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⁾. In other studies, supplementation did not have a preventive effect against influenza in women healthcare workers ⁽⁸²⁾, nor against bacterial vaginosis in pregnant women ⁽⁸³⁾.

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 indicate that probiotics may also have anti-carcinogenic potential. Oral administration of Lactobacillus casei BL23 had 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⁾. Gut microbiome may also modulate responses to anti PD-1 immunotherapy in melanoma patients ⁽⁸⁰⁾. In addition, a large epidemiological study reported 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: Systematic reviews found probiotic supplementation to affect reductions in the severity and frequency of treatment-associated diarrhea, and the need for anti-diarrheal medication in cancer patients ⁽²⁶⁾; and to promote recovery of gastrointestinal function following gastrointestinal cancer surgery  ⁽⁸⁹⁾.  In colorectal cancer patients, perioperative probiotic treatment reduced surgical site infections ⁽²⁷⁾, improved bowel function ⁽²⁸⁾, and a systematic review concluded that probiotics/synbiotics help modulate enteric microbiota, improve postoperative outcomes, gut barrier function and reduce inflammatory parameters ⁽⁸⁶⁾. Probiotics may also help prevent chemo-related cognitive impairment in breast cancer patients  ⁽⁹⁰⁾; decrease the severity of chemo- and radiotherapy-induced oral mucositis in patients with nasopharyngeal carcinoma ⁽⁸⁷⁾; and reduce oral Candida following radiotherapy in patients with head and neck cancer  ⁽⁸⁸⁾, although supplementation was ineffective in preventing radiation-induced mucositis ⁽⁷²⁾. Despite these promising findings, a systematic review evaluating safety and efficacy of probiotics in oncological surgery found substantial risk of bias across majority of the studies analyzed, warranting the need for well-designed studies  ⁽⁹¹⁾.

In addition to probiotics, other strategies used to modulate gut microbiota that have 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” and has been shown useful in controlling symptoms associated with IBS ⁽³⁰⁾; and may also benefit gut functioning in healthy community-dwelling elders ⁽⁸⁴⁾.
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 may improve certain health outcomes 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, and to determine long-term safety.

Of note, early observational data suggest that indiscriminate use of commercially available probiotics may be harmful in the setting of immune checkpoint blockade treatment in cancer patients ⁽⁹²⁾.