Inflammatory bowel disease (IBD) is a chronic inflammatory condition that includes Crohn’s Disease (CD) and Ulcerative Colitis (UC) [1] . Initially, IBD was associated with highly developed countries; however, currently, new cases are seen worldwide, including in Asia and Africa [2] [3] . According to the CDC data, in 2015 in the US, about 3 million adults were reported to be diagnosed with IBD. At the same time, about 7 million people worldwide have IBD, with an estimated cost of treatment being almost $23,000, according to the Crohn’s and Colitis Foundation.

Genetics, immunological, and environmental factors combined with intestinal barrier disturbances are considered critical elements in the pathogenesis of IBD. Although the exact etiology of IBD remains unknown, research suggests that gut microbiome changes are considered one of the factors involved in disease progression: an altered immune response triggered by environmental factors targeting gut and gut microbiota in a genetically susceptible individual [4] [5] [6] [7] . At the same time, microbiome products and antigens affect the immune cells and the connection between the epithelial cells, leading to increased susceptibility to inflammation and gut permeability. However, it remains unclear if altered gut microbiome is a cause or a consequence of inflammation in IBD patients [8] [9] .

Even though It’s known that prebiotics act on specific bacterial populations and enhance their growth, probiotics are living microorganisms that benefit the host by modifying the intestinal microbiota. Different probiotic strains have been isolated from food culturing, including Lactobacillus species, Bifidobacterium species, non-pathogenic E. coli, Saccharomyces boulardii, C. butyricum, Streptococcus salivarius, and Lactococcus lactis [10] . If taken in addition to the primary therapy, probiotics can change the efficacy of specific drug therapies commonly used in treating patients with IBD, such as anti-tumor necrosis factor-α or steroids.

According to the Crohn’s and Colitis Foundation, while the annual cost of healthcare is approximately 4 times higher for patients with IBD than for non-IBD patients, it keeps rising, with the most significant components being therapeutics (biologics, opioids, and steroids), comorbidities (anemia and psychiatric illness) and emergency room visits. The addition of probiotics to the standard regimen of IBD would allow for decreasing rates of IBD flare-ups, which in turn would lead to significantly reducing the cause associated with the addition of therapies to achieve remission in IBD.

The types and combinations of probiotic strains and whether probiotics should be supplemental or standalone therapy in patients with IBD remain controversial. The primary aim of our research study was to present a systematic review of available randomized controlled trials (RCTs) evaluating the types of strains, treatment courses, and outcomes in patients with IBD treated with probiotics.

Our review also aims to assess the efficacy and safety of probiotics in patients with IBD. This study was done to assess whether probiotics can be a low-cost addition to standard IBD therapy, with the goal of preventing frequent disease flare-ups and reducing the cost of care.

We performed a PubMed search on randomized controlled trial studies from 1997 to 2022, using the following keywords: Probiotics in Inflammatory Bowel Disease. The following criteria were used to perform the comparative analysis of the studies.

Inclusion criteria: All studies included adult patients with IBD 18 years old and above with preserved colon, oral administration of probiotics, RCTs that compared probiotics with placebo or any other non-probiotic intervention, and patients with and without maintenance therapy for IBD.

Exclusion criteria: Patients with prebiotic or symbiotic therapies; patients with subtotal/total colon or ileus removal; the study did not evaluate for objective clinical signs of disease activity or relapse rate; the study did not provide information about the bacterial strains included in probiotic, and the probiotic composition is not easily searchable online, probiotics as part of dairy produce-yogurt or kefir; probiotics not administered orally; the full text of the trial is not available online.

After discussion, both authors reviewed the studies independently and determined they were eligible if the criteria were met. The study inclusion and exclusion criteria and primary outcomes are outlined in the chart below, Figure 1 .

Out of 110 RCTs available in PubMed currently after applying keywords, 89 were removed from further analysis after the inclusion-exclusion criteria were used and duplicates were removed. Here, we reviewed data from the following probiotics ( Table 1 ) and summarized the results of 21 selected RCTs, including 1948 patients in Table 2 .

We examined the type and composition of bacterial strains included in probiotics, the treatment course, and the number of patients involved in the trial. We also evaluated outcomes such as disease activity index in treatment versus control groups, recurrence rates in treatment versus control groups, and adverse reactions.

Our analysis shows that out of 21 total RCTs—a total of 16 RCTs (76.2%) proved that probiotics are an effective therapy in patients with IBD to induce

Legend: NA-not available.

Continued

Legend: CD-Crohn’s Disease; CDAI-Crohn’s Disease Activity Index; IBD-inflammatory bowel disease, NA-Not Applicable since data were not provided, UC-Ulcerative Colitis; UCAI-Ulcerative Colitis Activity Index.

remission rates. In the analysis, 13 out of 16 RCTs (61.9%) showed decreased disease activity scores or recurrence rates in probiotic versus placebo groups. In these studies, the probiotics used were: Bifico: Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis (4 studies); VSL#3: four strains of Lactobacillus, three strains of Bifidobacterium, and one strain of Streptococcus salivarius subsp. Thermophilus (3 studies); a combination of Lactobacillus and Bifidobacterium species (2 studies); Saccharomyces boulardii (1 study); Bio-Three: Streptococcus faecalis T-110, Clostridium butyricum TO-A, and Bacillus mesentericus TO-A (1 study); Lactobacillus GG (1 study); BB536: Bifidobacterium longum 536 (1 study).

Out of 16 studies with the beneficial effect of probiotics in the treatment group, in 10 studies, 62.5% of patients continued their standard treatment regimen for IBD as long as medication doses were stable and probiotics were given as supplemental therapy. At the same time, no significant adverse reactions to probiotics were noticed.

2 studies out of 16 RCTs (9.5%) showed that the E. coli Nissle 1917 probiotic is equivalent in maintaining remission to the gold standard of treatment with mesalazine in patients with ulcerative colitis, and 1 study out of 16 RCTs (4.8%) showed that the balsalazide/VSL#3 combination was faster in obtaining remission than balsalazide alone or mesalazine.

5 studies out of 21 RCTs included in our analysis (23.8%) showed no significant clinical benefit from probiotic therapy.

Over 1 million residents in the USA and 2.5 million in Europe are estimated to have IBD, with substantial costs for health care, not counting the cost of altered quality of life [32] . Recent advances in next-generation sequencing technology have identified alteration of the composition and function of the gut microbiota in patients with IBD, called dysbiosis. Clinical and experimental data suggest that dysbiosis may play a pivotal role in the pathogenesis of IBD [33] , prompting the initiation of probiotics in patients with IBD.

In our analysis, we searched and analyzed available RCTs published in PubMed to assess the efficacy and safety of probiotics for the induction and maintenance of relapse rates in patients with IBD and to decrease them. According to our analysis, the vast majority of RCTs concluded that probiotics are an effective therapy to decrease remission rates in patients with IBD.

The mechanism of how probiotics can be effective in patients with IBD comes from animal studies. For example, experiments involving genetically engineered animals raised in germ-free environments showed an absence of intestinal inflammation. Interestingly, in a laboratory interleukin (IL)-10 deficient mice, IBD-like intestinal inflammation does not occur without an intestinal bacterial flora. However, an inflammatory response occurs after exposure to the standard microbial environment [34] [35] . In humans, the areas most affected by IBD are gut regions characterized by the highest bacterial populations, such as the terminal ileum and colon. At the same time, antibiotics are helpful in decreasing the severity of active inflammation in patients with IBD [36] [37] .

Recent studies have revealed that patients with IBD have decreased concentrations of bifidobacterium and lactobacillus and a significant increase in pathogenic and potentially harmful enterobacteria. The mechanisms through which probiotics benefit IBD patients can be explained in the following ways [36] :

1) Firstly, probiotics inhibit the attachment and invasion of enterotoxigenic and enteropathogenic bacteria to the gut epithelium by competing with microbial pathogens for the limited number of receptors on the surface of epithelia [38] .

2) Secondly, probiotics enhance epithelial tight junctions and barrier function by activating the antiapoptotic and inhibiting the activation of the pro-apoptotic pathways, which improves intestinal epithelial cells’ survival in environments rich in pro-apoptotic cytokines [39] .

3) Thirdly, probiotics modulate the immune response in intestinal epithelial and mucosal immune cells by downregulating the expression or secretion of various proinflammatory cytokines, such as TNFα, IL1β, interferon-gamma, nitric oxide synthase, and matrix metalloproteinase [40] [41] [42] [43] [44] .

4) Lastly, probiotics stimulate the secretion of antimicrobial substances by upregulating defensins, which are impaired in Crohn’s disease [36] .

While our analysis showed that probiotics could be an effective supplemental therapy to maintain remission in patients with IBD, we looked deeper into which bacterial strains showed the best outcomes in decreasing order:

VSL#3: Four strains of Lactobacillus, three strains of Bifidobacterium, and one strain of Streptococcus salivarius given as supplemental therapy in 4 studies showed a higher decrease in UCDAI scores in the VSL#3 group than in the placebo group.

Bifico: Bifidobacterium, Lactobacillus acidophilus, and Enterococcus faecalis in 3 studies showed decreased CDAI/UCAI scores and recurrence rates in the treatment group. While CDAI/UCAI scoring systems are built based on such criteria as stomachache, diarrhea, gross blood in stool, fecal incontinence, abdominal hyperalgesia, abdominal mass, and the number of complications, patients in the treatment group reported improvement in their symptoms after initiation of the probiotics.

Bio-Three probiotics containing Streptococcus faecalis T-110, Clostridium butyricum TO-A, and Bacillus mesentericus TO-A showed significantly lower relapse and remission rates in the treatment group in 1 RCT.

Lactobacillus and Bifidobacterium species combo in 2 studies showed significant remission induction in the treatment group, and in 1 study—no significant clinical benefit [28] .

In 3 trials, the E. coli Nissle 1917 probiotic was safe and effective in maintaining remission equivalent to the gold standard mesalazine in patients with ulcerative colitis. However, in 1 trial, there was no benefit in using E. coli Nissle as an add-on treatment to conventional therapies for active ulcerative colitis.

Saccharomyces boulardii alone did not show any beneficial effect in one study, but in another, it significantly lowered the percentage of patients with clinical relapses in the treatment group.

Lactobacillus alone in 2 trials didn’t show significant differences between treatment groups; however, in one trial, probiotics were considered effective and safe for remission.

BB536: Bifidobacterium longum 536 alone in 1 trial showed that probiotic supplementation was well tolerated and reduced UCDAI scores.

In other words, probiotics administered with Lactobacillus, Bifidobacterium, Streptococcus, or Enterococcus species show the best outcomes in decreasing disease activity and reducing remission rates, which correlates with most available literature data.

Our analysis had such limitations as not all trials had appropriate randomization of patients based on disease activity scores, laboratory and endoscopy findings before initiation of trial; sex and race of patients involved in RCTs varied broadly across studies, while some trials included patients on the continued regimen for IBD with probiotic being a supplemental therapy, other trials evaluated patients being only on monotherapy with probiotics or placebo number of patients; no gold equivocal stratified system accessing outcomes in patients with IBD and UC, with some studies using the short or full version of Ulcerative Colitis/Crohn’s Disease Activity Index (UCAI/CDAI) or Mayo systems, not using them at all or using another scoring system; objective evaluation of laboratory data and gut mucosa with endoscopy after trial completion was not performed in all trials as well; our analysis only included RCTs from PubMed.

It is essential to notice that in RCTs where probiotics showed a positive effect on decreasing relapse rates, they were given as supplemental therapy to conventional standard therapy for IBD treatment. That confirms that probiotics are not a stand-alone treatment for IBD, but they have proven potential to prolong remission and decrease relapse rates in patients with IBD.

The average admission cost for IBD patients varies significantly depending on factors such as the severity of the condition, the type of treatment required, and the duration of hospitalization. In the United States, for example, the average cost of hospital admission for IBD can range from several thousand to tens of thousands of dollars, depending on whether the patient requires surgery, specialized treatments, or prolonged hospital stays.

The opportunity to decrease relapse rate by adding probiotics would allow for avoiding hospitalization in patients with IBD, thus saving significant amounts of dollars for the patient and the healthcare system in general.

While probiotic therapy is safe and effective in managing patients with IBD, the absence of significant adverse reactions makes it a desirable supplement to decrease disease activity, prolong remission, and improve outcomes. However, we are advocating for the need to perform and analyze more standardized randomized controlled studies assessing the role of probiotics in patients with IBD.