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 supplements are currently promoted for the prevention and treatment of inflammatory bowel disease, gastroenteritis, irritable bowel syndrome, allergies, dental cavities, and for managing diarrhea induced by antibiotics, by the bacterium Clostridium difficile (C. difficile), and that associated with chemotherapy ⁽⁶⁴⁾.

The strongest evidence of effectiveness of probiotics is for acute infectious diarrhea ⁽⁷⁾. Supplementation also was shown useful in alleviating antibiotic-associated diarrhea ⁽⁸⁾. Although RCTs did not find benefit for managing C. difficile-associated diarrhea ⁽⁹⁾, data suggest effectiveness in preventing C. difficile infection ^(63) (93) and 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 on Crohn’s disease are not promising ⁽⁶⁵⁾. Based on the association of intestinal bacteria with symptoms of irritable bowel syndrome (IBS), supplementation has been explored in a few studies with promising findings but well-designed trials are lacking ⁽¹¹⁾. In a study of patients with systemic sclerosis, probiotics did not improve gastrointestinal symptoms ⁽⁶⁷⁾.
Analyses of the National Health and Nutrition survey results revealed consumption of yogurt or probiotics reduces the risk of proteinuric kidney disease ⁽¹²⁾, but definitive conclusions of benefit against 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 an RCT ⁽¹⁴⁾, and to improve memory impairment in a murine model ⁽¹⁵⁾. Probiotics conferred a moderate benefit for eczema prevention but not for other allergic conditions ⁽¹⁶⁾. Supplementation also reduced 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 prevent influenza in women healthcare workers ⁽⁸²⁾, nor bacterial vaginosis in pregnant women ⁽⁸³⁾, but shortened the healing time in patients with lactational breast abscesses  ⁽⁹⁴⁾.

As increasing evidence indicates that gut bacteria are important determinants of metabolic disorders, probiotics are being investigated as a possible therapeutic option. Thus far, benefits were reported against obesity and diabetes ⁽¹⁷⁾. Meta analyses suggest that 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 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 enteral supplementation is effective in preventing severe necrotizing enterocolitis in preterm infants  ⁽¹⁹⁾. A significant reduction in acute diarrhea was also reported in children, independent of the bacterial strains employed ^(7) (69). Additional studies showed efficacy of probiotics against antibiotic-associated diarrhea ^(20) (95) 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 murine melanoma model suggests that manipulating microbiota may modulate cancer immunotherapy by enhancing antitumor immunity through administering a Bifidobacterium strain ⁽⁷¹⁾. Gut microbiome may also modulate responses to anti PD-1 immunotherapy in melanoma patients ⁽⁸⁰⁾. Epidemiological data 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: Systematic reviews found 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⁾ and craniotomy ⁽⁹⁶⁾; 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 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⁾. A systematic review evaluating probiotics in oncological surgery found substantial risk of bias across majority of the studies analyzed, warranting the need for well-designed studies  ⁽⁹¹⁾.

Additional strategies used to modulate gut microbiota include “prebiotics” and “fecal microbiota transplantation” (FMT). Prebiotics or 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. Data on prebiotics for IBS are conflicting ⁽¹¹⁾. Because probiotics are short-lived, prebiotics are being co-administered to maintain their levels in the gut, and this combination is called “synbiotic therapy”. It was reported 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. FMT may benefit IBS patients although the quality of evidence is low ⁽³¹⁾. In oncology settings, FMT was found effective against 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⁾. A synbiotic mouthwash was effective in reducing and preventing oral mucositis intensity in oral cancer patients undergoing radiotherapy ⁽⁹⁷⁾. Synbiotic supplements also reduced chemo-induced diarrhea in children with acute lymphoblastic leukemia ⁽⁹⁸⁾.

In summary, available data suggest probiotics may improve certain health outcomes by inducing favorable changes in the intestinal bacteria. But 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⁾.