First and second generation probiotic therapeutics for Inflammatory Bowel Disease

Abstract

The interaction between the intestinal biota and humans have co-evolved, directing both to a state of complementary tolerance. However, dysbiosis in intestinal microbiota leads to Inflammatory Bowel Disease which results from an aggressive immune response towards specific components of the commensal, enteric bacteria in a genetically susceptible host. One of the popular strategies for prophylaxis and treatment of Inflammatory Bowel Disease has been the use of immune-regulatory probiotic formulations. The purpose of this review was to assess the status quo of these probiotic formulations. Clinical trials performed through a span of 2002–2019 with probiotics, synbiotic and second generation probiotic formulations were analysed. The review tries to understand whether the probiotic formulations have proven to be clinically effective IBD therapeutics.

Introduction

Inflammatory Bowel Disease (IBD) is a severe, uncontrolled inflammation of the gut which comprises of two persistent disorders, Ulcerative Colitis (UC) and Crohn's Disease (CD) [1,2]. UC, particular to the mucosa, tends to cause ulcers in the innermost lining of the colon and rectum, conversely, CD is confined to the entire bowel wall, causing severe inflammation in any part of the gastrointestinal system. The number of people affected by IBD is still expanding. The global burden of IBD has continued to increase in the recent years and reached more than 5 million cases worldwide. [3].

IBD is manifested by an increase in pro-inflammatory markers, oxidative stress, imbalance in the gut microflora, reduced oxidation of SCFAs, disrupted intestinal barrier, increased sulfide production and decreased methylation [4]. Colonic microflora plays a potential role in the pathophysiology of IBD. Several researchers have reported that IBD results in dysbiosis of the gut microflora, due to which there is an increase in the concentration of intramucosal bacteria, specifically from the aerobic, entero-adhesive species [5,6].

The first line of therapy for IBD involves oral and rectal formulations of 5-aminosalicylates (mesalazine) and the oral pro-drugs, sulfasalazine, olsalazine, and balsalazide. Patients non-responsive to the first line drugs are treated with oral corticosteroids, anti-TNF-α antibodies, and other immunosuppressive drugs. However, surgery becomes compulsory for patients with life-threatening conditions like perforation, fibrotic strictures, fistulas or rectal bleeding that is untreatable by the standard treatments [7,8].

Conventional therapies are linked to several disadvantages, such as side effects from the standard drugs, lower efficacy rate and requirement of resection surgery in patients already under medication. The currently available therapies and the degree of success obtained so far, indicates that there is scope for the development of alternate strategies for the treatment of IBD.

Intestinal microbiota plays a major role in the pathogenesis of UC and CD [9,10]. The key factor for IBD is a dysregulated immune response to specific components of the intestinal microbiota in a genetically susceptible host [11]. This aggravated immune response is an outcome of the interaction of several elements like host genetics, commensal microbiota, environmental factors, immune response that otherwise maintain mucosal homeostasis, besides its dysregulation leading to a series of hostile inflammatory responses [12].

Several studies have been reported on the genetic influence of the intestinal bacterial composition. CD is marked by the mutation of nucleotide-binding oligomerization domain 2 (NOD2), also known as CARD15 and IBD1 [13,14]. NOD2 gene is strongly associated with antimicrobial activity in the gut [15]. Other susceptibility genes include IBD5, IL23R, and ATG16L1 [16]. Issacs et al. reported that defects in IFN-γ producing T cells in CD patients, IL-4 producing T cells and IL-13 producing NKT cells in UC patients lead to chronic mucosal inflammation [17]. Defect in the anti-inflammatory marker, IL-10 is also one of the established reasons for the aggravated immune response in patients with IBD [18,19].

A complex crosstalk between the gut microbiota and intestinal cells have been established [20,21]. The human gut is abundant in Firmicutes and Bacteriodetes [[22], [23], [24]]. In recent years, a hypothesis has been circulating that relates compositional changes in the gut microbiota (dysbiosis) to the weakening of the immune system in IBD. Although a specific pathogen cannot be stated as an etiopathogenic factor, but it is a well-accepted fact that there is active involvement of gut microbiota in the pathogenesis of IBD. Dysbiosis results in the overall decrease of bacterial diversity with an increase in the antagonistic group of bacteria like Proteobacteria, Fusobacterium and Ruminococcus gnavus along with a reduction in the group of beneficial bacteria like Lachnospiraceae, Bifidobacterium, Roseburia, and Sutterella [12]. In addition to the disruption of the epithelial barrier, alteration in the mucus thickness and viscosity results in severe inflammation and tissue damage, making it susceptible to pathogen invasion. Several metagenomics, proteomics and metabolomic profiling have established the role of gut microbiota in the pathogenesis of this disease [25,26]. Certain bacterial species that mediate homeostasis in healthy individuals, show marked alteration in IBD patients. Faecalibacterium prausnitzii, a Clostridium species subset, which protects against IBD has been reported to be in significantly low numbers in IBD patients. Authors also reported the role of Faecalibacterium prausnitzii in the suppression of NF-κB activation and an increase in IL-10 production [27,28]. A polysaccharide from a commensal bacterium, Bacteroides fragilis, induced regulatory T cells to reduce the severity of colitis via TLR2 signalling in the presence of an ATG16L1- and NOD2-mediated autophagy [29].

The disruption of the balance between the gut microbiota and immune response has been characterized in animal model studies. Kitajima and co-workers [30] depicted that conventional mice treated with Dextran Sodium Sulphate (DSS) developed less severe inflammation compared to germ-free ones suggesting the role of the gut microbiota in regulation of immune responses. Interestingly, studies on human tissues from IBD patients by Sokol et al. indicated that the presence of Bifidobacteria, Lactobacillus and Faecalibacteria resulted in up-regulation of anti-inflammatory cytokine, IL-10 and down-regulation of the pro-inflammatory cytokines [27].

Past evidences suggest that while normal microflora has protective action, a disbalanced microbial composition leads to modification of immune response which predisposes the subject to clinical IBD [[31], [32], [33]]. Among the normal microflora having gut-protective effects are probiotics. Probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” by the Food and Agriculture Organization of the United Nations (FAO). Probiotics, Lactobacillus and Bifidobacteria have demonstrated beneficial effects in IBD patients [34]. In fact, probiotics are being considered as one of the strategies for improving the quality of life in IBD patients [35]. Several authors have reported the role of probiotics in the production of short chain fatty acid (SCFA) and lactate [36,37], maintaining the epithelial barrier integrity and conferring immunomodulation in hosts [38,39]. TLR9 activation by Lactobacillus rhamnosus GG aids in the suppression of NF-κB activation, thereby preventing the production of pro-inflammatory cytokines [40]. A mixture of probiotics including Lactobacillus acidophilus X37, Lactobacillus paracasei Z11, Lactobacillus casei CRL431, Lactobacillus rhamnosus GG, Bifidobacterium longum Q46, Bifidobacterium bifidum Z9, Bifidobacterium breve 20091, and Bifidobacterium bifidum 20082a resulted in reduction of IL-12 and TNF-α concentrations in culture supernatants [41]. Lorea Baroja reported that the consumption of Lactobacillus supplemented yogurt induced anti-inflammatory response in humans [42].

Prebiotics are selectively fermented short-chain carbohydrates that stimulate the growth and activity of beneficial microbes colonizing in the gut. Prebiotics are studied to have a major impact on immune regulation. Several authors have reported its role in limiting the activity of pro-inflammatory cytokines, production of SCFAs that inhibit mucosal inflammation and aids in increasing several advantageous bacteria with immunoregulatory properties by acting as substrates for them [37]. SCFAs are considered as an essential energy source for colonic epithelial cells. SCFA deficiency is known to play a major role in the pathogenesis of IBD. Production or modification of short-chain fatty acids (SCFAs) by the gut microbiota steadily influences the intestinal integrity and immune response [43].

Considering the suggested benefits of probiotics, the next section of the review focuses on the role of probiotics and synbiotics, on induction or maintenance of remission via different clinical trials on UC and CD patients.