In 1988 over nine million tourists travelled by air from Finland to various countries for business or pleasure. From the Medical Department, Finnair Oy, Helsinki, and Travelers’ Diarrhea Group, University of Tampere, Finland. Address and reprint requests: Pekka J. Oksanen, M.D., Medical Department, Finnair Oy, SF-01530 Vantaa, Finland.

Even among those with the lowest reported incidence of TD many enjoyable days were lost. To prevent an attack of TD various techniques have been tried. These include the use of certain antibiotics, active immunisation, non-antibiotic agents such as bismuth subsalicylate and various lactobacilli preparations. A new type of unique Lactobacillus strain known as GG has been isolated from healthy humans on the basis of its ability to resist acid and bile and to adhere to the intestinal mucosa (4). To test its efficacy against TD a randomized double-blind placebo-controlled study was undertaken with a freeze-dried form of Lactobacillus GG among Finnish tourists travelling to two Mediterranean resorts. The study was approved by the Ethical Committee of Tampere University Central Hospital and written informed consent was obtained from each subject.

Subjects and Methods During the summer months in 1988 Sun Tours Travel Agency of Finnair organised one and two week holiday tours from Finland to the resort towns of Alanya and Marmaris on the southern Mediterranean coast of Turkey. Every week 144 travellers stayed in Alanya and 432 in Marmaris. A letter explaining the main layout of the study and a reply card to participate in the study

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were sent through the travel agency to 1728 persons booked to these destinations in September 1988. Children under the age of ten were excluded. Initially 820 persons volunteered for the study, 528 of them travelling to Marmaris (350 for one week and 178 for two weeks) and 228 to Alanya (147 for one week and 81 for two weeks). The volunteers were randomized into two groups receiving either Lactobacillus GG powder (402 subjects) or a placebo containing ethyl cellulose powder (418 subjects) packed in identical sachets. Lactobacillus GG raw material was prepared by Valio Finnish Co-operative Dairies' Association, Helsinki, and the storage stability tests were performed by Leiras Pharmaceuticals Ltd, Tampere. The sachets were mailed to the subjects with instructions to take the contents of one sachet mixed in cold water twice daily starting two days before departure and continuing them during the trip. The daily dose of Lactobacillus GG was about 2 x lo9 bacteria. A Finnish physician was available during the trip at both destinations to register the cases of diarrhoea, to observe side effects and to give medical treatment when necessary. No living, eating or drinking restrictions were placed on the participants during the study. The weather in both resorts and the countryside was similar and typical for that time of the year; daytime temperatures reached 35"C, with mostly clear skies and no precipitation. During the return flight each participant completed a questionnaire (Table 1) which recorded the incidence of diarrhoea and related symptoms. The forms were cob lected by the cabin crew before arrival i n Helsinki. Diarrhoea was defined as three or more unformed stools lasting more than 24 hours or 1-2 unformed watery stools in less than 24 hours. Protection rates were calculated using the following formula (5): Protection rate = 100.

Saxelin, et al.

Table 1. Data requested in the diarrhoea questionnaire.





Name, age, sex Destination, length of trip Health status prior to the trip Chronic diseases, use of drugs History of chronic constipation, diarrhoea, flatulence, lactose intolerance Occurrence of diarrhoea during the trip Estimated number of stool productions during diarrhoea Day of the trip diarrhoea appeared, how long it lasted Other symptoms during the diarrhoea (fever, cramps, pain, vomiting etc.) Type of drugs utilized for the treatment of diarrhoea Use of prophylactic or preventive drugs against diarrhoea

Table 2. Reasons for non-compliance.

Incomplete information of form not returned Used simultaneously other lactic acid bacteria Ill on commencement of travel Forgot preparation at home Stopped taking preparation: - no reason - dizziness - nausea

44 subjects







6 1 1


1) 11

Ninety-two subjects were on a two week trip to Alanya, of whom 40 were in the Lactobacillus group and 52 in the placebo group; 185 subjects went on a two week trip in Marmaris with 87 taking Lactobacillus and 92 placebo. The total number of subjects with diarrhoea reported during the trip was 331 (43.8 Yo), of whom 178 (46.5 '10) were in the placebo group and 153 (41.0 O h ) in the Lac-

percent diarrhoea in placebo group - percent diarrhoea in Lactobacillus group percent diarrhoea in placebo group

Statistical evaluation of the data was performed at the University of Tampere by Ms. Tuula Poussa using Pearson chi-square and Yates corrected chi-square tests. The log-rank and Mantel-Cox methods were employed to determine the most significant factors affecting the survival patterns. Subjects staying two weeks on trip were considered as one-week travellers for the first week and then forming a separate subcategory for the second week.

A total of 756 (92.2 O h ) subjects completed the study. The reasons for non-compliance in 64 subjects are shown in Table 2. They were excluded from the trial. The age distribution of the study group was between 10 and 80 years with the mean age 43.8 k 13.9 (SD) years. Randomization of travellers to Alanya produced an equal age distribution in both Lactobacillus GG and placebo groups while the placebo group going to Marmaris was uneven containing more older subjects than the Lactobacillus GG group.

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tobacillus group (P = 0.065). The overall protection rate was 11.8 %. Of the total number of subjects with diarrhoeacases 189 (57.1 O h ) were reported during the first week and 142 (42.9 O/O) during the second week. When the two destinations were studied separately it was found that in Marmaris the number of travellers with diarrhoea cases during the first week was 74 (42.3 O h ) in the placebo group and 68 (38.9 O h ) in the Lactobacillus group (P = 0.51). The protection rate was 8 %. In those staying two weeks the corresponding numbers were 47 (51.6 O h ) and 49 (56.3 YO), respectively (P = 0.53). tn Alanya the number of travellers with diarrhoea was 30 (39.5 YO)in the placebo group and 17 (23.9 %) in the Lactobacillus group during the first week (P = 0.04). The corresponding numbers in volunteers staying two weeks were 27 (65.9 %) and 19 (47.5 O h , P = 0.10). The calculated protection rate in Alanya group was 39.5 O h for one week and 27.9 % for the second week. The number of cases and the incidence of diarrhoea among different weekly departures varied slightly as shown in Table 3.

Travellers' diarrhoea and Lactobacillus GG Table 3. The number of cases and the incidence of diarrhoea among different weekly departures. Number

Incidence %

Week Week Week Week

35, 36, 37, 38,

September September September September

1988 1988 1988 1988

94 58 84 52

45.2 32.4 38.7 34.2


p 5 5a







> 0.40 t A

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Table 4. Relation between travellers' ages and incidence of diarrhoea.


a 0

Age group

Marmaris Placebo

Lacfobacillus GG

-29 30-39 40-49 50-59 60-

52.6 /a' 41.8 Y~ 32.8 /a' 45.8 28.3 /a'

47.4 /'a 40.0 39.5 /'a 28.3 42.4 /'a



60.0 a/' 57.9 yU 35.1 /a' 26.1 23.1 /a'







Alanya Placebo Lacfobaci'lus GG


Figure 1. Protection rate of Lactobacillus GG against travellers' diarrhoea during one week stay in Alanya (P = 0.02).

7.1 /'a 22.7 39.5 a/' 33.3 9.1 %

Male travellers were as likely to be stricken with diarrhoea as female travellers. The observed incidences were 38.4 O/O in females and 37.7 O/O in males. Increasing age was negatively correlated with the incidence of diairhoea in the placebo group in Marmaris (Table 4). The results of the life table and regular survival analysis showed a definite protection against TD in subjects staying in Alanya in the Lactobacillus GG group both in one ( P = 0.02) and two ( P = 0.06) week groups as compared to the placebo groups (Figs. 1 , 2 ) . No significant protection against TD was found in subjects staying in Marmaris. No side effects related to Lactobacillus GG were observed.








1 0 1 2 1 4

TIME (DAYS) Figure 2. Protection rate of Lactobacillus GG against travellers' diarrhoea during two week stay in Alanya (P = 0.06).

Discussion and Conclusion The high percentage of travellers complaining of gastrointestinal symptoms during holiday travel is well documented in the present study. Diarrhoea is usually self-limited, but it can be a hazard to children and the elderly. Even small attacks can interrupt a holiday, causing inconvenience and discomfort. So the travelling public has a great interest in medications that could be used to prevent TD. Thus a safe, inexpensive and effective drug against TD would have important public health implications. There were striking contrasts in the effectiveness of Lactobacillus GG in the two different locations. Both resorts were very similar, small towns surrounded by sparsely populated countryside, and most of the food was produced on local farms. The resorts were far enough from each other to inhibit people from travelling between the two towns. This would lead to both resorts having their own distinct microbial environ-

ments. It could be postulated that Lactobacillus GG would offer dissimilar protections rate against TD, as a results of different pathogens in the two locations. Another possible contributing factor for the apparent ineffectiveness of Lactobacillus GG in Marmaris might have been the uneven age distribution of the Marmaris placebo group in which older people were very well represented. Lactobacillus GG was well tolerated in all subjects and no side effects could be demonstrated. The study suggests that Lactobacillus GG can safely be administered to healthy people in doses of 2 x lo9 bacteria for up to two weeks. Its use can diminish the risk of TD during trips abroad, although the results are not uniform in all locations. Nevertheless, careful selection of food and beverages in high-risk areas remains the most important preventive measure.

Ann Med 22

Oksanen Salminen Saxelin, et al.



2. Sleffen R, Van der Kinde F, Gyr K, et al. Epidemiology of diarrhea i n travelers. JAMA 1983;249: 1176-80. 3. Merson M, Morris G, Sack D, e l al. Travelers’ diarrhea i n i university , ~ h e authors wish to thank M ~~. ~poussa, Mexico. N Engl J Med 1976;294: 1300-5. ampere’ for her assistance in ,f 4. Deneke C. Goldin 6. Gorbach S. et al. Correlation between human intestinal cell colonizatibn and human cell binding by Lactobacillus strain GG. Annual Meeting of American References Society for Microbiology, 1988. 5. DuPont HL, Ericsson CD, Johnson PC, e l al. Prevention of G o r b a c h S. Travelers’ diarrhea. In: Gorbach S,ed. Infective travelers’ diarrhea by the tablet form of bismuth subsali1d i a r r h e a . Boston: Blackwell Scientific Publications, 1986: cylate. JAMA 1987;10: 1347-50,

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Prevention of travellers' diarrhoea by Lactobacillus GG.

A placebo-controlled double-blind study was conducted on the efficacy of Lactobacillus GG in preventing travellers' diarrhoea. Altogether 820 persons ...
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