Probiotics and Infectious DiarrheaJose Saavedra, M.D.Johns Hopkins Medical Center, Baltimore, Maryland

ABSTRACTNumerous probiotic agents have been studied for the man-agement of diarrheal disease. In particular, the preventionand management of acute viral diarrhea, the treatment ofrecurrentClostridium difficilediarrhea, as well as the con-trol of antibiotic-associated diarrhea seem to be areas ofsignificant potential benefit. A few agents, includingLac-tobacillus GG, Lactobacillus reuteri, and Saccharomycesboulardii, seem to be promising agents for the ameliorationof the course of acute diarrhea in children when used ther-apeutically. The use of other agents, particularlyBifidobac-teria, supplementing the regular feed of infants may have aneffect as prophylactic agents against acute diarrheal dis-eases. In general, in pediatric populations, the effect ofprobiotic agents appears to be most significant against viral(rotaviral) diarrhea, suggesting that an immunologicalmechanism is responsible for the beneficial effects. Thenumerous agents, doses, and populations used make gener-alization difficult. Nevertheless, it is clear probiotic agentsare becoming an important part of the armamentariumagainst gastrointestinal problems in infants and children.(Am J Gastroenterol 2000;95(Suppl.):S16–S18. © 2000 byAm. Coll. of Gastroenterology)

INTRODUCTION

Infectious diarrhea is a worldwide public health problem. Inmany developing countries, diarrheal disease remains aleading cause of illness and death among infants and chil-dren (1, 2). In more developed nations, nosocomially ac-quired diarrheal disease can significantly lengthen hospitalstays and increase both direct and indirect medical costs. Toaddress this problem, numerous probiotic agents have beenstudied in the management of infectious diarrheal disease.Preliminary experimental and clinical findings show thatprobiotics are emerging as an important, new therapy forpreventing and treating infectious diarrhea.

Despite a growing body of research about probioticagents, their defining characteristics have not been firmlyestablished. Many investigators accept Fuller’s descriptionof probiotics as living microorganisms that prevent or treatdisease by restoring balance to a disrupted gut microflora(3). However, there is no conclusive evidence to show thatprobiotics must be alive to be effective or what constitutesa so-called “balanced flora.” In fact, future studies may evenidentify specific areas in which the antibacterial substances

produced by probiotics are responsible for the benefit, ratherthan the probiotics themselves. In addition, probiotics maywork by restoring normal balance to a disrupted gut micro-flora, but this has not been clearly demonstrated. A usefuldefinition of a probiotic agent should account for theseclinical probabilities. Therefore, until the importance ofusing a living agent is shown and the mechanism of actionof these substances is clarified, probiotics should be de-scribed as microbial feed supplements that, when ingested,have a positive effect on the prevention or treatment of aspecific pathological condition.

PROPHYLACTIC THERAPY

A number of probiotics have been used, with varying suc-cess, to prevent diarrheal disease. The incidence of travel-er’s diarrhea, for instance, has been reduced with the pro-biotics Lactobacillus GG (LGG) and Saccharomycesboulardii. UsingLGG, Hilton and co-workers reported sig-nificantly reduced rates of diarrhea among 245 subjectstraveling from the United States to developing nations (4).Oksanenet al.conducted anLGG study among 756 Finnishpatients traveling to two resort locations in Turkey thatshowed significantly reduced risk at one of the two locations(5). Another study of traveler’s diarrhea was performed byKollaritch and co-workers, who evaluated the response toS.boulardii in 1016 people traveling from Europe to the Mid-dle East (6). The likelihood of developing diarrhea was notsignificantly reduced in the overall study population (39%of controls vs 29% of S. boulardii-treated subjects hadsymptoms), but significant reductions were observed in cer-tain patient subgroups. The differing outcomes seen withinlarge-scale probiotic studies suggest that the efficacy of aprobiotic is highly dependent on the type of patient selectedfor treatment. They also reaffirm that perceiving probiotictherapy as a battle between so-called “good” and “bad”bacteria oversimplifies the issue. Probiotic studies with largecohorts that only show significant effects in subgroups willshape future investigations, as they can help to identifywhich patients and which conditions are most likely torespond to prophylactic therapy.

ABORTIVE THERAPY

Most investigations in which probiotics are used as abortiveagents for infectious diarrhea have focused on infants and

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 95, No. 1, Suppl., 2000© 2000 by Am. Coll. of Gastroenterology ISSN 0002-9270/00/$20.00Published by Elsevier Science Inc. PII S0002-9270(99)00811-4

children, who have the greatest risk of serious illness ordeath from diarrhea (as well as the most urgent need for newtreatment options). For example, Wunderlichet al. foundthat Enterococcus faeciumreduced the duration of acutediarrhea in children (7), although the responsible pathogenwas not identified. However, in a more recent study, whereE. faeciumwas used to treatE. coli-associated diarrhea, noclinical difference between the probiotic and placebo wasobserved (8).Saccaromyces boulardiihas improved out-comes in acute diarrheal disease, both as part of oral rehy-dration therapy (9) and as a feeding supplement (10). In astudy of HIV-associated acute diarrhea, Saint Marc andco-workers reported that 56% of patients who were treatedwith S. boulardii had their symptoms resolved, comparedwith only 6% of placebo-treated patients (11). A probioticthat recently has been reported in the literature isLactoba-cillus reuteri. Shornikova and colleagues gaveL. reuteri to40 patients with acute diarrhea and found that the averageduration was 1.7 days, compared with 2.9 days for controls(12).

Lactobacillus GGhas significantly reduced the durationof acute diarrhea in numerous recent studies, and someinvestigators have observed a decrease in the rate ofrota-virus-associated diarrhea and rotaviral shedding with thisagent. For example, Isolauri and co-workers found that 90%of children treated withLGG had an IgA sASC (antibodysecreting cell) response torotavirus versus46% for placebo(13). Shortened duration of diarrhea and decreased rotaviralshedding were also reported withLGG by Guarinoet al.,confirming Isolauri’s results (14). The positive effects onviral diarrhea suggest that there is an immunological re-sponse withLGG. As rotavirus is the most common causeof acute gastroenteritis in early childhood (15), the earlyresults seen withLGG are particularly encouraging. More-over, a decrease inrotavirus shedding may lead to lessenvironmental exposure, potentially lowering the rate ofnosocomial infection in infants at increased risk for gastro-enteritis. Future studies ofLGG’s antiviral properties mayexplain the phenomenon and indicate other clinical appli-cations for this and other probiotics.

Infectious diarrhea has also been successfully treated byadding a combination ofBifidobacteriaand Streptococcusthermophilusto powdered formula. A study was conductedusing the combination to treat acute diarrhea in 55 infants ofsimilar ages and weights who were inpatients at a chroniccare facility (Table 1) (16). The infants were fed eithersupplemented formula or control for a total of 4447 patient-days, and there was no difference in formula intake between

the groups. Significantly fewer infants receiving the supple-mented formula than those receiving control formula devel-oped acute diarrheal disease during their stay at the clinic(Fig. 1) (16). In addition, the cumulative incidence of diar-rhea was significantly reduced in infants receiving the sup-plemented formula (16). Severity of diarrhea, as determinedby duration, number of stools per day, or stool weight perday, was similar between the two groups (Table 2) (16). Asseen withLGG, the combination ofB. bifidumandS. ther-mophilusalso reduced the rate ofrotavirus-associated diar-rhea (from 19% to 7%) and decreasedrotavirus shedding(Fig. 2) (16). Ongoing studies are examining safety issueswith this combination of agents, and preliminary results areencouraging.

CONCLUSIONS

Many recent studies have shown that probiotic agents canbenefit children with acute diarrheal disease. The most sig-nificant benefits have been seen inrotavirusdisease, whichcontinues to be the most important pathogen for pediatricdiarrheal disease worldwide. It is important to rememberthat although the benefits of probiotic treatment are modest,agents that can reduce the duration of disease by 1 or 2 days,such as probiotics, may have great epidemiological signif-icance. Probiotics, however, do not represent a panacea fordiarrheal disease management.

In the past decade, the quality of data being collected onprobiotics has improved, particularly when compared with

Table 1. Subject Characteristics

Supplemented Control

No subjects 29 26Age (months) 10.9 (6.1) 11.2 (5.7)Wt/age, z-score 23.1 (1.6) 22.8 (1.7)Ht/age, z-score 23.6 (2.6) 23.7 (2.4)

Figure 1. Fewer infants receiving formula with a combination ofBifidobacteria and Streptococcus thermophilusdeveloped acutediarrheal disease than those receiving control formula.

Table 2. Clinical Results: Diarrhea

Supplemented Control

Incidence 2 (6.9%) 8 (31%)Duration (d) 4 (1.4) 4.3 (1.4)Stool (g/d) 592 (78) 523 (146)Rotavirusshedding 3 (10.3%) 10 (38.5%)

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the large volume of anecdotal information that preceded therecent studies. However, with various researchers studyingdifferent populations with different probiotic species anddifferent strains, often using different doses and dosingpatterns, progress continues to be slow. In addition, manycurrently published studies have evaluated probiotics incases of relatively mild diarrhea in children who were wellnourished. Future work should identify the most effectiveprobiotics, their optimal doses, and their mechanism ofaction, in addition to the importance of delivery vehicles andassociated diet to outcomes. Studies are also needed amongother high-risk groups, such as immunocompromised HIV/AIDS or cancer patients. The use of probiotics in developingnations, possibly as a part of oral rehydration solutions, mayprovide enormous benefit and will contribute significantly toour knowledge base. Clinical research may show that pro-biotics are a practical method for preventing and treatingdiarrheal disease over a wide range of clinical and environ-mental conditions.

Reprint requests and correspondence:Jose Saavedra, M.D.,Johns Hopkins Medical Center, 600 No. Wolfe Street, Baltimore,MD 21287.

Received Mar. 17, 1999; accepted Sep. 7, 1999.

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16. Saavedra JM, Bauman NA, Oung I, et al. Feeding ofBi-fidobacterium bifidum, andStreptococcus thermophilusto in-fants in hospital for prevention of diarrhea, and shedding ofrotavirus. Lancet 1994;344:1046–9.

Figure 2. The formula containing a combination ofB. bifidumandS. thermophilusdecreased shedding ofrotavirus more than thecontrol formula.

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