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Gut Microbiome //

The collection of microbes and their genes that exist within and on the human body is collectively known as the microbiome. The human microbiome in different organs has emerged as a principal factor in human health and disease. Advancements in lab technologies have allowed for the characterization of microbiomes throughout the human body including the gut, in a myriad of human diseases and in health. The microbiome within the bowel known as the gut microbiome has especially emerged as being important not only in intestinal diseases but also in other immune-mediated inflammatory diseases (like rheumatoid arthritis or multiple sclerosis) and also in health. Researchers have shown that perturbations in the gut microbiome may impact on obesity and blood sugar control. In the past decade there has been an explosion of research undertaken to understand how alterations in the gut microbiome may lead to intestinal diseases, especially inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Our group has been at the forefront of this research. We partnered with a leading group at Stanford University in 2004 and published the first report of the human gut microbiome using sophisticated molecular biology techniques using colon biopsies and stool samples from 3 Manitobans who were healthy and volunteered to participate in our research study. We, identified hundreds of bacterial species in the human gut that had never previously been reported (Eckburg et al, Science 2005). Together with the Denis Krause lab in the Faculty of Agriculture at the University of Manitoba, we reported that a unique type of bacteria known as an adherent invasive E coli was more common in persons with Crohn’s disease including early in diagnosis. This finding was exciting because a handful of other research groups in Europe and North America had found similar bacteria in persons with Crohn’s disease. Then, with Gary van Domselaar’s lab at the National Microbiology Laboratory we reported on differences in the gut microbiome in the bowel lining from persons with Crohn’s disease, persons with ulcerative colitis and in healthy controls. We found that the most important differences were in the non-inflamed tissues from Crohn’s disease compared with the non-inflamed tissues from ulcerative colitis. One message from this study is that analyzing the inflamed tissue from disease states may not give as much information as analyzing the uninflamed tissue, tissue that is at risk of one day becoming inflamed.

 

There are reports in the scientific literature, as well as in the lay press, that changes in the gut microbiome in inflammatory bowel disease are well known and ready to be tapped for treatment. Some changes in the gut microbiome in IBD have been repeatedly reported, such as reduction in microbial diversity. This means that persons with IBD have less varied types of bacteria than healthy persons. However the reports that any one type of bacteria is reduced while other types are increased are variable. Hence, there has yet to be a probiotic developed that includes the specific bacteria thought to be diminished in IBD. It does make sense, though that once it is worked out what the consistently found changes are in the gut microbiome in specific types of IBD (and IBS as well) that drug development may turn to probiotic sidle medications; that is bacteria that can be protective and possibly anti-inflammatory).

Specific publications

  

Eckburg P, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson K, Relman DA. Diversity of the human intestinal microbial flora. Science 2005; 308:1635-1638.

 

Together with researchers at Stanford University in California, we were the first to report on the normal human gut microbiome. The human gut microbiome refers to the bacteria or ‘gut bugs’ that normally reside within the bowel. All humans have millions of bugs of different varieties in their bowels that help keep the bowels working properly.

Kotlowski R, Bernstein CN, Sepehri S, Krause DO. High prevalence of Escherichia coli belonging to the B2+D phylogenetic group in inflammatory bowel disease. Gut 2007; 56: 669-75.

Sepehri S, Kotlowski R, Bernstein CN, Krause DO. Microbial diversity of inflamed and non-inflamed gut biopsy tissues in inflammatory bowel disease.  Inflammatory Bowel Diseases 2007:13: 675-683.

Sepehri S, Kotlowski R, Bernstein CN, Krause DO. Phylogenetic analysis of inflammatory bowel disease associated Escherichia coli and the fimH virulence determinant. Inflammatory Bowel Diseases 2009; 15:1737-45.

Krause DO, Dowd SE, Little AC, Bernstein CN. Complete genome sequence of adherent invasive Escherichia coli UM146 isolated from ileal Crohn’s disease biopsy tissue. Journal of Bacteriology 2010; 193(2):583.

Sepehri S, Khafipour E, Bernstein CN, Coombes BK, Pilar AV, Karmali M,  Ziebell K, Krause DO. Characterization of Escherichia coli isolated from gut biopsies of newly diagnosed patients with inflammatory bowel disease. Inflammatory Bowel Diseases 2011: 17: 1451-63.

Together with researchers in the Faculty of Agriculture, University of Manitoba, we explored whether there were any gut bugs unique to IBD. We found a special type of Escherichia coli (E coli) that was especially common in Crohn’s disease. The E coli had properties of an adherent invasive E coli; this technical description refers to how the E coli interacts within its environment in the gut. What was exciting about this finding is that other labs in other countries were also discovering a similar E coli associated with Crohn’s disease, which confirmed we were on to something important. In a related study we analyzed tissue from a tissue bank of newly diagnosed patients established by the Crohn’s and Colitis Foundation of Canada, and we found an increased presence of this E coli in those tissues, suggesting that this bug is present early on in the disease process. Hence, it remains a possibility that this bug is a trigger for Crohn’s disease.

Forbes J, Van Domselaar G, Sargent M, Green C, Springthorpe S, Krause D, Bernstein CN. Microbiome profiling of drinking water in relation to incidence of inflammatory bowel disease. Canadian Journal of Microbiology 2016; 18:1-13.

 

For one year we collected water from firehalls and community centres from over 20 communities in Winnipeg and in rural Manitoba. We aimed for areas that were known to have either high or low incidence of IBD. We wanted to determine if there were bacteria in the water that were unique to high or low incidence areas or missing from high or low incidence areas so as to potentially target those bacteria for treatment of IBD. This work lays out a basis for further studies exploring water as a potential environmental source for IBD triggers. This work lays out a basis for further studies exploring water as a potential environmental source for IBD triggers.

Forbes J, Van Domselaar G, Bernstein CN. Microbiome survey of the inflamed and non-inflamed gut at different compartments within the gastrointestinal tract of inflammatory bowel disease patients. Inflammatory Bowel Diseases 2016; 22:817-25.

 

We compared the bacterial communities of inflamed and noninflamed bowel lining of patients with IBD and by analysis of the microbiota composition at distinct areas of the ileum and colon. There was no variation in any bacteria comparing inflamed to non-inflamed areas of the bowel within Crohn’s disease or within ulcerative colitis. The main differences were in comparing the non-inflamed mucosa between Crohn’s disease and ulcerative colitis: Groups (phyla) of organisms known as Bacteroidetesand Fusobacteria were detected more frequently in inflamed Crohn’s disease areas than in inflamed ulcerative colitis mucosa. Conversely, Proteobacteria and Firmicutes were more frequently observed in the inflamed ulcerative colitis mucosa. At the genus level (a smaller group of bacteria than phyla) the abundance of 13 groups were significantly different within the non-inflamed mucosa between Crohn’s disease and ulcerative colitis.

Forbes J, Van Domselaar G, Bernstein CN. The gut microbiota in immune-mediated inflammatory diseases. Frontiers in Microbiology 2016; 7:1081.

Bernstein CN, Forbes J. Gut microbiome in inflammatory bowel disease and other chronic immune-mediated inflammatory diseases. Intestinal Inflammatory Diseases 2017; 2: 116-123.

We undertook a review of the current scientific research on the gut microbiome not just in IBD but also in other chronic inflammatory diseases (such as rheumatoid arthritis and multiple sclerosis). Our report in frontiers in Microbiology was one of the highest cited papers in that journal for 2016. In our report in Inflammatory Intestinal Diseases we reviewed what could be learned in regards to IBD by studying the gut microbiome of non gut chronic inflammatory diseases (such as rheumatoid arthritis, multiple sclerosis, psoriasis and ankylosing spondylitis. We also reported on some of our own research comparing the gut microbiome from persons wit IBD, rheumatoid arthritis and multiple sclerosis and healthy controls.

Forbes JD, Bernstein CN, Tremlett H, Van Domselaar G, Knox NC. A fungal world: could the gut mycobiome be involved in neurological disease. Frontiers in Microbiology 2019; pages 1-13: doi:10.3389/fmicb.2018.03249.

The human microbiome has received decades of attention from scientific and medical research communities. The human gastrointestinal tract is host to immense populations of microorganisms including bacteria, viruses, archaea, and fungi (the gut microbiota). High-throughput sequencing and computational advancements provide unprecedented ability to investigate the structure and function of microbial communities associated with the human body in health and disease. Most research to date has largely focused on elucidating the bacterial component of the human gut microbiota. Study of the gut "mycobiota," which refers to the diverse array of fungal species, is a relatively new and rapidly progressing field. Though omnipresent, the number and abundance of fungi occupying the human gut is orders of magnitude smaller than that of bacteria. Recent insights however, have suggested that the gut mycobiota may be intricately linked to health and disease. Evaluation of the gut mycobiota has shown that not only are the fungal communities altered in disease, but they also play a role in maintaining intestinal homeostasis and influencing systemic immunity. In addition, it is now widely accepted that host-fungi and bacteria-fungi associations are critical to host health. While research of the gut mycobiota in health and disease is on the rise, little research has been performed in the context of neuroimmune and neurodegenerative conditions. Gut microbiota dysbiosis (specifically bacteria and archaea) have been reported in neurological diseases such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's, among others. Given the widely accepted bacteria-fungi associations and paucity of mycobiota-specific studies in neurological disease, this review discusses the potential role fungi may play in multiple sclerosis and other neurological diseases. Herein, we provide an overview of recent advances in gut mycobiome research and discuss the plausible role of both intestinal and non-intestinal fungi in the context of neuroimmune and neurodegenerative conditions.

Forbes JD, Chen CY, Knox NC, Marrie RA, EL Gabalawy H, de Kevit T, Alfa M, Bernstein CN. Van Domselaar G. A comparative study of the gut microbiota in immune-mediated inflammatory diseases - does a common dysbiosis exist? Microbiome 2018 Dec 13: 6 (1): 221: 1-15.

 

Immune-mediated inflammatory disease represents a substantial health concern. It is widely recognized that immune-mediated inflammatory disease patients are at a higher risk for developing secondary inflammation-related conditions. While an ambiguous etiology is common to all immune-mediated inflammatory diseases, in recent years, considerable knowledge has emerged regarding the plausible role of the gut microbiome in immune-mediated inflammatory diseases. This study used 16S rRNA gene amplicon sequencing to compare the gut microbiota of patients with Crohn's disease (N = 20), ulcerative colitis (N = 19), multiple sclerosis (N = 19), and rheumatoid arthritis (N = 21) versus healthy controls (N = 23). Biological replicates were collected from participants within a 2-month interval. This study aimed to identify common (or unique) taxonomic biomarkers of immune-mediated inflammatory disease s using both differential abundance testing and a machine learning approach. Significant microbial community differences between cohorts were observed. Richness and diversity were significantly different between cohorts and were lowest in Crohn’s disease while highest in healthy controls. Abundances of Actinomyces, Eggerthella, Clostridium III, Faecalicoccus, and Streptococcus were significantly higher in all disease cohorts relative to healthy controls, whereas significantly lower abundances were observed for Gemmiger, Lachnospira, and Sporobacter. Several taxa were found to be differentially abundant in immune-mediated inflammatory diseases versus healthy controls including significantly higher abundances of Intestinibacter in Crohn’s disease, Bifidobacterium in UC, and unclassified Erysipelotrichaceae in multiple sclerosis and significantly lower abundances of Coprococcus in Crohn’s disease, Dialister in multiple sclerosis, and Roseburia in rheumatoid arthritis. A machine learning approach to classify disease versus healthy controls was highest for Crohn’s disease followed by multiple sclerosis, rheumatoid arthritis and UC. Gemmiger and Faecalicoccus were identified as important features for classification of subjects to Crohn’s disease and health controls. In general, features identified by differential abundance testing were consistent with machine learning feature importance. This study identified several gut microbial taxa with differential abundance patterns common to immune-mediated inflammatory diseases. We also found differentially abundant taxa between immune-mediated inflammatory diseases. These taxa may serve as biomarkers for the detection and diagnosis of immune-mediated inflammatory diseases and suggest there may be a common component to immune-mediated inflammatory diseases etiology.

 

Knox N, Forbes JD, Van Domselaar, Bernstein CN. The gut microbiome as a target for IBD treatment: are we there yet? Current Treatment Options in Gastroenterology 2019; 17(1):115-126.

This review aims to highlight recent research on the gut microbiome in IBD and the application of microbiome-modulating therapies for the treatment of IBD including the use of the microbiome as an indicator for disease severity and treatment response. Despite the high number of gut microbiome studies and emerging evidence supporting the gut microbiome's involvement in disease pathogenesis, no single microorganism has been identified as a pathogenic agent in IBD. Retrospective studies and meta-analyses on antibiotic use in ulcerative colitis and Crohn's disease and long-term outcomes are conflicting. Similarly, the use of probiotics for the treatment of IBD remains inconclusive; however, some encouraging results are emerging as microbial concoctions are optimized to include beneficial bacterial strains. Fecal microbial transplantation is currently emerging as one of the more promising microbiome-modulating IBD therapies. Fecal microbial transplantation studies in ulcerative colitis have shown improved remission rates compared to placebo; however, relatively small study sample sizes and varied treatment methods, limit definitive conclusions. With clear evidence of an IBD gut dysbiosis, novel therapies to treat and prevent disease relapse will undoubtedly require a microbiome-modulating approach. The complexity and variability of IBD disease pathogenesis (disease phenotype, gut microbiome, host genetic susceptibility, and environmental factors) will likely require a personalized and multidimensional treatment approach where microbiome-modulating therapy is coupled with other therapies to target other IBD disease components

 

Knox N, Forbes JD, Van Domselaar, Bernstein CN.  The gut microbiome in other chronic immune disease: lessons for IBD. American Journal of Gastroenterology 2019; in press.

 

There is a growing appreciation for the role of the gut microbiome in human health and disease. Aided by advances in sequencing technologies and analytical methods, recent research has shown the healthy gut microbiome to possess considerable diversity and functional capacity. Dysbiosis of the gut microbiota is believed to be involved in the pathogenesis of not only diseases that primarily affect the gastrointestinal tract, but of other less obvious diseases, including neurologic, rheumatologic, metabolic, hepatic, and other illnesses. Chronic immune-mediated inflammatory diseases represent a group of diseases that share many underlying etiological factors including genetics, aberrant immunological responses, and environmental factors. Gut dysbiosis has been reported to be common to immune-mediated inflammatory diseases as a whole, and much effort is currently being directed towards elucidating microbiome-mediated disease mechanisms and their implications for causality. In this review, we discuss gut microbiome studies in several immune-mediated inflammatory diseases and show how these studies can inform our understanding of the role of the gut microbiome in inflammatory bowel disease.

 

 

See Epidemiology Studies tab for other studies related to gut microbiome and risk for IBD