What are Probiotics?
The word probiotic which means ‘ for life’ was coined in 1965 by Lilly and Stillwell  and is defined as live microorganisms, which when administered in adequate amounts confer a health benefit on the host. Probiotics are essentially the microorganisms that are normal commensal residents of our gastrointestinal tract. The most common probiotic strains belong to the genera Lactobacillus and Bifidobacterium. Common Lactobacillus probiotic strains include L. acidophilus, L. casei, L. rhamnosus, and L. reuteri. Bifidobacterium probiotic strains include B. bifidum, B. longum, and B. infantis.
Probiotics have gained immense popularity and their sale is rising as more and more people are becoming aware of their health benefits. Probiotics are available in the market as proprietary dietary supplements (as a single strain or a combination of different strains) and in the form of fermented foods such as yogurt, kefir, sauerkraut and kimchi.
Probiotics have been shown to confer health benefits by aiding in functions such as digestion, preventing pathogens from invasion , , supporting immune functions , enhancing intestinal barrier5], production of antimicrobial substances , production of short chain fatty acids important for growth of colonic cells  and improving overall microbial balance in the gut. Probiotics has also been investigated for their potential role in improving oral health .
Extensive research has been carried out to examine the potential effects of probiotics in mitigating diseases including gastrointestinal diseases such as Irritable bowel syndrome (IBS) , Inflammatory bowel disease(IBD) [10, lung diseases , central nervous system conditions , , liver diseases , metabolic diseases  and cancer . Thus, probiotics seem promising candidates for treating or preventing health problems.
[table id=1 /]
Safety of Probiotics
With so much effort and attention diverted towards demonstrating the health benefits of probiotics, examining the potential side effects of probiotics are often underestimated. Although the existing clinical data provides evidence of no increased risk of probiotics use, there are not enough studies that address important aspect of probiotic use. Overall, probiotics have been considered safe and have been used in many clinical cases. However, in some cases, adverse effects of probiotics have been also observed.
A report released by World Health Organization (WHO )in 2002 stated that probiotics may be responsible for four types of side effects . These include: 1) systemic infections, 2) deleterious metabolic activities, 3) excessive immune stimulation in susceptible individuals and 4) gene transfer. Several case studies reported that administration of probiotics Saccharomyces boulardii resulted in fungemia in patients suffering from different conditions , , , , .
- Bacteremia and Sepsis
Lactobacillus strains on one hand have been shown to confer protective effects in various patients but on the other hand have caused systemic infections and other complications. In a study, administration of Lactobacillus rhamnosus to children with acute diarrhea resulted in shorter duration of diarrhea, less chance of a protracted course, and faster discharge from the hospital . In another study, Lactobacillus rhamnosus GG was found to reduce antibiotic-associated diarrhea in children treated with oral antibiotics for common childhood infections . Other similar reports have demonstrated the protective effects of Lactobacilli , . In contrast, some case studies have reported bacteremia in patients after they ingested strains of Lactobacilli genus such as L.rhamnosus , , , L. acidophilus  and L.casei . Bacteremia was found to be associated with the use of other probiotics as well. One case of sepsis caused by Bifidobacterium breve was reported  .Two cases of Bifidobacterium longum bacteremia were reported in newborns receiving probiotics . Another case reported septicemia in response to probiotic Bacillus subtilis .
Endocarditis, an inflammation of the inner layer of the heart, was also reported to be associated with probiotic use. A study reported that consumption of a freeze-dried probiotic preparation containing Lactobacillus rhamnosus in a subject caused endocarditis . Another study revealed that a subject who consumed large quantities of probiotic yogurt developed endocarditis and septic arthritis caused by Lactobacillus rhamnosus .
- Can Cause Death
A randomized, double-blind, placebo-controlled trial examined the effect of multispecies probiotic preparation in patients with predicted severe acute pancreatitis (n=153) vs placebo (n=145). In this study, nine patients in the probiotics group developed bowel ischemia (eight fatal), compared with none in the placebo group. Use of probiotic was found to be associated with an increased risk of mortality in this study . These studies suggest that probiotics should be used with caution in human subjects especially in immunocompromised, hospitalized patients and infants. A detailed assessment of a probiotic strain to be used in patients should be carried out.
- Drug Resistance
Another significant concern regarding the safety of probiotics is their ability of gene transfer. Species of genus Lactobacillus are known to carry plasmids containing chloramphenicol resistance , tetracycline resistance  and erythromycin resistance . Plasmids are commonly found naturally occurring autonomous DNA molecules in bacteria that replicate independently of chromosomal DNA. A study demonstrated in mice, transfer of gene for vancomycin resistance (vanA) from an Enterococcus strain to L. acidophilus, providing evidence that transfer can take place in the gut .
One should also keep in mind that a probiotic strain or a combination of few strains which has been well studied in isolation may have different effects when it is administered in human or animal subjects owing to the complex nature and interactions of the gut microbial community. Although, some underlying mechanisms of how probiotics function are known, a detailed understanding of these mechanisms is still lacking thus complicating the predictability of the safety of a probiotic strain. Then there is an issue of presence of unlabeled microorganisms that are not indicated on the label of retail probiotics. Investigations using culture dependent and culture independent approaches have revealed these findings , , . This misrepresentation can potentially increase the unknown risk associated with a given probiotic supplement. In addition, reagents used in the production of probiotics and which are not properly labeled can also pose serious threat as exemplified by the case of anaphylactic reactions in two different case studies , .
Probiotics are proving to be very promising candidates for treating or preventing diseases. The existing data largely supports their efficacy and safety. However, not much attention has been devoted to understanding their safety and much works need to be done to evaluate this criteria. Studies are necessary to understand in details the underlying mechanisms of probiotic actions. Clinicians should more carefully assess the risks and benefits of probiotics before they can be prescribed. In general, probiotic supplements are not monitored strictly and thus the safety of these supplements in not guaranteed. Thus, one should be cautious and thorough in choosing these supplements when considering their use.
- Lilly, d. M. & stillwell, r. H. Probiotics: growth-promoting factors produced by microorganisms. Science 147, 747–8 (1965).
- Collado, M. C., Meriluoto, J. & Salminen, S. Role of commercial probiotic strains against human pathogen adhesion to intestinal mucus. Lett. Appl. Microbiol. 45, 454–60 (2007).
- Mack, D. R., Michail, S., Wei, S., McDougall, L. & Hollingsworth, M. A. Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression. Am. J. Physiol. 276, G941–50 (1999).
- Konieczna, P. et al. Immunomodulation by Bifidobacterium infantis 35624 in the murine lamina propria requires retinoic acid-dependent and independent mechanisms. PLoS One 8, e62617 (2013).
- Madsen, K. et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121, 580–91 (2001).
- Jones, S. E. & Versalovic, J. Probiotic Lactobacillus reuteri biofilms produce antimicrobial and anti-inflammatory factors. BMC Microbiol. 9, 35 (2009).
- Asarat, M., Apostolopoulos, V., Vasiljevic, T. & Donkor, O. Short-chain fatty acids produced by synbiotic mixtures in skim milk differentially regulate proliferation and cytokine production in peripheral blood mononuclear cells. Int. J. Food Sci. Nutr. 66, 755–65 (2015).
- Gungor, O. E., Kirzioglu, Z. & Kivanc, M. Probiotics: can they be used to improve oral health? Benef. Microbes 6, 647–56 (2015).
- Lee, B. J. & Bak, Y.-T. Irritable bowel syndrome, gut microbiota and probiotics. J. Neurogastroenterol. Motil. 17, 252–66 (2011).
- Whelan, K. & Quigley, E. M. M. Probiotics in the management of irritable bowel syndrome and inflammatory bowel disease. Curr. Opin. Gastroenterol. 29, 184–9 (2013).
- Mortaz, E. et al. Probiotics in the management of lung diseases. Mediators Inflamm. 2013, 751068 (2013).
- Messaoudi, M. et al. Assessment of psychotropic-like properties of a probiotic formulation ( Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br. J. Nutr. 105, 755–764 (2010).
- Desbonnet, L., Garrett, L., Clarke, G., Bienenstock, J. & Dinan, T. G. The probiotic Bifidobacteria infantis: An assessment of potential antidepressant properties in the rat. J. Psychiatr. Res. 43, 164–74 (2008).
- Abenavoli, L., Scarpellini, E., Rouabhia, S., Balsano, C. & Luzza, F. Probiotics in non-alcoholic fatty liver disease: which and when. Ann. Hepatol. 12, 357–63
- Aggarwal, J., Swami, G. & Kumar, M. Probiotics and their Effects on Metabolic Diseases: An Update. J. Clin. Diagn. Res. 7, 173–7 (2013).
- Shida, K. & Nomoto, K. Probiotics as efficient immunopotentiators: translational role in cancer prevention. Indian J. Med. Res. 138, 808–14 (2013).
- 95s-0316-rpt0282-tab-03-ref-19-joint-faowho-vol219.pdf. at <http://www.fda.gov/ohrms/dockets/dockets/95s0316/95s-0316-rpt0282-tab-03-ref-19-joint-faowho-vol219.pdf>
- Bassetti, S., Frei, R. & Zimmerli, W. Fungemia with Saccharomyces cerevisiae after treatment with Saccharomyces boulardii. Am. J. Med. 105, 71–2 (1998).
- Lherm, T. et al. Seven cases of fungemia with Saccharomyces boulardii in critically ill patients. Intensive Care Med. 28, 797–801 (2002).
- Niault, M., Thomas, F., Prost, J., Ansari, F. H. & Kalfon, P. Fungemia due to Saccharomyces species in a patient treated with enteral Saccharomyces boulardii. Clin. Infect. Dis. 28, 930 (1999).
- Riquelme, A. J. et al. Saccharomyces cerevisiae fungemia after Saccharomyces boulardii treatment in immunocompromised patients. J. Clin. Gastroenterol. 36, 41–3 (2003).
- Lestin, F., Pertschy, A. & Rimek, D. [Fungemia after oral treatment with Saccharomyces boulardii in a patient with multiple comorbidities]. Dtsch. Med. Wochenschr. 128, 2531–3 (2003).
- Guandalini, S. et al. Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial. J. Pediatr. Gastroenterol. Nutr. 30, 54–60 (2000).
- Vanderhoof, J. A. et al. Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children. J. Pediatr. 135, 564–8 (1999).
- Shornikova, A. V, Casas, I. A., Mykkänen, H., Salo, E. & Vesikari, T. Bacteriotherapy with Lactobacillus reuteri in rotavirus gastroenteritis. Pediatr. Infect. Dis. J. 16, 1103–7 (1997).
- Guarino, A., Canani, R. B., Spagnuolo, M. I., Albano, F. & Di Benedetto, L. Oral bacterial therapy reduces the duration of symptoms and of viral excretion in children with mild diarrhea. J. Pediatr. Gastroenterol. Nutr. 25, 516–9 (1997).
- De Groote, M. A., Frank, D. N., Dowell, E., Glode, M. P. & Pace, N. R. Lactobacillus rhamnosus GG bacteremia associated with probiotic use in a child with short gut syndrome. Pediatr. Infect. Dis. J. 24, 278–80 (2005).
- Zein, E. F. et al. [Lactobacillus rhamnosus septicemia in a diabetic patient associated with probiotic use: a case report]. Ann. Biol. Clin. (Paris). 66, 195–8
- Salminen, M. K. et al. Lactobacillus bacteremia during a rapid increase in probiotic use of Lactobacillus rhamnosus GG in Finland. Clin. Infect. Dis. 35, 1155–60 (2002).
- Ledoux, D., Labombardi, V. J. & Karter, D. Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin’s disease. Int. J. STD AIDS 17, 280–2 (2006).
- Tommasi, C. et al. Diagnostic difficulties of Lactobacillus casei bacteraemia in immunocompetent patients: a case report. J. Med. Case Rep. 2, 315 (2008).
- Ohishi, A. et al. Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele. J. Pediatr. 156, 679–81 (2010).
- Bertelli, C. et al. Bifidobacterium longum bacteremia in preterm infants receiving probiotics. Clin. Infect. Dis. 60, 924–7 (2015).
- Oggioni, M. R., Pozzi, G., Valensin, P. E., Galieni, P. & Bigazzi, C. Recurrent septicemia in an immunocompromised patient due to probiotic strains of Bacillus subtilis. J. Clin. Microbiol. 36, 325–6 (1998).
- Mackay, A. D., Taylor, M. B., Kibbler, C. C. & Hamilton-Miller, J. M. T. Lactobacillus endocarditis caused by a probiotic organism. Clin. Microbiol. Infect. 5, 290–292 (1999).
- Presterl, E. et al. Endocarditis by Lactobacillus rhamnosus due to yogurt ingestion? Scand. J. Infect. Dis. 33, 710–4 (2001).
- Besselink, M. G. H. et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet (London, England) 371, 651–9 (2008).
- Lin, C. F., Fung, Z. F., Wu, C. L. & Chung, T. C. Molecular characterization of a plasmid-borne (pTC82) chloramphenicol resistance determinant (cat-TC) from Lactobacillus reuteri G4. Plasmid 36, 116–24 (1996).
- Gevers, D., Danielsen, M., Huys, G. & Swings, J. Molecular characterization of tet(M) genes in Lactobacillus isolates from different types of fermented dry sausage. Appl. Environ. Microbiol. 69, 1270–5 (2003).
- Tannock, G. W. et al. Molecular characterization of a plasmid-borne (pGT633) erythromycin resistance determinant (ermGT) from Lactobacillus reuteri 100-63. Plasmid 31, 60–71 (1994).
- Mater, D. D. G., Langella, P., Corthier, G. & Flores, M.-J. A probiotic Lactobacillus strain can acquire vancomycin resistance during digestive transit in mice. J. Mol. Microbiol. Biotechnol. 14, 123–7 (2008).
- Masco, L., Huys, G., De Brandt, E., Temmerman, R. & Swings, J. Culture-dependent and culture-independent qualitative analysis of probiotic products claimed to contain bifidobacteria. Int. J. Food Microbiol. 102, 221–230 (2005).
- Hoa, N. T. et al. Characterization of Bacillus species used for oral bacteriotherapy and bacterioprophylaxis of gastrointestinal disorders. Appl. Environ. Microbiol. 66, 5241–7 (2000).
- Milazzo, I., Speciale, A., Musumeci, R., Fazio, D. & Blandino, G. Identification and antibiotic susceptibility of bacterial isolates from probiotic products available in Italy. New Microbiol. 29, 281–91 (2006).
- Moneret-Vautrin, D. A., Morisset, M., Cordebar, V., Codréanu, F. & Kanny, G. Probiotics may be unsafe in infants allergic to cow’s milk. Allergy 61, 507–8 (2006).
- Lee, T.-T. T. et al. Contamination of probiotic preparations with milk allergens can cause anaphylaxis in children with cow’s milk allergy. J. Allergy Clin. Immunol. 119, 746–7 (2007).