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Probiotics plus antibiotics: Regulating our bacterial environment
EDITORIALS
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 5
P
Probiotics plus antibiotics: Regulating our bacterial environment
The interest in the use of live microbial agents for the purpose of health maintenance and disease prevention or treatment has exploded over the last few years. Many of these organisms, under the generic name of probiotics, are being proposed as remedies for a broad number of gastrointestinal and other systemic conditions, ranging from diarrheal disease to allergy to cancer prevention. Several books and reviews have been dedicated to the topic.1-3 The term probiotic, as an antonym to the term antibiotic, was originally proposed in 1965 by Lilley and Stillwell,4 to be used for substances that favor the growth of microorganisms. More than 20 years later, Fuller5 broadly defined a probiotic as a “live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance.” The concept is not new. At the turn of the century, Metchnikoff6 suggested that the consumption of live microbes in fermented milk products to maintain this balance between pathogenic and nonpathogenic bacteria may be, at
least in part, an explanation for the longevity of certain ethnic groups. The human body lives in a heavily contaminated bacterial environment, and symbiosis with these microbes seems to be a condition for survival. A human individual has more prokaryotic organisms associated with skin, lung, and gut surfaces than human eukaryotic cells. The role and importance of the intestinal flora in the maintenance of the gut luminal milieu and its effects on colonic epithelium, mucosal integrity, vitamin and nutrient metabolism and absorption, and other systems or processes, have been well described. A logical management approach to situations that alter our microbial ecology (eg, diet, environment, antibiotics) would be to deliberately increase our association with specific nonpathogenic organisms to counter that alteration. Thus conceptually, the use of probiotics constitutes a purposeful attempt to modify the relationship with our immediate microbial environment in ways that may benefit human health. See related article, p. 564.
J Pediatr 1999;135:535-7. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/18/102777
A well-documented example is improvement of tolerance to lactose in individuals with lactose malabsorption.
When lactose is ingested with live lactase-producing organisms such as Streptococcus thermophilus, Lactobacillus bulgaricus (such as in yogurt), and other lactobacilli, luminal digestion is increased and absorption enhanced. Over the last few years, after the development of specific strains demonstrated to survive acid and bile digestion, clinical and basic research have led to a series of studies demonstrating and suggesting many other benefits.1,7 These include management of infectious and noninfectious diarrhea, inflammatory bowel disease, and food allergies, as well as other gastrointestinal disorders and vaginal infections. Preliminary investigation suggests that some agents may also have hypocholesterolemic and anti-tumoral properties. LGG
Lactobacillus GG
The use of antibiotics constitutes an assault to gastrointestinal flora, accepted as one of those risks taken to treat severe infections. Probiotics would be a reasonable alternative to help the gastrointestinal flora resist this aggression. In this issue of The Journal, Vanderhoof et al8 present us with a study evaluating the effect on diarrheal occurrence of concomitant ingestion of 535
EDITORIALS
Lactobacillus GG in children who receive prescribed antibiotics for various acute illnesses. They found that diarrhea, defined as two liquid stools per day, occurred in 25% of children in the placebo group versus only 8% in the treated group. Based on this definition, there was an average decrease in duration of 1.1 days of diarrhea in the treated group. An analog scale was used to assess stool consistency, and 48% versus 17% of children had an average stool consistency of less than “soft to loose.” Although randomization may have helped to decrease the effect of confounding variables, the lack of investigation for stool pathogens, previous bowel habits, and reporting mechanisms are potential limitations to generalization of the results. From the clinical relevance standpoint, the reduction of 1 day of two liquid stools over a 10day period in a child might be questioned. And the occurrence of two loose stools for 48 hours or less might barely make the definition of “diarrhea” for some clinicians. These considerations aside, this study does demonstrate that in this population of children, the ingestion of LGG can mitigate the effect on bowel habits (frequency and consistency) caused by antibiotics. The impact that this reduction would have on day-care absenteeism, health care seeking behaviors, or antibiotic treatment compliance could be of significance but remains speculative until a study is done to address this specifically. The population studied consisted of healthy children with very mild diarrheal disease, in whom the effect may not be as marked. It could be expected that studies of children in higher risk categories, particularly those in whom gastrointestinal function or flora may already be partially or chronically disrupted, might yield clinical benefits of a higher magnitude or significance. For example, in a study of undernourished children,9 LGG decreased the incidence of diarrheal disease in nonbreast-fed infants but had little effect on those who were being breast-fed. 536
THE JOURNAL OF PEDIATRICS NOVEMBER 1999 The alleged “maintenance of microbial balance” as a logical, albeit simplistic, mechanistic concept could be applied to the use of probiotics for control of gastrointestinal bacterial disease. For example, in uncontrolled reports, LGG has decreased the recurrence of Clostridium difficile diarrhea.10 However, there have been multiple studies documenting the effects of several probiotics on viral gastroenteritis. In these studies LGG, bifidobacteria, and other lactobacilli have been reported to prevent or to shorten the duration of and shorten viral shedding in rotaviral disease. The effects that bacteria can have on viral illness suggests that the mechanisms involved are likely more than simply overwhelming the gut lumen with “friendly” bacteria.11 Currently, many research efforts are directed toward elucidating the effect that oral bacterial administration may have on gut immunologic response and its systemic consequences. The possibilities of receptor competition, increased mucin secretion, bacterial “priming” of gut-associated lymphoid tissue, and immunomodulation of gut-associated lymphoid tissue response are all being considered. For example, the secretory IgA component of the intestine to rotaviral infection or to enteral vaccination can be augmented with the concomitant ingestion of specific probiotics.12 The exposure of gut epithelium to a large amount of specific nonpathogenic bacteria may in some ways counteract the bacterial environmental changes that have been induced with the advent of an aseptic food supply. These changes have indiscriminately reduced or eliminated all microorganisms, rather than selectively weeding out pathogens. Thus the possibility that probiotics may modify inadequate or exaggerated inflammatory responses (from intestines deprived of a “richer bacterial experience”), such as in allergy or inflammatory bowel disease, is now being explored, with encouraging results.13 Unfortunately, the wide variety of microorganisms used, the multiple
dosing patterns, and the different populations studied preclude blanket recommendations. Among the best demonstrated effects are the use of LGG and bifidobacteria for the treatment and prevention of diarrheal disease.14 Other lactobacilli and Saccharomyces boulardii (a probiotic yeast) have also been investigated, with positive results reported. But not all bacteria are created equal, and their effects are not same. Thus each “probiotic” strain or strains suggested for use must be carefully studied before making recommendations for the management of specific conditions. Evaluation of target populations and cost-benefit analyses may be needed in some cases to justify their use. Safety does not appear to be a significant concern. Centuries of use of these lactic acid–producing bacteria and lack of significant adverse effects with most strains currently in use are reassuring. A recent review identified 143 human clinical trials of probiotics between 1961 and 1998, involving more than 7500 subjects, with no adverse events reported.3 Nevertheless, we should remain vigilant. This level of comfort has been at least in part responsible for the lack of regulation of the commercialization of probiotic products. Many overthe-counter probiotics now widely available in health food stores are neither reliable as products nor effective as remedies.15 They are sold under the general umbrella of “probiotics” with disguised or sometimes overt claims. Sensible regulation of products and claims, as well as responsibility on the part of this industry, are sorely needed. In the area of probiotic research the hype, the misinformation, and the lack of regulation have blurred the line between scientifically acquired knowledge and anecdote or “pseudoscience.” But adequately designed and executed research in this field is finally sharpening our focus and should ultimately prevail. Jose M. Saavedra, MD Associate Professor
EDITORIALS
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 5 Department of Pediatrics Johns Hopkins University School of Medicine Baltimore, MD 21287
REFERENCES 1. Fuller R. Probiotics 2: applications and practical aspects. London: Chapman & Hall; 1997. p. 1. 2. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections [see comments]. JAMA 1996;275:870-6. 3. Naidu AS, Bidlack WR, Clemens RA. Probiotic spectra of lactic acid bacteria. In: Clydesdale FM, editor. Critical reviews in food science and nutrition. Boca Raton (FL): CRC Press LLC; 1999. p. 13-126. 4. Lilley DM, Stillwell RH. Probiotics: growth promoting factors produced
5. 6.
7.
8.
9.
10.
by microorganisms. Science 1965;147: 747-8. Fuller R. Probiotics in human medicine. Gut 1991;32:439-42. Metchnikoff E. The prolongation of life. New York: CP Putnam’s Sons; 1908. Tannock GW. Probiotics: a critical review. Wymondham, Norfolk (England): Horizon Scientific Press; 1999. p. 1. Vanderhoof JA, Whitney DB, Antonson DL, Hanner TL, Lupo JB, Young RJ. Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children. J Pediatr 1999;135:564-8. Oberhelman RA, Gilman RH, Sheen P, Taylor DN, Black RE, Cabrera L, et al. A placebo-controlled trial of Lactobacillus GG to prevent diarrhea in undernourished Peruvian children. J Pediatr 1999;134:15-20. McFarland LV. Biotherapeutic agents for Clostridium difficile—associated disease. In: Elmer GW, McFarland LV, Surawicz CM, editors. Biotherapeutic
11.
12.
13.
14.
15.
agents and infectious diseases. Totowa (NJ): Humana Press; 1999. p. 159-93. Saavedra JM. Microbes to fight microbes: a not so novel approach to controlling diarrheal disease. J Pediatr Gastroenterol Nutr 1995;21:125-9. Marteau P, Cellier C. Immunological effects of biotherapeutic agents. In: Elmer GW, McFarland LV, Surawicz CM, editors. Biotherapeutic agents and infectious diseases. Totowa (NJ): Humana Press; 1999. p. 121-44. Campieri M, Gionchetti P. probiotics in inflammatory bowel disease: New insight to pathogenesis or a possible therapeutic alternative? Gastroenterology 1999;116:1246-9. Saavedra JM, Abi-Hanna A. Clinical studies of probiotic agents. In: Hanson L, Yolken RH, editors. Probiotics. Other nutritional factors, and intestinal microflora. Philadelphia: Lippincott-Raven; 1999. p. 271-86. Hamilton-Miller JM, Shah S, Smith CT. “Probiotic” remedies are not what they seem [letter]. BMJ 1996;312:55-6.
537
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 5
P
Probiotics plus antibiotics: Regulating our bacterial environment
The interest in the use of live microbial agents for the purpose of health maintenance and disease prevention or treatment has exploded over the last few years. Many of these organisms, under the generic name of probiotics, are being proposed as remedies for a broad number of gastrointestinal and other systemic conditions, ranging from diarrheal disease to allergy to cancer prevention. Several books and reviews have been dedicated to the topic.1-3 The term probiotic, as an antonym to the term antibiotic, was originally proposed in 1965 by Lilley and Stillwell,4 to be used for substances that favor the growth of microorganisms. More than 20 years later, Fuller5 broadly defined a probiotic as a “live microbial feed supplement which beneficially affects the host animal by improving its intestinal microbial balance.” The concept is not new. At the turn of the century, Metchnikoff6 suggested that the consumption of live microbes in fermented milk products to maintain this balance between pathogenic and nonpathogenic bacteria may be, at
least in part, an explanation for the longevity of certain ethnic groups. The human body lives in a heavily contaminated bacterial environment, and symbiosis with these microbes seems to be a condition for survival. A human individual has more prokaryotic organisms associated with skin, lung, and gut surfaces than human eukaryotic cells. The role and importance of the intestinal flora in the maintenance of the gut luminal milieu and its effects on colonic epithelium, mucosal integrity, vitamin and nutrient metabolism and absorption, and other systems or processes, have been well described. A logical management approach to situations that alter our microbial ecology (eg, diet, environment, antibiotics) would be to deliberately increase our association with specific nonpathogenic organisms to counter that alteration. Thus conceptually, the use of probiotics constitutes a purposeful attempt to modify the relationship with our immediate microbial environment in ways that may benefit human health. See related article, p. 564.
J Pediatr 1999;135:535-7. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/18/102777
A well-documented example is improvement of tolerance to lactose in individuals with lactose malabsorption.
When lactose is ingested with live lactase-producing organisms such as Streptococcus thermophilus, Lactobacillus bulgaricus (such as in yogurt), and other lactobacilli, luminal digestion is increased and absorption enhanced. Over the last few years, after the development of specific strains demonstrated to survive acid and bile digestion, clinical and basic research have led to a series of studies demonstrating and suggesting many other benefits.1,7 These include management of infectious and noninfectious diarrhea, inflammatory bowel disease, and food allergies, as well as other gastrointestinal disorders and vaginal infections. Preliminary investigation suggests that some agents may also have hypocholesterolemic and anti-tumoral properties. LGG
Lactobacillus GG
The use of antibiotics constitutes an assault to gastrointestinal flora, accepted as one of those risks taken to treat severe infections. Probiotics would be a reasonable alternative to help the gastrointestinal flora resist this aggression. In this issue of The Journal, Vanderhoof et al8 present us with a study evaluating the effect on diarrheal occurrence of concomitant ingestion of 535
EDITORIALS
Lactobacillus GG in children who receive prescribed antibiotics for various acute illnesses. They found that diarrhea, defined as two liquid stools per day, occurred in 25% of children in the placebo group versus only 8% in the treated group. Based on this definition, there was an average decrease in duration of 1.1 days of diarrhea in the treated group. An analog scale was used to assess stool consistency, and 48% versus 17% of children had an average stool consistency of less than “soft to loose.” Although randomization may have helped to decrease the effect of confounding variables, the lack of investigation for stool pathogens, previous bowel habits, and reporting mechanisms are potential limitations to generalization of the results. From the clinical relevance standpoint, the reduction of 1 day of two liquid stools over a 10day period in a child might be questioned. And the occurrence of two loose stools for 48 hours or less might barely make the definition of “diarrhea” for some clinicians. These considerations aside, this study does demonstrate that in this population of children, the ingestion of LGG can mitigate the effect on bowel habits (frequency and consistency) caused by antibiotics. The impact that this reduction would have on day-care absenteeism, health care seeking behaviors, or antibiotic treatment compliance could be of significance but remains speculative until a study is done to address this specifically. The population studied consisted of healthy children with very mild diarrheal disease, in whom the effect may not be as marked. It could be expected that studies of children in higher risk categories, particularly those in whom gastrointestinal function or flora may already be partially or chronically disrupted, might yield clinical benefits of a higher magnitude or significance. For example, in a study of undernourished children,9 LGG decreased the incidence of diarrheal disease in nonbreast-fed infants but had little effect on those who were being breast-fed. 536
THE JOURNAL OF PEDIATRICS NOVEMBER 1999 The alleged “maintenance of microbial balance” as a logical, albeit simplistic, mechanistic concept could be applied to the use of probiotics for control of gastrointestinal bacterial disease. For example, in uncontrolled reports, LGG has decreased the recurrence of Clostridium difficile diarrhea.10 However, there have been multiple studies documenting the effects of several probiotics on viral gastroenteritis. In these studies LGG, bifidobacteria, and other lactobacilli have been reported to prevent or to shorten the duration of and shorten viral shedding in rotaviral disease. The effects that bacteria can have on viral illness suggests that the mechanisms involved are likely more than simply overwhelming the gut lumen with “friendly” bacteria.11 Currently, many research efforts are directed toward elucidating the effect that oral bacterial administration may have on gut immunologic response and its systemic consequences. The possibilities of receptor competition, increased mucin secretion, bacterial “priming” of gut-associated lymphoid tissue, and immunomodulation of gut-associated lymphoid tissue response are all being considered. For example, the secretory IgA component of the intestine to rotaviral infection or to enteral vaccination can be augmented with the concomitant ingestion of specific probiotics.12 The exposure of gut epithelium to a large amount of specific nonpathogenic bacteria may in some ways counteract the bacterial environmental changes that have been induced with the advent of an aseptic food supply. These changes have indiscriminately reduced or eliminated all microorganisms, rather than selectively weeding out pathogens. Thus the possibility that probiotics may modify inadequate or exaggerated inflammatory responses (from intestines deprived of a “richer bacterial experience”), such as in allergy or inflammatory bowel disease, is now being explored, with encouraging results.13 Unfortunately, the wide variety of microorganisms used, the multiple
dosing patterns, and the different populations studied preclude blanket recommendations. Among the best demonstrated effects are the use of LGG and bifidobacteria for the treatment and prevention of diarrheal disease.14 Other lactobacilli and Saccharomyces boulardii (a probiotic yeast) have also been investigated, with positive results reported. But not all bacteria are created equal, and their effects are not same. Thus each “probiotic” strain or strains suggested for use must be carefully studied before making recommendations for the management of specific conditions. Evaluation of target populations and cost-benefit analyses may be needed in some cases to justify their use. Safety does not appear to be a significant concern. Centuries of use of these lactic acid–producing bacteria and lack of significant adverse effects with most strains currently in use are reassuring. A recent review identified 143 human clinical trials of probiotics between 1961 and 1998, involving more than 7500 subjects, with no adverse events reported.3 Nevertheless, we should remain vigilant. This level of comfort has been at least in part responsible for the lack of regulation of the commercialization of probiotic products. Many overthe-counter probiotics now widely available in health food stores are neither reliable as products nor effective as remedies.15 They are sold under the general umbrella of “probiotics” with disguised or sometimes overt claims. Sensible regulation of products and claims, as well as responsibility on the part of this industry, are sorely needed. In the area of probiotic research the hype, the misinformation, and the lack of regulation have blurred the line between scientifically acquired knowledge and anecdote or “pseudoscience.” But adequately designed and executed research in this field is finally sharpening our focus and should ultimately prevail. Jose M. Saavedra, MD Associate Professor
EDITORIALS
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 5 Department of Pediatrics Johns Hopkins University School of Medicine Baltimore, MD 21287
REFERENCES 1. Fuller R. Probiotics 2: applications and practical aspects. London: Chapman & Hall; 1997. p. 1. 2. Elmer GW, Surawicz CM, McFarland LV. Biotherapeutic agents. A neglected modality for the treatment and prevention of selected intestinal and vaginal infections [see comments]. JAMA 1996;275:870-6. 3. Naidu AS, Bidlack WR, Clemens RA. Probiotic spectra of lactic acid bacteria. In: Clydesdale FM, editor. Critical reviews in food science and nutrition. Boca Raton (FL): CRC Press LLC; 1999. p. 13-126. 4. Lilley DM, Stillwell RH. Probiotics: growth promoting factors produced
5. 6.
7.
8.
9.
10.
by microorganisms. Science 1965;147: 747-8. Fuller R. Probiotics in human medicine. Gut 1991;32:439-42. Metchnikoff E. The prolongation of life. New York: CP Putnam’s Sons; 1908. Tannock GW. Probiotics: a critical review. Wymondham, Norfolk (England): Horizon Scientific Press; 1999. p. 1. Vanderhoof JA, Whitney DB, Antonson DL, Hanner TL, Lupo JB, Young RJ. Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children. J Pediatr 1999;135:564-8. Oberhelman RA, Gilman RH, Sheen P, Taylor DN, Black RE, Cabrera L, et al. A placebo-controlled trial of Lactobacillus GG to prevent diarrhea in undernourished Peruvian children. J Pediatr 1999;134:15-20. McFarland LV. Biotherapeutic agents for Clostridium difficile—associated disease. In: Elmer GW, McFarland LV, Surawicz CM, editors. Biotherapeutic
11.
12.
13.
14.
15.
agents and infectious diseases. Totowa (NJ): Humana Press; 1999. p. 159-93. Saavedra JM. Microbes to fight microbes: a not so novel approach to controlling diarrheal disease. J Pediatr Gastroenterol Nutr 1995;21:125-9. Marteau P, Cellier C. Immunological effects of biotherapeutic agents. In: Elmer GW, McFarland LV, Surawicz CM, editors. Biotherapeutic agents and infectious diseases. Totowa (NJ): Humana Press; 1999. p. 121-44. Campieri M, Gionchetti P. probiotics in inflammatory bowel disease: New insight to pathogenesis or a possible therapeutic alternative? Gastroenterology 1999;116:1246-9. Saavedra JM, Abi-Hanna A. Clinical studies of probiotic agents. In: Hanson L, Yolken RH, editors. Probiotics. Other nutritional factors, and intestinal microflora. Philadelphia: Lippincott-Raven; 1999. p. 271-86. Hamilton-Miller JM, Shah S, Smith CT. “Probiotic” remedies are not what they seem [letter]. BMJ 1996;312:55-6.
537