Probiotics

• How It Works

  Probiotics have been shown effective against diarrhea and certain inflammatory disorders. But data from well-designed clinical trials are needed to establish their use.

  Probiotics are defined by the Food and Agriculture Organization of the World Health Organization as “live microorganisms, which when consumed in adequate amounts, confer a health effect on the host”. Majority of probiotics contain bacteria that produce lactic acid, such as Lactobacillus, Streptococcus, Bifidobacterium, Propionibacterium and Enterococcus or yeasts such as Saccharomyces boulardii that are not harmful.

  Probiotics have grown popular over the last two decades because they are thought to improve digestion, immune function and nutrient absorption but the most important being the reversal of dysbiosis (changes in the function or composition of gut microbes) that is thought to play a role in the development of many chronic and degenerative diseases. Although gut microbiota is known to develop at birth, nutrition, lifestyle, and changes in the host genome during later years can shift its makeup and activity, which in turn influences overall health and the risk of developing disease. Antibiotic use has also been associated with gut microbiota disruption in general population, increasing the risk of chronic disease; in patients undergoing allogeneic hematopoietic cell transplantation; as well as in allogeneic bone marrow transplantation patients. Furthermore, antibiotics were found to inhibit the benefits of immune checkpoint-inhibitors in patients with advanced cancer. Studies are underway to determine strategies for modulating the gut microbiome to improve immune response in cancer.

  Probiotic supplementation is promoted for the prevention and treatment of inflammatory bowel disease, gastroenteritis, irritable bowel syndrome, allergies, dental cavities, and for the management of diarrhea due to antibiotic use, due to the bacterium Clostridium difficile, and that associated with chemotherapy.

  Other methods used to change the gut microbiota include “prebiotics” and “fecal microbiota transplantation” (FMT). Prebiotics, also known as functional foods, are non-digestible food ingredients that benefit the host by selectively promoting growth or activity of helpful gut bacteria. Because probiotics are short-lived, prebiotics are sometimes added to probiotics to maintain their levels in the gut. This combination of pro- and prebiotics is called “synbiotic therapy.” FMT involves administration of fecal matter from a healthy donor into a recipient by enema, colonoscopy or through the upper gastrointestinal tract in the form of oral capsules, via nasogastric, nasoduodenal or nasoenteric tube, or by endoscopy.

  Current evidence indicates that probiotics may be useful for the treatment of some inflammatory disorders, and also have anti-carcinogenic activity. But the drawbacks of the studies include small sample size and poor methodology. Well-designed trials and guidelines are needed to recommend use of probiotics. Probiotics are generally considered safe, but their long-term safety is not known. Bacteremia (presence of bacteria in the blood), fungemia (presence of fungi in the blood), and endocarditis (inflammation in the lining of the heart) have been reported following use in newborns and in immunocompromised individuals.

• Purported Uses
  • Diarrhea
    Several studies have shown that probiotics are effective in treating diarrhea caused by antibiotics, due to a bacterium known as Clostridium difficile, and diarrhea due to chemotherapy.
  • Inflammatory bowel disease
    Probioitics were shown to benefit patients with pouchitis (inflammation of the ileal pouch after colectomy) and ulcerative colitis, but not those with Crohn’s disease.
  • Gastroenteritis
    There is strong evidence to support use of probiotics for controlling acute infectious diarrhea, which is the main cause of gastroenteritis.
  • Irritable bowel syndrome
    Some studies indicate a benefit, but they are not well-designed. Clinical trials with good methodology are needed.
  • Urinary tract infections
    Evidence to support use is lacking.
  • Obesity
    Probiotics were shown to have beneficial effects.
  • Diabetes
    There is evidence in favor of probiotics for individuals with diabetes.
  • Allergies
    Probiotic use had a moderate benefit in the prevention of eczema, but not other allergic conditions.
  • Dental cavities
    Probiotics were shown to increase resistance to the formation of cavities.
  • Cancer treatment-associated side effects
    Probiotic use is effective in controlling diarrhea due to chemo, in reducing infections at the site of surgery and in improving bowel function in colorectal patients.
  • Immunomodulation
    Studies done in mice show that probiotics can activate certain cells of immune system.
• Do Not Take If

  You are taking drugs that are substrates of hepatic drug-metabolizing enzymes: VSL3, a probiotic mixture of 8 bacterial strains, was shown to affect their activity.

• Side Effects

  Pediatric Case Reports:

  • Bacteremia associated with Escherichia coli and Bifidobacterium species: In pre-term infants as well as a newborn following probiotic use.
  • L. rhamnosus pneumonia: In a 11-month-old baby, secondary to a respiratory viral infection. She recovered after antibiotic therapy.
  • D-lactic acid encephalopathy, involving intermittent ataxia (inability to control volunteer muscle movement): In a 5-year-old girl following use of probiotics to control diarrhea. She was treated with oral antibiotics.
  • Bacteremia associated with Lactobacillus: In a 17-year-old boy with ulcerative colitis. His symptoms, which included fever, flushing and chills resolved following treatment with antibiotics.

  Adult Case Reports:

  • Fungemia involving Saccharomyces cerevisiae: In a patient with Clostridium difficile-associated diarrhea who was treated orally with the probiotic yeast Saccharomyces boulardii.
  • Sepsis (inflammation due to an infection) associated with Saccharomyces cervesiae: In a 34-year-old woman with extensive burns, and administered Saccharomyces boulardii to improve the digestive tolerance to enteral feeding (food given through a tube into the stomach or small intestine).
  • Fungemia: In a 79-year-old woman following treatment with Sacchaflor (a probiotic consisting of S. boulardii) for Clostridium difficile-associated diarrhea. Her symptoms improved after stopping use of Sacchaflor.
  • Lactobacillus empyema (presence of pus): In a 54-year-old HIV-infected lung transplant patient, after taking a probiotic containing Lactobacillus rhamnosus GG. His symptoms resolved with antibiotic treatment.
  • Lactobacillus acidophilus bacteremia: In a patient with AIDS and Hodgkin’s disease following probiotic therapy containing L. acidophilus.
  • Sepsis due to preoperative administration of probiotics containing Lactobacillus rhamnosus: In a 24-year-old woman following an aortic valve replacement. She was treated with antibiotics.
  • Bloodstream infection: In a critically ill 64-year-old patient with acute pancreatitis (inflammation of the pancreas), following administration of a symbiotic formula containing Pediococcus pentosaceus. He was treated with antibiotics.
• Clinical Summary

  The term “Probiotic” (Greek for “prolife”) came into being in the 1960s to define substances produced by protozoa, which support the growth of other microorganisms ⁽¹⁾. Following revisions over the years, probiotics are currently defined by the Food and Agriculture Organization of the World Health Organization as “live microorganisms, which when consumed in adequate amounts, confer a health effect on the host” ⁽²⁾. Most probiotics consist of lactic-acid producing, non-virulent bacteria, such as Lactobacillus, Streptococcus, Bifidobacterium, Propionibacterium and Enterococcus or non-pathogenic yeasts such as Saccharomyces boulardii. Probiotics have gained immense popularity over the last two decades for their perceived health benefits which include improved digestion, immune function and nutrient absorption but the most important being the reversal of dysbiosis (changes in the function or composition of gut microbes or “microbiota”) that is hypothesized to play a role in the development of several chronic and degenerative diseases ⁽³⁾. Although gut microbiota is known to develop at birth, nutrition, lifestyle, and changes in the host genome during later years can shift its makeup and activity, which in turn influences overall health and the risk of developing disease. Antibiotic use has also been associated with gut microbiota disruption in general population, increasing the risk of chronic disease ⁽⁷⁷⁾; in patients undergoing allogeneic hematopoietic cell transplantation ⁽⁴⁾, with the greatest shifts occuring between stem cell infusion and reconstitution of healthy immune cells ⁽⁷⁵⁾; as well as in allogeneic bone marrow transplantation patients ⁽⁵⁾. Furthermore, antibiotics were found to inhibit the benefits of immune checkpoint-inhibitors in patients with advanced cancer ⁽⁷⁸⁾; and patients who were administered antibiotics before, and not during, immune checkpoint-inhibitor therapy had worse treatment response and overall survival  ⁽⁷⁹⁾. Research is underway to determine strategies for modulating the gut microbiome to improve immune response in cancer.

  Probiotic supplementation is currently promoted for the prevention and treatment of inflammatory bowel disease, gastroenteritis, irritable bowel syndrome, allergies, dental cavities, and for the management of diarrhea induced by antibiotics, by the bacterium Clostridium difficile (C. difficile), and that associated with chemotherapy ⁽⁶⁴⁾. However, authoritative guidelines for probiotic use have not yet been established nor is there a consensus about the minimum number of microorganisms needed to derive benefits.

  Probiotics have been evaluated in randomized controlled trials and the strongest evidence of their effectiveness is for acute infectious diarrhea, the main cause of acute gastroenteritis ⁽⁷⁾. Probiotic supplementation also was shown useful in alleviating antibiotic-associated diarrhea ⁽⁸⁾. Although randomized trials did not find any benefit for managing C. difficile-associated diarrhea ⁽⁹⁾, a meta analysis suggests moderate quality evidence to support use of probiotics for preventing C. difficile infection ⁽⁶³⁾. The role of probiotics in the treatment of inflammatory bowel disease (IBD) has been the focus of many studies and available data support their efficacy for pouchitis (inflammation of the ileal pouch in post-colectomy patients). Interestingly, even though a range of products were shown useful in treating and sustaining remissions of mild to moderately active ulcerative colitis, findings of Crohn’s disease are not promising ⁽⁶⁵⁾. Based on the association of intestinal bacteria with symptoms of irritable bowel syndrome (IBS), probiotic supplementation has been explored in a few studies. Although current data are encouraging, well-designed trials to support use are lacking ⁽¹¹⁾. In a study of patients with systemic sclerosis, probiotics did not improve gastrointestinal symptoms ⁽⁶⁷⁾.
  In addition, analyses of the National Health and Nutrition survey results revealed that consumption of yogurt or probiotics reduces the risk of proteinuric kidney disease ⁽¹²⁾, but definitive conclusions about the role of probiotics for the treatment of urinary tract infections ⁽¹³⁾ or bacterial vaginosis ⁽⁶⁰⁾ are lacking. Probiotic use was also shown to increase resistance to risk factors associated with dental caries in a randomized trial ⁽¹⁴⁾, and to improve memory impairment in a murine model ⁽¹⁵⁾. The utility of probiotics in preventing allergies has been addressed as well, with studies showing a moderate benefit for eczema prevention but not for other allergic conditions ⁽¹⁶⁾. Probiotic supplementation was also shown useful for the reduction of glycemic and inflammatory markers in patients with non-alcoholic fatty liver disease ⁽⁵⁸⁾. But evidence to support its role in managing cystic fibrosis is lacking ⁽⁶¹⁾.

  As increasing evidence indicates that gut bacteria are important determinants of metabolic disorders, probiotics are being investigated as a possible therapeutic option. Thus far, beneficial effects have been reported against obesity and diabetes in mice and in humans ⁽¹⁷⁾. Meta analyses suggest that probiotic supplementation helps reduce periodontal parameters and halitosis associated with severe periodontitis ⁽⁶⁸⁾, helps prevent oral candidiasis in the elderly ⁽⁶²⁾, may lower fasting blood glucose level in adults ⁽⁵⁹⁾ and may also improve lipid metabolism by lowering the levels of LDL and total cholesterol ⁽¹⁸⁾.

  Another important application of probiotic therapy is in pediatrics for the treatment of gastrointestinal disorders and allergies. Meta analyses indicate that enteral supplementation of probiotics is effective in preventing severe necrotizing enterocolitis in preterm infants ⁽¹⁹⁾. And a significant reduction in acute diarrhea was reported in children, independent of the bacterial strains employed ^(7) (69).  Studies also indicate efficacy of probiotics against antibiotic-associated diarrhea ⁽²⁰⁾ and for lowering the incidence of eczema in late infancy ⁽⁷⁰⁾. But available evidence does not support use for allergic diseases ⁽²¹⁾, and data are insufficient to assess effects in children with short bowel syndrome, a malabsorption disorder ⁽²²⁾.

  Preliminary studies also suggest that probiotics may have anti-carcinogenic potential. Preclinical data show that oral administration of Lactobacillus casei BL23 has a protective effect against dimethyl hydrazine-induced colorectal cancer ⁽²³⁾, and a probiotic mixture attenuated the growth of hepatocellular carcinoma ⁽²⁴⁾. A study done in a murine model of melanoma suggests that manipulating the microbiota may modulate cancer immunotherapy, by enhancing antitumor immunity in vivo through administering a Bifidobacterium strain ⁽⁷¹⁾. Findings also suggest that gut microbiome may modulate responses to anti PD-1 immunotherapy in melanoma patients ⁽⁸⁰⁾. Data from a large epidemiological study suggest an association between consumption of non-pasteurized dairy products and lower incidence of colorectal cancer ⁽²⁵⁾. Probiotics may also aid in controlling symptoms associated with cancer treatments. Results from a systematic review showed a reduction in the severity and frequency of treatment-associated diarrhea, and the need for anti-diarrheal medication in cancer patients following probiotic supplementation ⁽²⁶⁾. In other studies, perioperative probiotic treatment reduced surgical site infections in patients undergoing colorectal cancer surgery ⁽²⁷⁾ and improved bowel function ⁽²⁸⁾. But supplementation was ineffective for preventing radiation-induced mucositis in patients with head and neck cancer ⁽⁷²⁾. More studies are underway ⁽²⁹⁾.

  In addition to probiotics, other strategies used to modulate gut microbiota that have recently gained attention include “prebiotics” and “fecal microbiota transplantation” (FMT). Prebiotics, also known as functional foods, are non-digestible food ingredients that benefit the host by selectively promoting growth or activity of helpful gut bacteria. Currently used prebiotics include the fructans inulin and fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), and lactulose. A few studies have evaluated the utility of prebiotics for IBS but data are conflicting ⁽¹¹⁾. Because probiotics are short-lived, prebiotics are being co-administered to maintain their levels in the gut. This combination of pro- and prebiotics is called “synbiotic therapy” that has been shown useful in controlling symptoms associated with IBS ⁽³⁰⁾. FMT involves administration of fecal matter from a healthy donor into a recipient by enema, colonoscopy or through the upper gastrointestinal tract in the form of oral capsules, via nasogastric, nasoduodenal or nasoenteric tube, or by endoscopy, to restore normal gut flora. Some studies indicate that FMT might benefit IBS patients although the quality of evidence is low ⁽³¹⁾. In oncology settings, FMT has been reported effective for treating immune checkpoint inhibitor (ICI)-associated colitis ⁽⁸¹⁾; and autologous fecal microbiota transplantation (auto-FMT), for reestablishing intestinal microbiota composition in patients with gut microbiota depletion due to antibiotic treatment during allogeneic hematopoietic stem cell transplantation ⁽⁷⁶⁾.

  Although an increasing number of studies suggest that probiotics improve health by inducing favorable changes in the intestinal bacteria, the overall evidence to support their use is limited due to small sample size, poor methodology, variation in the species and strains of bacteria, and in the dosage and duration of administration. Variation in the response to probiotics is also an important factor to consider because genes that respond to probiotic intake were shown to be strain-specific ⁽³²⁾ and to cluster according to the individual and not by intervention ^(32) (33). Furthermore, gut colonization is not always achieved despite supplementation with probiotics ⁽⁷³⁾.  In another study that examined post-antibiotic recovery in humans, administration of probiotics was associated with a delay in gut-microbiome reconstitution ⁽⁷⁴⁾. Well-designed studies and specific recommendations are needed to establish probiotic use for different age groups and disorders.

  Probiotics are generally considered safe, but their long-term safety has not been determined. Bacteremia, fungemia, and endocarditis have been reported following use in newborns and in immunocompromised individuals.

• Food Sources

  Yogurt, miso, tempeh, kefir, pickled vegetables, sauerkraut, kimchi and buttermilk

• Purported Uses
  • Diarrhea
  • Inflammatory bowel disease
  • Gastroenteritis
  • Irritable bowel syndrome
  • Urinary tract infections
  • Obesity
  • Diabetes
  • Allergies
  • Dental cavities
  • Cancer treatment-associated side effects
  • Immunomodulation
• Mechanism of Action

  Proposed mechanisms by which probiotics influence colonization in the gut include production of inhibitory compounds to suppress the growth of pathogenic microorganisms, and production of substrates to promote the growth of beneficial bacteria. Probiotics can also indirectly influence shifts in microbiota by interacting with the mucosal system, which affects systemic immunity; and by reducing pro-inflammatory markers implicated in many disorders ^(34) (35).

  Studies using murine models indicate that administration of S. boulardii to type-2 diabetic and obese mice resulted in reduced inflammation, body weight, fat mass, and hepatic steatosis, along with decreased bacterial population that has been previously associated with obesity and type-2 diabetes ⁽³⁶⁾. Probiotic treatment also affected a reduction in food intake and an improvement in glucose tolerance via release of the hormone glucagon-like protein-1 (GLP-1), a physiological regulator of appetite and food intake ⁽³⁷⁾.

  Immunomodulation is one of the ways in which probiotics are thought to influence host health. A subspecies of Bifidobacterium longum prevented Salmonella-associated infection in mice by inducing T-regulatory cells and by attenuating the activation of nuclear factor-kappa B, which plays a role in the expression of pro-inflammatory genes ⁽³⁸⁾. Induction of T-regulatory cells was also shown in humans along with a reduction in pro-inflammatory biomarkers ⁽³⁹⁾. In addition probiotic administration was shown to reduce pain perception, and to induce changes in the colonic expression of genes that mediate pain and inflammation ⁽⁴⁰⁾. And a probiotic mixture reduced the growth of hepatocellular carcinoma by shifting the gut microbes toward beneficial bacteria, which produce anti-inflammatory metabolites ⁽²⁴⁾. Protective effects of probiotics were also reported in a murine model of mammary carcinogenesis. Oral administration of a supplement containing Lactobacillus reuteri resulted in inhibition of mammary tumor formation by triggering CD4+/CD25+ lymphocytes, which play a critical role in controlling immune responses ⁽⁴¹⁾. Because intestinal bacteria have been shown to influence carcinogenesis and response to anticancer therapy, manipulating them selectively may be a potential strategy to enhance the efficacy of anticancer treatments ⁽⁶⁶⁾.

• Contraindications
  • Patients who are immunocompromised, or have a central venous catheter or critically ill should not take probiotics containing S. boulardii ⁽⁴²⁾.
  • Probiotics should not be given to newborns with very low birth weight, clinical instability, umbilical catheters, and to those with congenital abnormalities or stage III asphyxia ⁽⁴³⁾.
• Adverse Reactions

  Pediatric Case Reports:

  • Bacteremia associated with Escherichia coli and Bifidobacterium species: In pre-term infants ^{(44) (45) (46)} as well as a newborn ⁽⁴⁷⁾ following probiotic therapy.
  • Probiotic-associated L. rhamnosus pneumonia: In a 11-month-old baby, secondary to a respiratory viral infection. She recovered after antibiotic therapy ⁽⁴⁹⁾.
  • D-lactic acid encephalopathy, involving intermittent ataxia: In a 5-year-old girl following use of probiotics to control diarrhea. She was treated with oral antibiotics ⁽⁵⁰⁾.
  • Bacteremia associated with Lactobacillus: In a 17-year-old boy with ulcerative colitis. His symptoms, which included fever, flushing and chills resolved following treatment with antibiotics ⁽⁴⁸⁾.

  Adult Case Reports:

  • Fungemia involving Saccharomyces cerevisiae: In a patient with Clostridium difficile-associated diarrhea who was treated orally with the probiotic yeast Saccharomyces boulardii ⁽⁵¹⁾.
  • Sepsis associated with Saccharomyces cervesiae: In a 34-year-old woman with extensive burns, and administered Saccharomyces boulardii to improve the digestive tolerance to enteral feeding ⁽⁵²⁾.
  • Fungemia: In a 79-year-old woman following treatment with Sacchaflor (a probiotic consisting of S. boulardii) for Clostridium difficile-associated diarrhea. Her symptoms improved after discontinuing use of Sacchaflor ⁽⁵³⁾.
  • Lactobacillus empyema: In a 54-year-old HIV-infected lung transplant patient, after taking a probiotic containing Lactobacillus rhamnosus GG. His symptoms resolved with antibiotic treatment ⁽⁶⁾.
  • Lactobacillus acidophilus bacteremia: In a patient with AIDS and Hodgkin’s disease following probiotic therapy containing L. acidophilus ⁽⁵⁴⁾.
  • Sepsis due to preoperative administration of a probiotic containing Lactobacillus rhamnosus: In a 24-year-old woman following an aortic valve replacement. She was treated with antibiotics ⁽⁵⁵⁾.
  • Bloodstream infection: In a critically ill 64-year-old patient with acute pancreatitis, following administration of a symbiotic formula containing Pediococcus pentosaceus. He was treated with antibiotics ⁽⁵⁶⁾.
• Herb-Drug Interactions

  Hepatic drug-metabolizing enzymes: In mice, administration of VSL3, a probiotic mixture of 8 bacterial strains, was shown to modify the expression of Cyp4v3, alcohol dehydrogenase 1, carboxyesterase 2a, and multiple phase II glutathione-S-transferases ⁽⁵⁷⁾. Human data are lacking.

• References

  1. Lilly DM, Stillwell RH. PROBIOTICS: GROWTH-PROMOTING FACTORS PRODUCED BY MICROORGANISMS. Science. Feb 12 1965;147(3659):747-748.

  2. FAO. Joint FAO/WHO working group report on drafting guidelines for the evaluation of probiotics in food. 2002. Accessed December 11, 2019.

  3. Nicholson JK, Holmes E, Kinross J, et al. Host-gut microbiota metabolic interactions. Science. Jun 8 2012;336(6086):1262-1267.

  4. Taur Y, Xavier JB, Lipuma L, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. Oct 2012;55(7):905-914.

  5. Jenq RR, Ubeda C, Taur Y, et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. May 7 2012;209(5):903-911.

  6. Luong ML, Sareyyupoglu B, Nguyen MH, et al. Lactobacillus probiotic use in cardiothoracic transplant recipients: a link to invasive Lactobacillus infection? Transpl Infect Dis. Dec 2010;12(6):561-564.

  7. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Efficacy of probiotics in prevention of acute diarrhoea: a meta-analysis of masked, randomised, placebo-controlled trials. Lancet Infect Dis. Jun 2006;6(6):374-382.

  8. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. May 9 2012;307(18):1959-1969.

  9. Crow JR, Davis SL, Chaykosky DM, Smith TT, Smith JM. Probiotics and Fecal Microbiota Transplant for Primary and Secondary Prevention of Clostridium difficile Infection. Pharmacotherapy. Nov 2015;35(11):1016-1025.

  10. Whelan K, Myers CE. Safety of probiotics in patients receiving nutritional support: a systematic review of case reports, randomized controlled trials, and nonrandomized trials. Am J Clin Nutr. Mar 2010;91(3):687-703.

  11. Distrutti E, Monaldi L, Ricci P, Fiorucci S. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies. World J Gastroenterol. Feb 21 2016;22(7):2219-2241.

  12. Yacoub R, Kaji D, Patel SN, et al. Association between probiotic and yogurt consumption and kidney disease: insights from NHANES. Nutr J. 2016;15(1):10.

  13. Schwenger EM, Tejani AM, Loewen PS. Probiotics for preventing urinary tract infections in adults and children. Cochrane Database Syst Rev. 2015;12:CD008772.

  14. Nishihara T, Suzuki N, Yoneda M, Hirofuji T. Effects of Lactobacillus salivarius-containing tablets on caries risk factors: a randomized open-label clinical trial. BMC Oral Health. 2014;14:110.

  15. Woo JY, Gu W, Kim KA, Jang SE, Han MJ, Kim DH. Lactobacillus pentosus var. plantarum C29 ameliorates memory impairment and inflammaging in a D-galactose-induced accelerated aging mouse model. Anaerobe. Jun 2014;27:22-26.

  16. West CE, Jenmalm MC, Kozyrskyj AL, Prescott SL. Probiotics for treatment and primary prevention of allergic diseases and asthma: looking back and moving forward. Expert Rev Clin Immunol. Jan 28 2016.

  17. Le Barz M, Anhe FF, Varin TV, et al. Probiotics as Complementary Treatment for Metabolic Disorders. Diabetes Metab J. Aug 2015;39(4):291-303.

  18. Cho YA, Kim J. Effect of Probiotics on Blood Lipid Concentrations: A Meta-Analysis of Randomized Controlled Trials. Medicine (Baltimore). Oct 2015;94(43):e1714.

  19. AlFaleh K, Anabrees J. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Evid Based Child Health. Sep 2014;9(3):584-671.

  20. Szajewska H, Canani RB, Guarino A, et al. Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Children. J Pediatr Gastroenterol Nutr. Mar 2016;62(3):495-506.

  21. Fiocchi A, Pawankar R, Cuello-Garcia C, et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J. 2015;8(1):4.

  22. Reddy VS, Patole SK, Rao S. Role of probiotics in short bowel syndrome in infants and children—a systematic review. Nutrients. Mar 2013;5(3):679-699.

  23. Lenoir M, Del Carmen S, Cortes-Perez NG, et al. Lactobacillus casei BL23 regulates T and Th17 T-cell populations and reduces DMH-associated colorectal cancer. J Gastroenterol. Jan 9 2016.

  24. Li J, Sung CY, Lee N, et al. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice. Proc Natl Acad Sci U S A. Feb 16 2016.

  25. Campbell TC. A study on diet, nutrition and disease in the People’s Republic of China. Part I. Bol Asoc Med P R. Mar 1990;82(3):132-134.

  26. Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: a systematic review. Ann Oncol. Oct 2014;25(10):1919-1929.

  27. Aisu N, Tanimura S, Yamashita Y, et al. Impact of perioperative probiotic treatment for surgical site infections in patients with colorectal cancer. Exp Ther Med. Sep 2015;10(3):966-972.

  28. Yang Y, Xia Y, Chen H, et al. The effect of perioperative probiotics treatment for colorectal cancer: short-term outcomes of a randomized controlled trial. Oncotarget. Jan 27 2016.

  29. Probiotics and Cancer. https://clinicaltrials.gov/ct2/results?term=probiotics+and+cancer&Search=Search. Accessed December 11, 2019.

  30. Bittner AC, Croffut RM, Stranahan MC. Prescript-Assist probiotic-prebiotic treatment for irritable bowel syndrome: a methodologically oriented, 2-week, randomized, placebo-controlled, double-blind clinical study.Clin Ther. Jun 2005;27(6):755-761.

  31. Bowman KA, Broussard EK, Surawicz CM. Fecal microbiota transplantation: current clinical efficacy and future prospects. Clin Exp Gastroenterol. 2015;8:285-291.

  32. van Baarlen P, Troost F, van der Meer C, et al. Human mucosal in vivo transcriptome responses to three lactobacilli indicate how probiotics may modulate human cellular pathways. Proc Natl Acad Sci U S A. Mar 15 2011;108 Suppl 1:4562-4569.

  33. Bron PA, van Baarlen P, Kleerebezem M. Emerging molecular insights into the interaction between probiotics and the host intestinal mucosa. Nat Rev Microbiol. Jan 2012;10(1):66-78.

  34. Sanders ME. Impact of probiotics on colonizing microbiota of the gut. J Clin Gastroenterol. Nov 2011;45 Suppl:S115-119.

  35. Thomas LV, Suzuki K, Zhao J. Probiotics: a proactive approach to health. A symposium report. Br J Nutr. Dec 2015;114 Suppl 1:S1-15.

  36. Everard A, Matamoros S, Geurts L, Delzenne NM, Cani PD. Saccharomyces boulardii administration changes gut microbiota and reduces hepatic steatosis, low-grade inflammation, and fat mass in obese and type 2 diabetic db/db mice. MBio. 2014;5(3):e01011-01014.

  37. Yadav H, Lee JH, Lloyd J, Walter P, Rane SG. Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. J Biol Chem. Aug 30 2013;288(35):25088-25097.

  38. O’Mahony C, Scully P, O’Mahony D, et al. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation. PLoS Pathog. 2008;4(8):e1000112.

  39. Groeger D, O’Mahony L, Murphy EF, et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. Jul-Aug 2013;4(4):325-339.

  40. Distrutti E, Cipriani S, Mencarelli A, Renga B, Fiorucci S. Probiotics VSL#3 protect against development of visceral pain in murine model of irritable bowel syndrome. PLoS One. 2013;8(5):e63893.

  41. Lakritz JR, Poutahidis T, Levkovich T, et al. Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice.Int J Cancer. Aug 1 2014;135(3):529-540.

  42. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. May 2010;31(5):431-455.

  43. Parker R. Probiotic guideline for necrotizing enterocolitis prevention in very low-birth-weight neonates. Adv Neonatal Care. Apr 2014;14(2):88-95.

  44. Guenther K, Straube E, Pfister W, Guenther A, Huebler A. Sever sepsis after probiotic treatment with Escherichia coli NISSLE 1917. Pediatr Infect Dis J. Feb 2010;29(2):188-189.

  45. Bertelli C, Pillonel T, Torregrossa A, et al. Bifidobacterium longum bacteremia in preterm infants receiving probiotics. Clin Infect Dis. Mar 15 2015;60(6):924-927.

  46. Jenke A, Ruf EM, Hoppe T, Heldmann M, Wirth S. Bifidobacterium septicaemia in an extremely low-birthweight infant under probiotic therapy. Arch Dis Child Fetal Neonatal Ed. May 2012;97(3):F217-218.

  47. Ohishi A, Takahashi S, Ito Y, et al. Bifidobacterium septicemia associated with postoperative probiotic therapy in a neonate with omphalocele. J Pediatr. Apr 2010;156(4):679-681.

  48. Vahabnezhad E, Mochon AB, Wozniak LJ, Ziring DA. Lactobacillus bacteremia associated with probiotic use in a pediatric patient with ulcerative colitis. J Clin Gastroenterol. May-Jun 2013;47(5):437-439.

  49. Doern CD, Nguyen ST, Afolabi F, Burnham CA. Probiotic-associated aspiration pneumonia due to Lactobacillus rhamnosus. J Clin Microbiol. Aug 2014;52(8):3124-3126.

  50. Munakata S, Arakawa C, Kohira R, Fujita Y, Fuchigami T, Mugishima H. A case of D-lactic acid encephalopathy associated with use of probiotics. Brain Dev. Sep 2010;32(8):691-694.

  51. Santino I, Alari A, Bono S, et al. Saccharomyces cerevisiae fungemia, a possible consequence of the treatment of Clostridium difficile colitis with a probioticum. Int J Immunopathol Pharmacol. Jan-Mar 2014;27(1):143-146.

  52. Stefanatou E, Kompoti M, Paridou A, et al. Probiotic sepsis due to Saccharomyces fungaemia in a critically ill burn patient. Mycoses. Sep 2011;54(5):e643-646.

  53. Thygesen JB, Glerup H, Tarp B. Saccharomyces boulardii fungemia caused by treatment with a probioticum. BMJ Case Rep. 2012;2012.

  54. Ledoux D, Labombardi VJ, Karter D. Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin’s disease. Int J STD AIDS. Apr 2006;17(4):280-282.

  55. Kochan P, Chmielarczyk A, Szymaniak L, et al. Lactobacillus rhamnosus administration causes sepsis in a cardiosurgical patient—is the time right to revise probiotic safety guidelines? Clin Microbiol Infect. Oct 2011;17(10):1589-1592.

  56. Papanikolaou MN, Balla M, Papavasilopoulou T, Kofinas G, Karatzas S. Probiotics: an obedient ally or an insidious enemy? Crit Care. 2012;16(6):456.

  57. Selwyn FP, Cheng SL, Klaassen CD, Cui JY. Regulation of Hepatic Drug-Metabolizing Enzymes in Germ-Free Mice by Conventionalization and Probiotics. Drug Metab Dispos. Feb 2016;44(2):262-274.

  58. Sepideh A, Karim P, Hossein A, et al. Effects of Multistrain Probiotic Supplementation on Glycemic and Inflammatory Indices in Patients with Nonalcoholic Fatty Liver Disease: A Double-Blind Randomized Clinical Trial. J Am Coll Nutr.2016 Aug;35(6):500-505.

  59. Nikbakht E, Khalesi S, Singh I, Williams LT, West NP, Colson N.Effect of probiotics and synbiotics on blood glucose: a systematic review and meta-analysis of controlled trials. Eur J Nutr. 2016 Sep 3. [Epub ahead of print]

  60. Tan H, Fu Y, Yang C, Ma J. Effects of metronidazole combined probiotics over metronidazole alone for the treatment of bacterial vaginosis: a meta-analysis of randomized clinical trials. Arch Gynecol Obstet. 2017 Jun;295(6):1331-1339.

  61. Nikniaz Z, Nikniaz L, Bilan N, Somi MH, Faramarzi E. Does probiotic supplementation affect pulmonary exacerbation and intestinal inflammation in cystic fibrosis: a systematic review of randomized clinical trials. World J Pediatr. 2017 Apr 29. doi: 10.1007/s12519-017-0033-6. [Epub ahead of print]

  62. Ai R, Wei J, Ma D, Jiang L, Dan H, Zhou Y, Ji N, Zeng X, Chen Q. A meta-analysis of randomized trials assessing the effects of probiotic preparations on oral candidiasis in the elderly. Arch Oral Biol. 2017 Apr 30;83:187-192.

  63. Johnston BC, Lytvyn L, Lo CK et al. Microbial Preparations (Probiotics) for the Prevention of Clostridium difficile Infection in Adults and Children: An Individual Patient Data Meta-analysis of 6,851 Participants. Infect Control Hosp Epidemiol. 2018 Jul;39(7):771-781.

  64. Vanderhoof JA, Young R. Probiotics in the United States. Clin Infect Dis. 2008 Feb 1;46 Suppl 2:S67-72; discussion S144-51.

  65. Derwa Y, Gracie DJ, Hamlin PJ, Ford AC. Systematic review with meta-analysis: the efficacy of probiotics in inflammatory bowel disease. Aliment Pharmacol Ther. 2017 Aug;46(4):389-400.

  66. Zitvogel L, Galluzzi L, Viaud S, Vétizou M, Daillère R, Merad M, Kroemer G. Cancer and the gut microbiota: an unexpected link. Sci Transl Med. 2015 Jan 21;7(271):271ps1.

  67. Marighela TF, Arismendi MI, Marvulle V, Brunialti MKC, Salomão R, Kayser C. Effect of probiotics on gastrointestinal symptoms and immune parameters in systemic sclerosis: a randomized placebo-controlled trial. Rheumatology (Oxford). 2019 May 5. pii: kez160.

  68. Soares LG, Carvalho EB, Tinoco EMB. Clinical effect of Lactobacillus on the treatment of severe periodontitis and halitosis: A double-blinded, placebo-controlled, randomized clinical trial. Am J Dent. 2019 Feb;32(1):9-13.

  69. Sudha MR, Jayanthi N, Pandey DC, Verma AK. Bacillus clausii UBBC-07 reduces severity of diarrhoea in children under 5 years of age: a double blind placebo controlled study. Benef Microbes. 2019 Mar 13;10(2):149-154.

  70. Schmidt RM, Pilmann Laursen R, et al. Probiotics in late infancy reduce the incidence of eczema: A randomized controlled trial. Pediatr Allergy Immunol. 2019 May;30(3):335-340.

  71. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015 Nov 27;350(6264):1084-9.

  72. DE Sanctis V, Belgioia L, Cante D, et al. Lactobacillus brevis CD2 for Prevention of Oral Mucositis in Patients With Head and Neck Tumors: A Multicentric Randomized Study. Anticancer Res. 2019 Apr;39(4):1935-1942.

  73. Zmora N, Zilberman-Schapira G, Suez J, et al. Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features. Cell. 2018 Sep 6;174(6):1388-1405.e21.

  74. Suez J, Zmora N, Zilberman-Schapira G, et al. Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT. Cell. 2018 Sep 6;174(6):1406-1423.e16.

  75. Morjaria S, Schluter J, Taylor BP, et al. Antibiotic-Induced Shifts in Fecal Microbiota Density and Composition during Hematopoietic Stem Cell Transplantation. Infect Immun. 2019 Aug 21;87(9). pii: e00206-19.

  76. Taur Y, Coyte K, Schluter J, et al. Reconstitution of the gut microbiota of antibiotic-treated patients by autologous fecal microbiota transplant. Sci Transl Med. 2018 Sep 26;10(460). pii: eaap9489.

  77. Wilkins LJ, Monga M, Miller AW. Defining Dysbiosis for a Cluster of Chronic Diseases. Sci Rep. 2019 Sep 9;9(1):12918.

  78. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018 Jan 5;359(6371):91-97.

  79. Pinato DJ, Howlett S, Ottaviani D, et al. Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer. JAMA Oncol. 2019 Sep 12.

  80. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103.

  81. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018 Dec;24(12):1804-1808.