Probiotic foods have recently become popular in the United States, although such products have been marketed for decades in Europe and Asia.¹ Probiotics are defined as living organisms that, when administered in sufficient numbers, are beneficial to the host. One probiotic food is Activia. It is a line of yogurt containing Lactobacillus, Streptococcus thermophilus, and Bifidobacterium animalis bacteria, and it is advertised to aid regularity. While new to the U.S., Activia has been sold in Europe since 1987.¹ Most probiotic products can be found in the dairy case of supermarkets or as dietary supplements. There are probiotic frozen yogurts and dairy-based drinks such as DanActive, a probiotic yogurt drink that contains Lactobacillus casei immunitas cultures. Its manufacturer (Dannon) indicates that the product is clinically proven to “help strengthen your body’s defenses.”² Products sold in the pharmacy include, among others, Culturelle (Lactobacillus GG), Florastor (Saccharomyces boulardii) and Lactinex (Lactobacillus acidophilus, Lactobacillus bulgaricus), which are indicated to reduce the chance of developing diarrhea due to antibiotics.³ The FDA takes a neutral position on probiotics, policing food packages to ensure that companies do not try to equate probiotic products with disease-curing drugs. 

The growth of probiotics comes as many scientists are now focused on the role of beneficial bacteria to aid digestion, boost natural defenses, and fight off bacteria that could cause health problems. Intestinal bacteria can benefit health by breaking down toxins, synthesizing vitamins, and defending against infection. They may also play a role in preventing such diseases as peptic ulcers, colorectal cancer, and inflammatory bowel disease.⁴ This article will describe the genesis and evolution of our indigenous microbial community, the size and makeup of its inhabitants, its effects, its benefits, and new research. 

Genesis and Evolution

Most of us are aware that bacteria are a part of a healthy human ecosystem (i.e., an assembly of species and the organic and inorganic constituents characterizing a particular site). According to one author, the armies of bacteria that sneak into our bodies the moment we are born are the “primal illegal immigrants.”⁵ Most are industrious and friendly, minding their own business in tight-knit, long-lived communities, doing the grunt biochemical work we all rely on to stay alive.⁵ The ecosystem forms at birth, but the human-microbe alliance begins months before. Midway through pregnancy, a hormonal shift directs the cells lining the vagina to begin stockpiling sugary glycogen, the favorite food of sausage-shaped bacteria called lactobacilli. By fermenting the sugar into lactic acid, these bacteria lower the pH of the vagina to levels that discourage the growth of potentially dangerous invaders.⁶ 

The infant mouth’s first inoculation of bacteria includes a generous sampling of the lactobacilli present in the mother’s birth canal. With the first gulp of breast milk, these lactobacilli are joined by millions of bifidobacteria, a related group of acid-producing microbes.⁶ The source of these bacteria is the mother’s nipples, where the bacteria appear during the eighth month of pregnancy. Bifidobacteria secrete acids and antibiotic chemicals that repel potentially dangerous organisms, including Staphylococcus aureus. Bifidobacteria and lactobacilli are soon joined by acid-tolerant Streptococcus salivarius bacteria, which appear on a baby’s tongue during the first day of life. Bifidobacteria are anaerobic, pleomorphic rods that break down dietary carbohydrate and synthesize and excrete water-soluble vitamins.⁷ Their name is derived from the observation that they often exist in a Y-shaped, or bifid, form.⁸ These organisms predominate in the colons of breastfed babies, account for up to 95% of all culturable bacteria, and protect against infection.⁹ Strangely, they do not occur in such high numbers in adults.⁸ Several other streptococci, along with one or more kinds of Neisseria bacteria, settle in during the first week. The vast majority emanate from the mother’s mouth, which is always within reach of a nursing baby’s fingers.¹⁰ 

As the baby begins nursing or drinking formula, the bacterial population inside the mouth increases. These bacteria consume enough oxygen to create a zone where anaerobic bacteria can thrive. By the time the baby is 2 months old, a microscopic close-up of the gums will reveal clusters and chains of bacteria and fungi. Another wave of bacteria arrive when the first teeth appear. The first is Streptococcus sanguis, followed by Streptococcus mutans. By middle childhood, the diversity inside the mouth surpasses a hundred species, and their total number is greater than 10 billion.⁶ Bacteria also settle in the nasal cavities, which are connected to the mouth via the upper respiratory tract. The bacteria eventually lodge in the intestinal tract. In the small intestine, incoming microbes engage the infant’s dormant immune system. Pits on the surface of the Peyer’s patches (aggregated lymphoid tissue in the ileum) capture passing bacteria, where they are ushered into the underlying lymph tissue. Interaction on the Peyer’s patches triggers the production of an abundance of immunoglobulin A (IgA) antibodies. Instead of marking the bacteria for destruction, IgA clusters across the bacterial surface, preventing the bacteria from attaching to the intestinal wall. This action also leads to the proliferation of T and B cells that will marshal an attack against these same bacteria should they turn up in the blood or other forbidden areas.⁶ The small intestine must provide a platform for nutrient absorption, but at the same time the epithelium and its associated immune cells must keep out pathogens that escape the inhospitable environment of the stomach. To satisfy these responsibilities, small intestinal epithelial cells divide at a rate of 13 to 16 cells every hour.⁶ 

When the child reaches adulthood, his or her intestine becomes home to an almost inconceivable number of microorganisms. The size of the population—up to 100 trillion—far exceeds all other microbial communities associated with the body’s surfaces and is more than 10 times greater than the total number of our somatic and germ cells combined.¹¹ (There is a significant variation in both the total number of bacteria and the composition of the bacterial flora in different body regions.¹²) Since humans depend on their microbial inhabitants (microbiome) for various essential services, a person should really be considered a superorganism, consisting of his or her own cells and those of all the commensal bacteria. 

Humans are not inherently endowed with a healthy immune or digestive system. Fortunately, the microbiome in our intestinal tract provides us with genetic and metabolic attributes we have not been required to evolve on our own, including the ability to harvest otherwise inaccessible nutrients and to modify host immune reactivity.¹¹ 

Inhabitants

The adult human gastrointestinal (GI) tract contains all three domains of life—bacteria, archaea, and eukaryotes.¹¹ Archaea are a group of prokaryotic and single-celled micro-organisms, and while similar to bacteria, have evolved differently. Archaea were originally described in extreme environments but have since been found in all habitats including the digestive tracts of animals such as ruminants, termites, and humans.¹³ Eukaryotes are organisms whose cells contain a limiting membrane around the nuclear material (the nucleus). Bacteria living in the human gut achieve the highest cell densities recorded for any ecosystem.¹⁴ The vast majority belong to two divisions, the Bacteroidetes (48%) and the Firmicutes (51%). Bacteroidetes include a number of Bacteroides genera, which have yet to be encountered in any environment other than animal GI tracts. Firmicutes include the genera Clostridium, Lactobacillus, Eubacterium, Ruminococcus, and several others. In the first comprehensive molecular survey of the gut microbiota (normal microflora), 395 bacterial and one archaeal phylotype (bacteria defined by their ribosomal RNA gene sequence) were identified.¹⁴ Thus, the gut microbiota is a tremendously diverse bioreactor. Eight divisions with divergent lineages are represented. This diversity is desirable for ecosystem stability. There appears to be a strong host selection for specific bacteria whose behavior is beneficial to the host. Cooperative activity by bacteria is required to break down nutrients and provide the host with energy. Populations of bacteria are remarkably stable within the human gut, which implies that mechanisms exist to suppress undesirable bacteria and promote the abundance of those that are needed.¹¹ 

Bacteroides thetaiotaomicron is the prominent and remarkable bacterial species in the distal intestinal tract of adult humans. It is a very successful anaerobic glycophile (“sugar-loving” microbe) whose prodigious capacity for digesting otherwise indigestible dietary polysaccharides is reflected in its genome. It encodes 241 glycoside hydrolases and polysaccharide lyases. This means that the organism has the ability to break down xylan-, pectin- and arabinose-containing polysaccharides that are common components of dietary fiber.¹⁵ When dietary polysaccharides are scarce, B thetaiotaomicron turns to host mucus by deploying a different set of polysaccharide-binding proteins and glycoside hydrolases. Other Bacteroides species include B vulgatus, B distasonis, and B fragilis. All play a role in the digestive process.

New Research

Microbiologists from Louis Pasteur (1822-1895) and Ilya Mechnikov (1845-1916) to present-day scientists have emphasized the importance of understanding the contributions of our microbiota to human health and disease. Mechnikov, who won the Nobel Prize for Physiology and Medicine in 1908, was one of the first researchers to study the flora of the human intestine.¹⁶ He developed a theory that senility is due to poisoning of the body by the products of these bacteria. To prevent them from multiplying, he suggested a diet containing milk fermented by bacilli, which produce large quantities of lactic acid.¹⁶ 

Today, science is on the verge of understanding how the body maintains a state of equilibrium with its incredibly complex enteric microflora.¹⁷ Appropriate immune recognition is also essential to host-bacteria symbiosis (i.e.,  the biological association of two individuals or populations of different species). It has recently been shown that the recognition of commensal bacteria by epithelial cells protects against intestinal injury.¹⁷ Other research indicates that use of antibiotics reduces the capacity of intestinal microflora to metabolize phytochemicals into compounds that may protect against cancer.¹⁸ However, antibiotic use also disrupts the intestinal microflora metabolism of estrogens, which results in lower levels that might decrease the risk of some hormonal cancers. Use of antibiotics may be associated with cancer risk through effects on immune function and inflammation, although little is known about these mechanisms.^19,20 

Intestinal bacteria release chemical signals recognized by specific receptors—called toll-like receptors (TLRs)—of the innate immune system. The interaction helps to maintain the architectural integrity of the intestinal surface and enhance the ability of the epithelial surface to withstand injury. A deficiency in any of the numerous signaling molecules can induce intestinal inflammation, which may be a precursor of inflammatory bowel disease. Research is now ongoing to understand various types of  TLR activation to ascertain how this information can be used to treat irritable bowel syndrome, Crohn’s disease, and other types of intestinal inflammatory conditions.²¹ 

A group of medical researchers in Ireland recently identified five probiotic bacteria than can prevent Salmonella infection in pigs and, if translatable to humans, could potentially reduce Salmonella-induced foodborne illnesses, which cause between 500 and 1,000 deaths every year in the U.S.⁴ This same group is also investigating the human microbiome for antimicrobials against pathogens. They have isolated a compound called lacticin 3147 from the harmless bacterium Lactococcus lactis, which is used to make cheese. Recently, lacticin 3147 has demonstrated antimicrobial activity against a range of genetically distinct Clostridium difficile strains isolated from the human gut. This indicates that lacticin 3147 may offer a new treatment for C difficile–associated diarrhea, a serious condition that affects 3 million people per year in the U.S. and is a major problem in hospitals.⁴ 

There is evidence confirming the effects of Lactobacillus GG in preventing diarrhea and atopy in children.^22,23 These organisms are thought to occupy binding sites in the gut mucosa that prevent pathogenic bacteria from adhering. Lactobacilli also produce bacteriocins that act as local antibiotics. Diarrhea associated with antibiotics may result when the antibiotics disrupt the normal flora in the gut of a healthy person. Such disruptions cause dysfunction of the gut’s ecosystem and allow pathogens to colonize the gut and gain access to the mucosa. A number of organisms have been studied as probiotics to prevent antibiotic- and C difficile–associated diarrhea (TABLE 1).²⁴ Whether probiotic supplements stop this process by reducing the disruption or by acting as substitutes for healthy flora is unclear. 

Final Thoughts

Recent evidence has shown that microbes and their genes play important roles in the development of our immune systems, in the production of fatty acids that enhance healthy intestinal cell growth, in elaborating molecules that inhibit the growth and virulence of enteric bacterial pathogens, and in the detoxification of ingested substances that could otherwise lead to cancerous cell growth or alter our ability to metabolize medicines.^25,26 Pharmacists will thus become more involved in counseling patients interested in taking probiotics. In Europe, probiotics are regarded as medicines and prescribed along with antibiotics.²⁷ In the U.S., pharmacists can advise patients to take such probiotic products as Culturelle, Florastor, or Lactinex while on antibiotics and for 3 to 7 days thereafter.³ The same products can be taken to help prevent traveler’s diarrhea. They should be taken a few days before the trip and continued through its duration. Instruct patients to separate any probiotic and antibiotic doses by 2 hours to prevent the antibiotic from destroying the probiotic organisms.³ Immunocompromised patients should be advised not to use probiotics because of the potential for systemic infections. Other side effects can include GI upset (e.g., flatulence, discomfort). 

REFERENCES

1. Martin A. In live bacteria, food makers see a bonanza. NY Times. January 22, 2007. www.nytimes.com/2007/01/22/ business/22yogurt.html. Accessed September 2, 2009.
2. DanActive. Dannon. www.danactive.com. Accessed September 10, 2009.
3. Probiotics for digestive health. Pharmacist’s Letter. 2006;7(22):220704.
4. Friedrich MJ. Benefits of gut microflora under study. JAMA. 2008;299:162.
5. Zuger A. Separating friend from foe among the body’s invaders. NY Times. November 27, 2007. www.nytimes.com/2007/11/27/health/27book.html. Accessed September 2, 2009.
6. Sacks JS. Good Germs, Bad Germs. New York, NY: Hill & Wang; 2007.
7. Macfarlane GT, Cummings JH. Probiotics and prebiotics: can regulating the activities of  intestinal bacteria benefit health? BMJ. 1999;318:999-1003.
8. Intestinal flora. http://tuberose.com/ Intestinal_Flora.html. Accessed September 2, 2009.
9. Bullen CL, Willis AT. Resistance of the breast-fed infant to gastroenteritis. BMJ. 1971;3:338-343.
10. Berkowitz RJ, Turner J, Green P. Maternal salivary levels of Streptococcus mutans and primary oral infection of infants. Arch Oral Biol. 1981;26:147-149.
11. Backhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915-1920.
12. Leyden JJ, McGinley KJ, Nordstrom KM, Webster GF. Skin microflora. J Invest Dermatol. 1987;88(suppl 3):65s-72s.
13. Introduction to the archaea. University of California Museum of Paleontology.  www.ucmp.berkeley.edu/archaea/ archaea.html. Accessed September 2, 2009.
14. Whitman WB, Coleman DC, Wiebe WJ. Prokaryotes: the unseen majority. Proc Natl Acad Sci USA. 1998;95:6578-6583.
15. Gordon JI, Ley RE, Wilson R, et al. Extending our view of self: the human gut microbiome initiative. Center for Genome Sciences. www.genome.gov/Pages/Research/ Sequencing/SeqProposals/
HGMISeq.pdf. Accessed September 2, 2009.
16. Ilya Mechnikov. The Nobel Prize in Physiology or Medicine 1908. Biography. http://nobelprize.org/nobel_ prizes/medicine/laureates/1908/mechnikov-bio. html. Accessed September 2, 2009.
17. Fiocchi C. One commensal bacterial molecule—all we need for health? N Eng J Med. 2005;353:2078-2080.
18. Velicer CM, Heckbert SR, Lampe JW, et al. Antibiotic use in relation to the risk of breast cancer. JAMA. 2004;291:827-835.
19. Velicer CM, Lampe JW, Heckbert SR, et al. Hypothesis: is antibiotic use associated with breast cancer? Cancer Causes Control. 2003;14:739-747.
20. Reed MJ, Purohit A. Aromatase regulation and breast cancer. Clin Endocrinol. 2001;54:563-571.
21. Madara J. Building an intestine—architectural contributions of commensal bacteria. N Eng J Med. 2004;351:1685-1686.
22. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published, randomized, double-blind placebo-controlled trials. J Pediatr Gastroenterol Nutr. 2001;33(suppl):S17-S25.
23. Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in primary prevention of atopic disease: a randomized placebo-controlled trial. Lancet. 2001;357:1076-1079.
24. Rohde CL, Bartolini V, Jones N. The use of probiotics in the prevention and treatment of antibiotic-associated diarrhea with special interest in Clostridium difficile-associated diarrhea. Nutr Clin Pract. 2009;24:33-40.
25. Mindell DP. Evolution in the everyday world. Sci Am. 2009;300:82-89.
26. Sherman PM, Ossa JC, Johnson-Henry K. Unraveling mechanisms of action of probiotics. Nutr Clin Pract. 2009;24:10-14.
27. Berger A. Science commentary: probiotics. BMJ. 2002;324:1364. 

To comment on this article, contact rdavidson@jobson.com.