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Probiotics

Nutrient Names: Probiotic intestinal flora and prebiotics.
Synonyms: Healthy bacteria, intestinal microbiota, probiotic flora, symbiotic flora.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Antibiotics Antimicrobials / /	Antibiotic agents, particulary repeated courses or high-dose administration, will damage the intestinal flora that are indigenous and intrinsic to the gut ecology and play significant roles in immune, endocrine, detoxification, and other body systems. Repletion of such commensal bacteria and rebuilding of gut ecology through diverse and vigorous probiotic cultures can provide both short- and long-term strategic benefits for preventing or treating many conditions, with minimal risk of adverse effects. Mechanisms and effects established, but controversy exists regarding necessity. Research warranted and ongoing as to particulars and strategies, such as species, strains, dose, and duration.	Administer, especially after high-dose or extended antibiotic therapy; several months may be necessary. Saccharomyces boulardii (an antibiotic-resistant probiotic yeast) during or after antibiotic course may also be necessary to counter adverse effects, such as C. difficile overgrowth (antibiotic-associated colitis).
Lansoprazole- Amoxicillin- Metronidazole (LAM) triple therapy	Coadministration of probiotic flora with triple (or quadruple) therapy can enchance efficacy in eradicating Helicobacter pylori . Preliminary supportive evidence; mechanisms partially understood.	Coadminister.

nutrient description

NUTRIENT DESCRIPTION

Chemistry and Forms

Probiotics

Bifidobacterium adolescentis, B. animalis, B. bifidus (bifidum), B. breve, B. infantis, B. lactis, B. longum, B. thermophilum; Lactobacillus acidophilus, L. brevis, L. bulgaricus, L. casei, L. cellobiosus, L. crispatus, L. curvatus, L. fermentum, L., Lactobacillus GG (L. rhamnosus or L. casei subsp. rhamnosus), L. johnsonii, L. plantarum, L. salivarus; Saccharomyces boulardii, S. cerevisiae.

Lactobacillus bulgaricus and Streptococcus thermophilus are the “yogurt species.” Lactococcus lactis and L. lactis subspecies cremoris (Streptococcus cremoris) are also part of milk souring and are used as probiotics.

Enterococcus faecium (also in the streptococcal family) has also been used in the management of diarrheal illness.

Prebiotics

The most common prebiotics are inulin, a long-chain oligosaccharide (2-60 sugars), and fructooligosaccharide (FOS), a short-chain oligosaccharide (2-7 sugars). Almost all fibers function as prebiotics to some extent, as do many of the sugar alcohols (e.g., lactitol, maltitol, xylitol).

Related Substances

Probiotics: Live-culture foods; kefir, yogurt.
Prebiotics: Artichokes, onions, chicory, garlic, leeks; foods known to contain low-molecular-weight carbohydrates classified as FOS.

Physiology and Function

Probiotics are known by many names, including “live foods,” yogurt, lactobacilli, acidophilus, and “cultured” dairy products. The human gastrointestinal (GI) tract is home to more than a trillion live bacteria from about 400 species. The average adult body contains about 20 times more bacteria than it does somatic cells. ¹ In the natural environment, a delicate symbiosis evolves between these endogenous bacteria and their host. These live organisms act beneficially by affecting the host animal, improving its intestinal microbial balance. The vital contribution of natural flora to normal intestinal development is underscored by studies of animals raised in a germ-free environment. These animals have hypoplastic intestinal epithelia, reduced gut immunity, and impaired peristalsis, all of which improve only when normal gut flora are introduced. ² Scientific discoveries continue to highlight the multifaceted functions of intestinal microflora within multiple body systems. For example, emerging research regarding the vermiform appendix suggests that its major physiologic function may be to harbor and protect the commensal colonic flora, so that they are preserved and available to repopulate the colon after severe diarrheal illnesses such as cholera or other types of severe infectious gastroenteritis.^2a

Probiotics change the metabolic activities or composition of microbiota and modulate immune system reactivity in ways that benefit healthy function. Exogenous probiotics are administered therapeutically to individuals in whom this naturally beneficial symbiosis has been disturbed, in an attempt to restore normal flora. A 2004 Cochrane review reports that probiotic therapy is effective in reducing diarrhea. ³ A 2005 report summarizing 185 studies found that probiotics successfully treated 68 different conditions in diverse populations. ⁴

Lactobacillus and Bifidobacterium each represent a genus of probiotics most often used therapeutically. Some species and strains are derived from the intestinal microbiota of healthy humans. Some bifidobacteria that have been perpetuated as probiotics for babies have been derived from human milk. Other species are nonhuman probiotics used in the fermentation of dairy products. Species from other bacterial genera, such as Streptococcus, Bacillus, and Enterococcus have also been used as probiotics, but concerns surround the safety of such probiotics because these genera also contain pathogenic species, particularly Enterococcus . ^5-9Nonbacterial microorganisms such as yeasts from the genus Saccharomyces, most notably S. boulardii, have also been used as probiotics for many years.

Probiotics, as implied by their collective name, are a class of bacteria and yeast that are essentially life supporting in their action within human physiology. Historically, they have always been part of the human digestive tract ecology, with breastfeeding establishing the initial colonization process before the immune system has fully developed the distinction between self and other. Thus, in an immune sense, probiotics are within the boundaries of self in a presumably lifelong symbiotic relationship.

Microflora of the large intestine complete digestion through fermentation, playing a key role in the endogenous synthesis of vitamins (e.g., niacin, folic acid, biotin, K, B12, B6), short-chain fatty acids, amino acids (e.g.,L-arginine,L-cysteine,L-glutamine), and other “gut” nutrients. Microflora protect against overgrowth of opportunistic bacteria and fungi. These layers of tissue facilitate detoxification and stimulate the development of the immune system. For example, the metabolism of food by Lactobacillus acidophilus results in the production of lactic acid, hydrogen peroxide, and other beneficial byproducts that support changes in the gut environment hostile to unwanted organisms. Many of these bacteria are able to tolerate environments with a pH of 3 and 2% to 8% concentrations of bile acid. Probiotics in the diet can modify the composition and some metabolic activities of the intestinal microflora.

Certain probiotics are found as the live microorganisms in foods, such as active yogurt culture. Acidophilus organisms can act as a source of lactase. The microorganisms can survive passage through the gut and temporarily bring the benefits of normal gut flora. Bifidobacteria are anaerobic pleomorphic rods or club-shaped organisms that normally have an important role in breaking down dietary carbohydrate and interact directly with the host metabolism. Bifidobacteria also excrete water-soluble vitamins, but species and strains are considerably different. The healthy human gut, without pharmacological disruption, contains a wide range of bacterial species, and once established, variable strains normally grow in number and diversity. Fructooligosaccharides are naturally occurring carbohydrates that support the growth of bifidobacteria and cannot be digested or absorbed by humans.

Pharmacokinetic data suggest that human intestinal flora are essential for hydrolysis of the glycoside forms of the anthocyanin and proanthocyanin moities, as well as the glycoside forms of isoflavones and phytoestrogens. ^10-12These data suggest that iatrogenic reduction in microflora induced by antibiotics may reduce the bioavailability of at least some plant food polyphenols, although clinical evidence is not available.

The ideal probiotic should remain viable at the level of the large intestine and should adhere to the intestinal epithelium to confer a significant health benefit. Viable bacteria have greater immunological effects than nonviable bacteria and killed bacteria have been associated with adverse effects in some cases. ^13,14Some of the best-characterized probiotics have been shown to adhere strongly to intestinal epithelium through in vivo and in vitro studies. ¹⁵ Probiotics must also be resistant to gastric acid digestion and to bile salts to reach the intestinal tract intact, and they should be nonpathogenic. ¹⁶

nutrient in clinical practice

Known or Potential Therapeutic Uses

Probiotics have been clinically used to protect against intestinal permeability resulting from intestinal inflammation induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Probiotics are also used to help reduce the adverse side effect of antibiotic-induced diarrhea. The concern about overuse of antibiotics has recently been noted because of the more frequent overgrowth of antibiotic-resistant bacteria such as Clostridium difficile, which causes a severe form of colitis due to antibiotic therapy. Probiotic yeast such as Saccharomyces boulardii have been used as specific therapy for C. difficile colitis. Probiotics are used to enhance immune system factors to aid in the sequelae of asthma, allergies, upper respiratory infections, eczema, and other autoimmune disorders. Probiotics help replenish the intestinal flora when it is depleted by the factors surrounding infectious diarrhea, irritable bowel syndrome, and other intestinal disorders partly created by a depletion of healthy gut flora.

Historical/Ethnomedicine Precedent

Probiotics in the form of Streptococcus thermophilus and Lactobacillus bulgaricus in fermented milk have been ingested by humans for thousands of years in the belief they have health benefits. Fermented dairy products such as yogurt have been prepared and consumed since the third millenniumBCE, with the earliest uses most likely deriving from experiences of ingesting materials created through spontaneous fermentation by naturally occurring bacteria living on the goatskin bags used by the Bulgars (or Hunno-Bulgars). The development of food derived from fermentation of soy represents a parallel culinary evolution in East Asia. Likewise, in Biblical history, it was written that Abraham owed his fertility and longevity to the regular ingestion of yogurt. In the early twentieth century, the Russian immunologist Elie Metchnikoff proposed that lactic acid bacilli may have beneficial health effects and attributed his own longevity to regular probiotic ingestion.

Possible Uses

Allergic airway disease, allergic reactions (risk reduction and treatment), antibiotic-induced diarrhea, arthritis, atopy (particularly in infants), bone mineralization, calcium absorption, cancer, candidiasis, carcinogenic compound reduction in GI tract, cholesterol, constipation, Crohn's disease, diarrhea, digestive problems, dysbiosis, eczema, enteritis, food intolerances/sensitivities, food poisoning, glutamate synthase, Helicobacter pylori infection, hypercholesterolemia, immune enhancement/support, immune system development, intestinal permeability from NSAID-induced intestinal inflammation, irritable bowel disorder, irritable bowel syndrome, lactose intolerance, malnutrition, obesity, oral thrush, osteoporosis, pollen allergy, pouchitis, pseudomembranous colitis, seasonal allergies, sinusitis, surgery recovery, traveler's diarrhea, ulcerative colitis, vaginal infections, vulvovaginitis, workplace wellness (decreased sick leave), yeast infections.

Deficiency Symptoms

The absence of healthy live bacteria in the intestines have led to hypoplastic intestinal epithelia, reduced gut immunity, and impaired peristalsis. ² The depletion of such organisms tend to increase gut permeability, leaky gut syndrome, dysbiosis, abdominal distention, bloating, abdominal cramping, loose stools, fatigue, constipation, and acute/chronic diarrhea.

Dietary Sources

A wide variety of foods have live bacteria that contain mixtures of lactobacilli and bifidobacteria. These foods include yogurt, kefir, fermented foods such as sauerkraut and kimchi, probiotic foods, and prebiotic foods; most yogurt preparations are usually mixtures of lactobacilli and bifidobacteria, sometimes with Streptococcus thermophilus . Some “soil organisms” are primarily derived from soil, rather than mammals.

Nutrient Preparations Available

Bifidobacteria, acidophilus, lactobacillus, yogurt, yeasts, fermented foods. Probiotic Escherichia coli are available in Germany. The most common prebiotics are inulin and fructooligosaccharides (see Chemistry and Forms).

Dosage Forms Available

Capsule, enema, liquid (oral), liquid (topical), powder.

Most commercially available forms of probiotic supplements are refrigerated until consumption because culture viability remains an important issue in achieving therapeutic effects. Some manufacturers market probiotic products that they claim do not require refrigeration to maintain stability due to freeze-drying or other processes. Nevertheless, shelf life viability of all preparations is somewhat shorter at room temperature than under refrigeration.

Source Material for Nutrient Preparations

Cow's milk, goat milk, human milk; carrots, corn; soil.

Dosage Range

Dosage is represented as number of organisms per dose/serving (often noted as “CFU” for “colony-forming units”).

Adult

Dietary: None established.

Supplemental/Maintenance: One capsule or teaspoon per day orally, typically providing 1 to 2 billion CFU.

Pharmacological/Therapeutic: Dosage in clinical trials has ranged from 1 to 20 billion microflora. A typical therapeutic dose of probiotic bacteria is 2 to 4 billion CFU, two to four times daily, and that of Saccharomyces boulardii yeast is 500 mg, standardized to provide 3 billion CFU per gram, twice daily. S. boulardii is usually administered concurrently with antibiotic therapy, and bacterial probiotics are given after completion of a course of antibiotics, for 1 to 6 months.

Toxic: No toxicity has been established.

Pediatric (<18 Years)

Dietary: None established.

Supplemental/Maintenance: One capsule or teaspoon per day orally, typically providing 1 to 2 billion CFU.

Pharmacological/Therapeutic: See Adult. Toxic: None established.

Laboratory Values

Select laboratories have tests for presence, number, types, and characteristics of bacteria, as well as presence of pathogenic microorganisms and excessive gut permeability.

safety profile

Overview

Generally, medical literature reports probiotics as safe for human consumption. Potential benefits must be considered against possible harm, knowing that the data will never be absolute. Relevant data can be divided into two categories: population surveys, both retrospective and prospective, and anecdotal case reports that retrospectively try to establish some connection to prior ingestion of probiotics. Neither category provides a definitive scientific evidence–based overview of the safety of probiotics. Some clinical scientists assert that there will never be definitive clinical data. ¹⁷

Based on Finnish estimates that 0.02% of blood cultures test positive for lactobacilli, more than 166,000 patients would need to be studied prospectively to detect a 10% increase in bacteremia caused by Lactobacillus . Even with this estimate, given that blood was cultured in the Finnish study only for clinical indications, the expected yield would likely be lower if blood from healthy patients who ingested probiotics prophylactically were routinely cultured.

Although immunocompromised patients are especially vulnerable to infection, prospective studies have shown that probiotics are safe in immunocompromised adults and children with human immunodeficiency virus (HIV). ^18,19

In preterm neonates, probiotics reduce the incidence and severity of necrotizing enterocolitis, with no secondary probiotic infections seen to date. ^20,21

Sepsis from Lactobacillus has not been reported in prospective randomized studies of probiotics. The risk of sepsis from Lactobacillus should be weighed against risk of sepsis with more pathological species of bacteria and against risk of the disease that probiotic therapy was meant to prevent. ¹⁷ Many Lactobacillus species are intrinsically vancomycin resistant but have had a long history of safe use as probiotics. There is no indication thus far that vancomycin-resistant lactobacilli could transfer the resistance to other bacteria by plasmids or other means. ²² Although rare, reports indicating the presence of probiotic bacteria in samples isolated from infected tissues have raised concerns about their intrinsic properties as well as their potential pathogenicity. ^23,24Improperly stored probiotic products may cause nausea and minor GI distress resulting from degradation.

In a paper reviewing safety issues, Hammerman et al. ¹⁷ presented anecdotal adverse reports that clinical Lactobacillus infections do exist, most often in elderly patients. The most often cited case is a well-qualified report of a 74-year-old woman who developed a liver abscess after ingesting Lactobacillus rhamnosus for 4 months. After direct “gram-staining of a hepatic abscess aspirate demonstrated an abundance of polymorphonuclear leukocytes and gram-positive coccobacilli,” the authors observed that the “fermentation pattern and enzymatic reactions of this isolate were compatible with a probiotic strain L. rhamnosus GG used in dairy products in Finland since 1990.” ⁷ However, they also noted that the “incidence of severe infections caused by lactobacilli is very low.” Notably, the case report does not disclose the comedications used by the woman, diagnosed as an adult-onset diabetic, which might reveal the impact of potential adverse effects of any pharmacodynamic interaction occurring with her liver. Another concern would be medications or conditions that might lead to intestinal ulceration, thus providing a portal of entry to the bloodstream for ingested probiotic bacteria. In other case reports, a 67-year-old man with mitral valve regurgitation developed Lactobacillus endocarditis and sepsis after a tooth extraction, ⁸ and a 6-week-old infant developed Lactobacillus sepsis, although the child had severe underlying medical problems. ²⁵

Nutrient Adverse Effects

General Adverse Effects

Mild to moderate flulike symptoms, flatulence, abdominal bloating, nausea, and loose stools, resulting from “die-off” of pathogenic yeast and bacteria in the gut, are common in the first week of dosing with probiotics, a phenomenon also known as Jarisch-Herxheimer reaction. Temporary dose reduction or temporary cessation and titration of dose and administration interval typically alleviates the discomfort.

Adverse Effects Among Specific Populations

None confirmed.

Pregnancy and Nursing

None established.

Infants and Children

None established. There have been numerous studies illustrating the safety and effectiveness of probiotics with infants. ^26-32

Effect and Mechanism of Action

Probiotics change the metabolic activities or composition of microbiota and modulate immune system reactivity that benefits health. Exogenous probiotics are given therapeutically to individuals in whom this naturally beneficial symbiosis has been disturbed, in an attempt to restore normal flora.

Contraindications

Probiotic agents are potentially contraindicated in immunosuppressed individuals, particularly those with or at risk for ulcerations of the GI tract. Although administration of probiotics is often a core tactic within integrative nutritional therapeutic strategies for immunocompromised patients, a single unqualified case report described an immunosuppressed patient who developed a Lactobacillus infection after eating yogurt. ³³

interactions review

Strategic Considerations

Probiotics have been advocated for the prevention and treatment of a wide range of diseases, and strong evidence exists for their efficacy in some clinical scenarios. Probiotics are now widely used in many countries by both consumers and in clinical practice. Given the increasingly widespread use of probiotics, a thorough understanding of their risks and benefits is imperative.

Dietary modulation of gut microbiota with prebiotics and probiotics is an important function in nutritional sciences. In addition, some nutritional approaches use other nutraceuticals and botanicals, such as a modified butyric acid, as well as Chinese herbal formulae and the essential oil of oregano as sequential or symbiotic therapies. Prebiotics are defined as a functional food that has nondigestible food ingredients that beneficially affects the host by selectively stimulating the growth and activity of one or a limited number of symbiotic bacteria in the colon. Prebiotics can be nondigestible oligosaccharides and fibers, but also may be poorly absorbed sugars (e.g.,D-tagatose) or sugar alcohols (e.g., lactitol, xylitol), which promote the growth of symbiotic colonic microflora. Among the oligosaccharides, inulin and oligofructose have been shown to inhibit growth of pathogens and to display clear bifidogenic properties. ³⁴

The status of human intestinal ecology radically changed in the past 60 years in a direction far removed from anything comparable to millennia of evolutionary experience. Up until the middle of the twentieth century, the GI tract of adult humans, in both industrialized and undeveloped cultures, was populated by trillions of diverse organisms that might compose 6 to 8 pounds of living mass. ³⁵ However, the status of bacterial microbiota playing their symbiotic role in digestive, immune, and other functions has been significantly altered by the decline of breastfeeding, the introduction of chlorine in water supplies, declining levels of biological activity in agricultural soil, and the massive upsurge in the medical and animal husbandry use of antimicrobial agents, particularly broad-spectrum antibiotics. Subsequently, recognition has grown steadily as to the profound and widespread systemic implications of the depletion of this intimate natural resource within the human ecology and economy. Health care professionals have long recognized the immediate and long-term impact of antibiotic therapy on the intestinal flora, but the pervasive and cumulative, local and systemic sequelae of overgrowth of pathogenic yeast and anaerobic bacteria, with the attendant loss of metabolic activities and buffering presence for the gut mucosa of the symbiotic bacteria, have been more subtle.

Nevertheless, research into the particulars of such adverse effects has been absent or negligible. Scientific experiments and well-designed clinical trials are needed to investigate critical issues such as the variable susceptibilities within patient populations based on perinatal and infant nutrition, the divergent impact of antibiotics versus other medications as well as specific versus broad-spectrum antibiotics, and the differential effects of short-term versus chronic medication regimens and isolated versus repeated antibiotic administration. In addition, high-quality studies are needed regarding the efficacy of intake of cultured foods such as yogurt versus probiotic products on symbiont repletion, and on the effectiveness of various therapeutic repletion tactics, such as flora constituents (e.g., species, strains), methods of gut preparation and role of prebiotics in reestablishing a dynamic symbiotic microbiota, necessary numbers of organisms, combinations and duration of intake, methods of preparation, and methods of stabilization and delivery of probiotic organisms. In many respects, these concerns include the inherently related and increasingly critical issue of antibiotic-resistant pathogens. Moreover, critical investigation is required to determine the degree to which botanical and nutritional agents might also decimate and disrupt, or support and enhance, healthy flora and gut ecology.

Probiotic repletion and rejuvenation of the gut mucosa have long played a central role in the therapeutic strategies of experienced practitioners within nutritional, naturopathic, and integrative medicine. Given the patient population and their typical medical histories, it is often assumed that healthy flora are lacking and that degradation of the gut integrity and ecology has ensued to such a degree as to participate in a general decline in health and an increase in susceptibility because of decreased function and increased toxic load. Thus, in so many cases, whether labeled with such vaguely defined syndromes as “fibromyalgia,” “chronic fatigue,” or “food sensitivities,” or more conventionally as asthma and atopy, irritable bowel, or constipation, the initial stages of treating a patient with chronic conditions centers around improving dietary habits and reconstructing the gut ecology. However, as in so many areas of integrative medicine's maturation, it is necessary to move past naive assumptions that naturally occurring substances are inherently benign and universally beneficial. Such an approach must give way to a scientifically based and clinically efficacious approach employing all agents, regardless of origins, as potential tools in evolving and multidisciplinary strategies personalized to optimal intervention, given individual pharmacogenomic and biochemical variability and responses to therapeutic interventions.

A cursory review of the scientific literature over the past 20 years reveals a rapidly ascending curve representing the numbers of scientific studies and published papers focusing on the physiology and therapeutics of probiotics, prebiotics, and related topics. For example, there is clinical evidence to show that probiotics may help children with food sensitivities, whereas there was no effect in those without food sensitivities. ³⁶

Probiotic therapy has been applied for decades, if not millennia, in many clinical circumstances, from treating asthma and irritable bowel syndrome to preventing thrush or constipation. Research into the safety, applicability, and efficacy of probiotics needs to keep pace with their rapidly expanding popularity in the consumer market and their continued expansion within professional medical contexts.

nutrient-drug interactions

Antibiotics/Antimicrobial Agents (Systemic)

Aminoglycoside Antibiotics:Amikacin (Amikin), gentamicin (G-mycin, Garamycin, Jenamicin), kanamycin (Kantrex), neomycin (Mycifradin, Myciguent, Neo-Fradin, NeoTab, Nivemycin), netilmicin (Netromycin), paromomycin (monomycin; Humatin), streptomycin, tobramycin (AKTob, Nebcin, TOBI, TOBI Solution, TobraDex, Tobrex). Beta-Lactam Antibiotics:Methicillin (Staphcillin); aztreonam (Azactam injection); carbapenem antibiotics: meropenem (Merrem I.V.); combination drug: imipenem and cilastatin (Primaxin I.M., Primaxin I.V.); penicillin antibiotics: amoxicillin (Amoxicot, Amoxil, Moxilin, Trimox, Wymox); combination drug: amoxicillin and clavulanic acid (Augmentin, Augmentin XR, Clavulin); ampicillin (Amficot, Omnipen, Principen, Totacillin); combination drug: ampicillin and sulbactam (Unisyn); bacampicillin (Spectrobid), carbenicillin (Geocillin), cloxacillin (Cloxapen), dicloxacillin (Dynapen, Dycill), mezlocillin (Mezlin), nafcillin (Unipen), oxacillin (Bactocill), penicillin G (Bicillin C-R, Bicillin L-A, Pfizerpen, Truxcillin), penicillin V (Beepen-VK, Betapen-VK, Ledercillin VK, Pen-Vee K, Robicillin VK, Suspen, Truxcillin VK, V-Cillin K, Veetids), piperacillin (Pipracil); combination drug: piperacillin and tazobactam (Zosyn); ticarcillin (Ticar); combination drug: ticarcillin and clavulanate (Timentin). Cephalosporin Antibiotics:Cefaclor (Ceclor), cefadroxil (Duricef), cefamandole (Mandol), cefazolin (Ancef, Kefzol), cefdinir (Omnicef), cefepime (Maxipime), cefixime (Suprax), cefoperazone (Cefobid), cefotaxime (Claforan), cefotetan (Cefotan), cefoxitin (Mefoxin), cefpodoxime (Vantin), cefprozil (Cefzil), ceftazidime (Ceptaz, Fortaz, Tazicef, Tazidime), ceftibuten (Cedax), ceftizoxime (Cefizox), ceftriaxone (Rocephin), cefuroxime (Ceftin, Kefurox, Zinacef), cephalexin (Keflex, Keftab), cephapirin (Cefadyl), cephradine (Anspor, Velocef); imipenem combination drug: imipenem and cilastatin (Primaxin I.M., Primaxin I.V.); loracarbef (Lorabid), meropenem (Merrem I.V.). Fluoroquinolone (4-Quinolone) Antibiotics:Cinoxacin (Cinobac, Pulvules), ciprofloxacin (Ciloxan, Cipro), enoxacin (Penetrex), gatifloxacin (Tequin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox), nalidixic acid (Neggram), norfloxacin (Noroxin), ofloxacin (Floxin, Ocuflox), sparfloxacin (Zagam), trovafloxacin (alatrofloxacin; Trovan). Macrolide Antibiotics:Azithromycin (Zithromax), clarithromycin (Biaxin), dirithromycin (Dynabac), erythromycin, oral (EES, EryPed, Ery-Tab, PCE Dispertab, Pediazole), troleandomycin (Tao). Sulfonamide Antibiotics:Sodium sulfacetamide (AK-Sulf, Bleph-10, Sodium Sulamyd), sulfamethoxazole (Gantanol), sulfanilamide (AVC), sulfasalazine (salazosulfapyridine, salicylazosulfapyridine, suphasalazine; Apo-Sulfasalazine, Azulfidine, Azulfidine EN-Tabs, PMS-Sulfasalazine, Salazopyrin, Salazopyrin EN-Tabs, SAS), sulfisoxazole (Gantrisin); combination drug: sulfamethoxazole and trimethoprim (cotrimoxazole, co-trimoxazole, SXT, TMP-SMX, TMP-sulfa; Bactrim, Bactrim DS, Cotrim, Septra, Septra DS, Sulfatrim, Uroplus); triple sulfa (Sultrin Triple Sulfa). Chemotherapy, Cytotoxic Antibiotics:Bleomycin (Blenoxane), dactinomycin (Actinomycin D, Cosmegen, Cosmegen Lyovac), mitomycin (Mutamycin), plicamycin (Mithracin). Miscellaneous Antibiotics/Antimicrobials:Bacitracin (Caci-IM), chloramphenicol (Chloromycetin), chlorhexidine (Peridex), clindamycin, oral (Cleocin), colistimethate (Coly-Mycin M), dapsone (DDS, diaminodiphenylsulphone; Aczone Gel, Avlosulfon), furazolidone (Furoxone), lincomycin (Lincocin), linezolid (Zyvox), nitrofurantoin (Macrobid, Macrodantin), trimethoprim (Proloprim, Trimpex), vancomycin (Vancocin).

	Prevention or Reduction of Drug Adverse Effect
	Beneficial or Supportive Interaction, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Probability: 2. Probable or 1. Certain
Evidence Base:

AMPERSANDthinsp; Preliminary or

AMPERSANDthinsp; Emerging

Effect and Mechanism of Action

Probiotics play a critical role in normal functions of the digestive, immune, endocrine, and other body systems but also inhibit growth of potential pathogenic organisms. The potential pathogens produce indole, skatol, putricine, cadaverine, endo-, exo-, and enterotoxins as well as other pathogenic materials; notably, both pathogenic and probiotic bacteria are capable of producing lactic acid and bacteriocins. The inhibition caused by probiotics is antagonistic to pathogen growth. Probiotics provide a competitive environment that does not favor the growth of enteric pathogens. Probiotics trigger cytokine synthesis from enterocytes by attaching to their surfaces. Probiotics restore the normal intestinal flora after antibiotic therapy and produce metabolites, such as hydrogen peroxide and bacteriocins, that are toxic to many pathogenic bacteria. Probiotics also produce butyric and other short-chain fatty acids that both nourish and increase the turnover of enterocytes. Probiotics are also capable of neutralizing many dietary carcinogens.

Research

Antibiotic resistance of pathogens is at the forefront of medical challenges in both the clinical and the public health arena. Bacteria have mutated over the last 60 years to become resistant to many antibiotic therapies. Even though antibiotics are an effective tool in the treatment of many serious infections, the spread of resistance genes and resistant bacteria impedes the effectiveness of antibiotics as a clinical tool. ³⁷ The risks potentially associated with antibiotic therapy, as a general rule, are multifaceted. The selection of resistant forms can occur during or after microbial treatment. Antibiotic residues can be found for long periods after treatment. Stuart Levy ³⁷ notes that “there is a mounting use of other agents aimed at destroying bacteria, namely the surface antibacterials now available in many household products.” The term “multidrug resistance” (MDR) initially described resistant mammalian tumor cells and later strains of Mycobacterium tuberculosis;MDR now describes multidrug resistance in any organism—bacterium, fungus, or parasite. ^38-44

Diarrhea is a common adverse effect of antimicrobial therapy, largely from the elimination of beneficial bacteria normally found in the colon. Controlled studies have shown that coadministration of probiotic microorganisms such as Lactobacillus casei, L. acidophilus, Bifidobacterium longum,or Saccharomyces boulardiican prevent or resolve antibiotic-induced diarrhea. ⁴⁵ The diarrhea experienced by many patients after antibiotic therapy is sometimes caused by an overgrowth of the anaerobic bacterium Clostridium difficile, which causes a disease known as pseudomembranous colitis. Controlled studies have shown that coadministration of probiotic yeast, specifically S. boulardiior Saccharomyces cerevisiae,helps prevent recurrence of this infection. In one study, administration of 500 mg S. boulardiitwice daily enhanced the effectiveness of vancomycin in preventing recurrent Clostridiuminfection. ^45,46

The general literature suggests that two categories define the interactions between uses of probiotics and antibiotics. First, the antibiotics may deplete or interfere with the absorption, viability, or function of the probiotics; theoretically, ingesting these organisms may help replenish them. Second, the probiotic may reduce the likelihood or severity of the potential adverse effects of the antibiotics.

Probiotic therapies can offset the loss of GI flora associated with antibiotic therapy. ⁴⁷ Probiotic therapy can be fundamental to strategic case management for a wide range of chronic conditions, particularly digestive and immune conditions, within the diverse disciplines of natural medicine, nutritional therapeutics, and integrative care. In persons with suspected or diagnosed yeast/fungal intestinal overgrowth, probiotics are typically administered in conjunction with or following antifungal agents, along with nutrients intended to reduce gut permeability and reestablish integrity and normal function of mucous membranes of the GI tract.

The strongest evidence for the use of probiotics is in the management of diarrheal diseases. ¹⁶ A meta-analysis of randomized controlled trials demonstrated that many probiotics are effective in preventing antibiotic-associated diarrhea. ⁴⁸ The agents cited in this meta-analysis included the yeast strain Saccharomyces boulardii, as well as the bacterium Lactobacillus acidophilusin combination with L. bulgaricus, L. rhamnosusstrain GG [American Type Culture Collection (ATCC) 53103;LGG], and Enterococcus faeciumstrain SF68. Separate meta-analysis of randomized controlled trials showed a variety of probiotics, including Lactobacillusspecies, Enterococcusspecies, and S. boulardii, to be efficacious with infective diarrhea in both children and adults. ¹⁶ Probiotics were found to reduce the duration of diarrhea by more than 30 hours. Efficacy in this setting is also supported by a randomized clinical trial of a probiotics mix. The mix included 3×10 ¹¹ CFU L. bulgaricus, L. casei, L. plantarum, L. acidophilus, Bifidobacterium longum, B. breve, B. infantis, and Streptococcus thermophilus.

A different probiotic mix, Bifidobacterium lactisBb12 and Lactobacillus reuteri(ATCC55730) at 1×10 ⁷ CFU, has been shown to be useful in preventing flares of chronic pouchitis in patients with inflammatory bowel disease and diarrheal illness in infants attending child care. ^49,50 ( Pouchitisrefers to inflammation of the rectal stump in patients who are status/post–colectomy with ileostomy.) The use of probiotic species, including B. longum, L. acidophilus, L. casei, S. boulardii, and Saccharomyces cerevisiae, provide a reduction and prevention of the potential adverse effect of diarrhea with antibiotics. ^{3,45,46,51-55}

The scientific literature provides only minimal evidence from laboratory experiments and clinical trials investigating the differential impact of various antibiotic agents and classes on particular native species and strains of gut flora or the preventive or therapeutic application of probiotics in conjunction with or after particular antibiotics. However, the primary focus of scientific research and clinical administration of probiotic therapy continues to center on Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus casei, Saccharomyces boulardii,and Saccharomyces cerevisiae,which can prevent or reduce the severity of diarrhea, a significant and often serious potential adverse effect. ^{3,45,46,51-54} S. boulardiiprovides a supportive interaction that may support and enhance the therapeutic activity of the concomitant antibiotic. ^55,56 In addition, L. acidophilusGG enables the recolonization of human colonic mucosa and enhances the therapeutic efficacy of the antibiotic agent. ^15,57-59

Important examples of clinical applications for probiotic therapy are discussed next.

Antibiotic-Induced Diarrhea

Many studies have examined probiotic therapy in the prevention of antibiotic-associated diarrhea. A study of patients receiving extensive antibiotic treatment indicates that 2 years of probiotic therapy (at 2×10 ¹⁰ CFU daily) provided a protective strategy for reestablishing healthy flora in these patients. ⁵⁵

Atopic Dermatitis and Food Sensitivity

The use of probiotic therapy as part of treatment for atopic dermatitis is well documented and is often considered most efficacious in treating patients with food sensitivities who are also affected by atopic dermatitis. ³⁶

Clostridium difficile Pseudomembranous Colitis

The higher risk of serious GI diseases caused by antibiotic therapy makes probiotics a unique protective and therapeutic agent. Clostridium difficileinfection is usually curable but can be very debilitating, especially in elderly or seriously ill patients. It also recurs repeatedly in some patients and occasionally causes life-threatening inflammation of the colon. This strain presents a growing challenge across North America and Europe. A virulent, once-rare strain has driven a string of recent outbreaks and is suspected to be responsible for much of the overall increase in the disease. New resistance to widely used antibiotics seems to have made the microbe more likely to cause diarrhea in sick and elderly people. At the same time, researchers are concerned about scattered cases of C. difficileamong people not normally susceptible to the organism. In the United States, “the rate of C-diff in hospital patients doubled between 2000 and 2003,” reports McDonald et al. ⁶⁰ of the Centers for Disease Control and Prevention (CDC) in Atlanta. Saccharomyces boulardiihas been successfully used in treatment of C. difficilecolitis, usually after failure of metronidazole and oral vancomycin. ⁴⁵ Anecdotal clinical experience suggests that prophylactic use of 9 to 10 billion CFU daily of S. boulardiiconcomitantly with broad-spectrum antibiotics may prevent overgrowth of C. difficile. Adequately powered, randomized clinical trials of this strategy would appear justified in view of this growing problem among hospitalized patients.

Enteric Colonization of Candida in Neonatal Patients

Oral coadministration of Lactobacillus caseisubspecies rhamnosus(LGG) reduces the incidence and intensity of enteric colonization by Candidaspecies in very-low-birth-weight neonates. The ability of LGG to prevent colonization by fungi might translate into a similar ability to prevent fungal infections. In a randomized trial involving 80 preterm neonates, Manzoni et al. ⁶¹ administered LGG (6×10 ⁹ CFU/day), delivered in human milk and compared to human milk alone, for 6 weeks until discharge from the neonatal intensive care unit. They observed that the incidence of fungal enteric colonization was significantly lower in the LGG group than in the control group (23.1% vs. 48.8%). Furthermore, the number of fungal isolates obtained from each neonate and each colonized neonate was also significantly lower in the LGG group. Overall, the reduction in GI colonization reached significance in neonates with a birth weight of 1001 to 1500 g, but was not significant in those with a lower birth weight. LGG was not isolated from blood cultures or other specimens, and there were no adverse effects.

Inflammatory Bowel Disease

Probiotics, prebiotics, and antibiotics can provide significant benefit to patients with inflammatory bowel disease (IBD). Probiotics and prebiotics are the type of therapy that appeals to most patients with IBD. Probiotics have no significant adverse effects, except possibly a transient increase in abdominal gas with prebiotics, and thus far appear to be entirely safe. More than a dozen studies using probiotics in IBD indicate clear benefit in pouchitis and possibly in Crohn's disease. Further clinical trials are warranted investigating treatment of ulcerative colitis. The use of oligosaccharide and other prebiotics within conventional therapy for IBD is in its infancy, although significant effects on both the luminal and the mucosa-associated flora have been demonstrated in healthy subjects. Probiotics and prebiotics could play a central role in standard treatment of patients with IBD, although these therapies carry an uncertain risk of potential adverse effects. Their efficacy in clinical studies varies, with Crohn's disease and pouchitis reporting more benefit than ulcerative colitis. However, the ideal combination of conventional interventions, probiotics, and prebiotics and criteria for their application has not been determined. ⁶²

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians can prevent and treat a wide range of disorders and support restoration of healthy physiological function by instituting a strategy built around probiotic repletion. Survey data and anecdotal experience strongly indicate that probiotics, usually in combination with prebiotics and other supportive measures, are often self-prescribed by individuals during or after antibiotic therapy.

Common therapeutic applications of probiotics include improving general gut health; improving the body's natural defenses; reversing patterns of fungal overgrowth, deteriorated intestinal function, and immune compromise; and reducing blood cholesterol levels. The American College of Nutrition recommends, in its nutrition specialist certification review materials, that 6 months of probiotic therapy, with at least 10 billion probiotic organisms daily, is usually indicated to reverse the effects of antibiotic therapy and reestablish healthy gut microbiota.

Helicobacter pylori Triple Therapy (LAM)/Quadruple Therapy

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Sulfasalazine

nutrient-nutrient interactions

Oligosaccharides and Other Prebiotics

Health care professionals trained and experienced in nutritional therapeutics and integrative care strategies often use prebiotic therapy to “fertilize” the gut before probiotic therapy and thereby enhance its effectiveness. For example, using a murine influenza vaccination model examining a specific prebiotic-oligosaccharide mixture, with stimulation of delayed-type hypersensitivity, Vos et al. ⁶⁵ suggest that application use of galactooligosaccharides (GOS) and fructooligosaccharides (FOS) in dietary products might provide an opportunity to stimulate the adaptive immune response in a direction favoring T-helper cell type 1 (Th1) immunity and subsequently inhibit infections and T-helper 2 (Th2)–related immune disorders (e.g., allergic/atopic disease) in humans. ⁶⁵

Oligosaccharides in breast milk or added to infant formula modulate postnatal immune development by altering bowel flora and have a potential role in primary allergy prevention during infancy. Infant formulas enhanced with prebiotic oligosaccharides were found to modify intestinal bacteria and more than halve the risk of atopic dermatitis among high-risk babies. In a 6-month, double-blind, randomized, placebo-controlled trial of 259 infants at risk for atopy, only 10 of 102 infants given prebiotics in their formula developed atopic dermatitis, according to an online report in the July 2006 Archives of Disease in Childhood. By contrast, 24 of 104 controls given formula without probiotics developed the disorder. ⁶⁶

The effect of oligofructose (OF, prebiotic) on microflora in infants is being increasingly studied. A double-blind placebo-controlled trial assessed the effect of daily OF administration on the intestinal microflora, intestinal tolerance, and well-being of healthy infants age 7 to 19 months, with 8 days of observation, 21 days of administration, and 15 days of posttreatment. Exclusion criteria included antibiotic use and intake of another prebiotic or probiotic any time after enrollment. Fecal flora were analyzed by culture methods, and health information was recorded daily. Bifidobacteria tended to increase slightly with OF administration, but not with placebo. Simultaneously, a decrease in potential pathogens, significant for clostridia but not for staphylococci, was observed in the OF group. These modifications did not persist during the posttreatment period. OF intake was accompanied by less flatulence, diarrhea, vomiting, and fever events. ³⁴

Administration of probiotics and prebiotics can reduce incidence of eczema in infants. Eczema, also known as atopic dermatitis (AD), is one of the first signs of allergy during the early days of life and is believed to result from delayed development of the immune system. According to the American Academy of Dermatologists, eczema affects 10% to 20% of all infants, but almost half will “grow out” of eczema between ages 5 and 15. The research adds to a 2003 study from Finland that reported children exposed to the Lactobacillus rhamnosusGG (LGG) bacteria around birth were 40% less likely to develop AD at 4 years of age compared with children in a placebo group. In the new study (2006), Kukkonen et al. ⁶⁷ from the University of Helsinki built on these earlier results by examining the effects of a probiotic and prebiotic combination on allergy prevention in a much larger population of allergy-prone infants than previously studied. The researchers randomized 1223 pregnant women to receive either placebo or daily probiotic formulation containing four probiotic strains: Lactobacillus rhamnosusGG, L. rhamnosusLC705, Bifidobacterium breveBb99, and Propionibacterium freudenreichiissp. shermaniiJS. The women were treated for the 2 to 4 weeks before delivery. The newborns then received either the same probiotics in combination with GOS (461 babies) or placebo (464 babies) for 6 months. Researchers have found that breast milk naturally contains prebiotic oligosaccharides, believed to stimulate bifidobacteria that facilitate the release of energy and nutrients from the diet. No significant differences were observed between the treated and placebo groups with regard to allergic disease overall, but the researchers reported that administration of the probiotic/prebiotic mixture was associated with a 26% reduction in eczema and a 34% reduction in atopic eczema specifically. Fecal samples revealed that the probiotic/prebiotic group had significantly higher lactobacilli, propionibacteria, and bifidobacteria populations. This result indicated “successful intervention and good adherence.” According to the researchers: Our prospective study indicates, for the first time to our knowledge, an inverse association between the prevalence of eczema and the abundance of certain species of the indigenous gut microbiota, thus supporting the important role of commensal bacteria in the pathogenesis of eczema…. Gut microbiota contact directly with extensions of dendritic cells, which orchestrate the mucosal immune homeostasis. Commensal bacteria stimulate the innate immune system and contribute to the generation of regulatory lymphocytes, which, through IL-10 and TGF-beta, establish and maintain mucosal immune tolerance. ⁶⁷

The results show that probiotics and prebiotics offer an “easily accessible, inexpensive, and safe” way of reducing eczema in infants, particularly high-risk infants. The researchers said that continued follow-up on these same infants will show if this effect is maintained later in life, and if any impact on airway allergies such as asthma is observed. ⁶⁷

Milk formulas containing prebiotics help floral inoculation with beneficial bacteria. Antibiotics exert deleterious effects on the intestinal microbiota, favoring the emergence of opportunistic bacteria, pathogenic yeasts, other fungi, and diarrhea. Prebiotics are nondigestible food components that stimulate the growth of bifidobacteria and other symbionts. To study the effects of probiotic administration after antibiotic treatment, Brunser et al. ⁶⁸ conducted a randomized, double-blind, controlled clinical trial involving 140 infants 1 to 2 years of age distributed into two groups after being treated for acute bronchitis with a 1-week course of amoxicillin (50 mg/kg/day). For 3 weeks the children received greater than 500 mL/day of a prebiotic formula (4.5 g/L) or placebo. Fecal samples obtained at the beginning of the antibiotic treatment (“day seven”), at the end of the treatment and before formula administration (“day zero”), and during formula administration (“days seven and twenty-one”) were evaluated for Bifidobacterium, Lactobacillus- Enterococcus, Clostridium lituseburiensecluster, Clostridium histolyticumcluster, Escherichia coli,and Bacteroides-Prevotella. The authors reported that amoxicillin decreased total fecal bacteria and increased E. coli, whereas the prebiotic group exhibited significantly increased bifidobacteria, from 8.17±1.46 on day zero to 8.54±1.20 on day seven, compared with the control 8.22±1.24 on day zero versus 7.95±1.54 on day seven. The Lactobacilluspopulation showed a similar tendency, but the other bacteria were unaffected. Adverse GI symptoms were absent during the prebiotic administration. The authors concluded that prebiotics “in a milk formula increase fecal bifidobacteria early after amoxicillin treatment without inducing gastrointestinal symptoms.” ⁶⁸ Continued research is warranted to investigate further the synergistic use of prebiotics and probiotics directly after antibiotic therapy or in response to long-term sequelae associated with, or aggravated by, the adverse effects of antibiotic therapy.

Prebiotics and calcium exhibit a synergistic relationship in the process of bone mineralization. In a randomized, placebo-controlled trial, Abrams et al. ⁶⁹ found that a combination of prebiotic short-chain and long-chain inulin-type fructans enhances calcium absorption and long-term bone mineralization in young adolescents. The investigators randomly assigned pubertal adolescents to receive 8 g/day of a mixed short and long degree of polymerization, inulin-type fructan product (fructan group) or maltodextrin placebo (as control). At baseline and after 1 year, they measured bone mineral content, bone mineral density, and calcium absorption; they also determined polymorphisms of the Fok1 vitamin D receptor gene. Subsequently, they observed that after both 8 weeks and 1 year, calcium absorption was significantly greater in the fructan group than in the control group. Notably, an “interaction with Fok1 genotype was present such that subjects with an ff genotype had the least initial response to fructan.” After 1 year, the “fructan group had a greater increment in both whole-body bone mineral content … and whole-body bone mineral density … than did the control group.” The authors concluded that daily “consumption of a combination of prebiotic short- and long-chain inulin-type fructans significantly increases calcium absorption and enhances bone mineralization during pubertal growth.” They also added that effects of “dietary factors on calcium absorption may be modulated by genetic factors, including specific vitamin D receptor gene polymorphisms.” ⁶⁹

These findings indicate that further research investigating this synergistic intervention is warranted (preferably with calcium, vitamin D, and magnesium administration controlled), especially given the critical importance of establishing maximal bone density during adolescence and early adulthood. Similar study of the potential impact of prebiotic nutritional support in adults of different age groups, particularly perimenopausal and postmenopausal women, also appears highly relevant.

herb-nutrient interactions

Echinacea

Ginseng, Chinese/Korean

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NUTRIENT DESCRIPTION

Probiotics

Prebiotics

Related Substances

Physiology and Function

Known or Potential Therapeutic Uses

Historical/Ethnomedicine Precedent

Possible Uses

Deficiency Symptoms

Dietary Sources

Nutrient Preparations Available

Dosage Forms Available

Source Material for Nutrient Preparations

Dosage Range

Adult

Pediatric (<18 Years)

Laboratory Values

Overview

Nutrient Adverse Effects

General Adverse Effects

Adverse Effects Among Specific Populations

Pregnancy and Nursing

Infants and Children

Effect and Mechanism of Action

Contraindications

Strategic Considerations

Effect and Mechanism of Action

Research

Antibiotic-Induced Diarrhea

Atopic Dermatitis and Food Sensitivity

Clostridium difficile Pseudomembranous Colitis

Enteric Colonization of Candida in Neonatal Patients

Inflammatory Bowel Disease

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Nutritional Therapeutics, Clinical Concerns, and Adaptations