Why study probiotics for inflammatory bowel diseases?

Inflammatory bowel disease (IBD) is a collective term for chronic inflammatory diseases of the gastrointestinal (GI) tract, which include Crohn’s disease (CD) and ulcerative colitis (UC). These conditions are characterized by alternating phases of inflammation and mucosal tissue damage (active flare), and symptom-free periods of remission. Symptoms vary among patients, but can include debilitating abdominal pain, and irregular stool frequency and composition. Clinical disease management strategies are generally not curative, and focus on reducing GI inflammation during active flare and prolonging disease remission.

While the precise etiology of IBD has remained equivocal, previous decades of research indicated that it is related to a complex interplay between host genetics (such as NOD2 and ATG16L1 variants), environmental conditions (including diet), irregular pro- and anti-inflammatory T cell responses (including TNF-α and nitric oxide), compromised epithelial barrier function, and psychosocial factors (anxiety and depression). And there’s a new factor emerging in IBD pathogenesis: the gut microbiome.

A considerable amount of evidence links IBD with an altered gut microbiome composition. In a metagenomics analysis assessing the relative abundance of 155 microbial species, it was possible to separate those with IBD from healthy participants, and to distinctly identify UC and CD. Comparison of IBD patients with healthy volunteers resulted in, on average, 25% fewer microbial genes detected in fecal samples. CD patients showed a reduced α-diversity in fecal microbiome samples when compared to healthy adults, which was also evident in a study with monozygotic twins discordant for CD. Within the same patient with CD, a reduced bacterial biodiversity and lower bacterial load were found in inflamed versus non-inflamed tissues. Antibiotic use, which is known to transiently reduce intestinal microbial diversity, is associated with a higher incidence of CD diagnosis.

Generally, individuals with IBD appear to have altered pro- and anti-inflammatory bacterial species in their gut microbiomes, but there is not a clear consensus in the scientific literature regarding which bacterial species are altered. Tao Zuo and Siew Ng (2018) do an excellent job at summarizing the available (inconclusive) literature.

Although the weight of evidence unequivocally suggests the inflammation-linked gut microbiome plays a key role in the pathogenesis of IBD, it must be noted that it is not clear whether dysbiosis is the cause or consequence.

Due to the variable efficacy, high costs, and adverse drug reactions associated with clinical IBD treatments, there is a strong impetus to develop new treatment solutions. Despite the paucity of evidence from clinical trials, probiotics are widely used by IBD patients and are sometimes recommended by physicians as an adjunctive treatment. They are also marketed as dietary supplements and functional foods, although the quality of different products varies, with many probiotic products on the market not having been tested for bacteria viability through their shelf-life or even having their precise composition defined.

In 2013, an expert panel convened by the International Scientific Association for Probiotics and Prebiotics (ISAPP) agreed the existing Food and Agricultural Organization of the United Nations and the World Health Organization’s published definition of probiotics as “living microorganisms which when administered in adequate amounts confer health benefits on the host” was still relevant and sufficiently accommodating. The idea of ingested microbes conferring a health benefit is not new. Nobel laureate Elie Metchnikoff introduced probiotics to the scientific community in his 1907 report linking Bulgarian longevity with the consumption of fermented milk containing lactobacilli.

The aim of some studies in recent years has been to demonstrate the colonization of a probiotic species, and this has largely yielded ambiguous results. The better question may be whether the transient colonization or presence of probiotics moving through the GI tract is sufficient to exert beneficial health effects.

There are multiple mechanisms whereby probiotics might positively impact the gut microbiome, which have been extensively reviewed by Peera Hemarajata and James Versalovic (2013). For instance, probiotics may manipulate the gut microbiome and suppress pathogenic growth via production of β-defensin and IgA, fortify the intestinal barrier by maintaining tight junction integrity and inducing mucin production, modulate the immune system, and/or influence gut motility and nociception via the regulation of pain receptor expression and secretion of neurotransmitters.

Additionally, probiotics may also promote microbiota stability, reinforcing the colonizing microbiota’s ability to either resist perturbation by stressors or quickly recover from them. For example, a study showed less antibiotic-induced microbiota disruption in healthy, probiotic-supplemented adults than in those who did not take a probiotic. This protective effect would only occur while the probiotic was being consumed regularly, and is therefore a transient effect.

So what about probiotics specifically in people with IBD? Although probiotics have been shown to exhibit positive effects in reducing inflammation and maintaining gut intestinal barrier function in in vitro and in mouse models of IBD, their efficacy in human clinical trials has been limited.

Several systemic reviews and meta-analyses have assessed the published results of all available human clinical trials assessing probiotic use in IBD subpopulations. The studies pointed towards a lack of evidence supporting probiotic use with CD. On the other hand, probiotics may be promising for UC. Stefano Guandalini and Naire Sansotta (2019) suggested a multi-species probiotic showed potential as an adjunct medical therapy. Yannick Derwa (2017), suggested the same formulation induced remission of active UC and may be as effective as 5-aminosalicylates in preventing relapse. Similarly, Mahboube Ganji-Arjenaki and Mahmoud Rafieian-Kopaei (2017) found a positive trend combining Lactobacillus with a multi-species probiotic in children with IBD.

Many factors may have contributed to the current less-than-favourable outcome of probiotic efficacy in the clinical trials. First, IBD is a heterogeneous disease containing many subgroups of diseases with distinct characteristics. For example, a clinical trial of several well-known probiotic strains did not yield the expected clinical outcome, particularly in CD. Half of all CD patients have one or more mutations in the NOD2 gene, and the anti-inflammatory mechanism of action of the Lactobacillus strain in the study (L. salivarius Ls33) is NOD2-dependent. Host genetics, therefore, likely contributed to the failure rates. This highlights the importance of understanding the genetics, disease subgroups, and specific probiotic strains in each study. Furthermore, since probiotic strains and species can have different mechanisms of action, care must be taken when combining them to create multi-species formulations that work synergistically in IBD, as opposed to antagonistically.

Future translational research might include harnessing metagenomics techniques or developing novel in vivo and in vitro models to identify and characterize probiotic strains with enhanced efficacy with IBD, or even to create more effective strains. Exploring combined strains that have the potential to act synergistically, or combining with nutritional strategies, including prebiotics, may also be beneficial. Finally, more research is needed to understand the molecular mechanisms of commensal and pathogenic bacteria in those with IBD, as well as to characterize IBD subpopulations (and whether they may be stratified based on their gut microbiota), perhaps enabling the development of targeted tailor-made probiotics.

About Microbiome Insights

Microbiome Insights, Inc. is a global leader providing end-to-end microbiome sequencing and comprehensive bioinformatic analysis. The company is headquartered in Vancouver, Canada where samples from around the world are processed in its College of American Pathologist (CAP) accredited laboratory. Working with clients from pharma, biotech, nutrition, cosmetic and agriculture companies as well as with world leading academic and government research institutions, Microbiome Insights has supported over 925 microbiome studies from basic research to commercial R&D and clinical trials. The company's team of expert bioinformaticians and data scientists deliver industry leading insights including biomarker discovery, machine-learning based modelling and customized bioinformatics analysis.