How IBD disrupts the microbiome: Research reveals IBD can trigger adverse immune responses

03 Jun 2019 --- The second research phase of the Human Microbiome Project (HMP), under the US National Institutes of Health (NIH) Common Fund, explores the complex set of chemical and molecular events that disrupt the microbiome and trigger immune responses during flare-ups of inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis. Findings from the study, to be published May 29, 2019 in Nature, reveal that different forms of IBD can have effects on the activity and composition of the microbiome, which in turn may cause adverse immune responses.

The researchers say the findings provide promising new targets for potential IBD treatments, including polyunsaturated fatty acids, bile acid derivatives and human immune response pathways, as well as new data, tools and protocols that will enable future research on IBD and the microbiome.

“The Human Microbiome Project overall has been a flagship effort in understanding the microbiome's contributions to health, and in creating a community of researchers who can study the microbiome to discover new diagnostics and therapies for disease,” says Curtis Huttenhower, Professor of Computational Biology and Bioinformatics at Harvard Chan School and Associate Member at the Broad Institute and senior author of the study. "Our results from this study pave the way for early detection of upcoming flares in disease activity – which can then be aggressively treated – or potentially for new biochemical therapeutic opportunities to encourage complete remission of IBD."

While previous studies have cataloged microbial changes during IBD, the researchers in this study developed a “unique biotechnology toolbox” to better understand why microbiota change during IBD and how this provokes an unhealthy inflammatory reaction. These tools allowed them to measure microbial chemical changes and human gene regulatory shifts, paving the way for new therapies.

In recent times, advancements in the space of microbiome research have lead to the emergence of a new category of therapies for immune-mediated diseases, which use live human microbiome-derived bacteria. A notable player in this field is Vedanta Biosciences, a microbiome start-up specializing in the identification and cultivation of human commensal bacteria that induce a range of immune responses, including regulatory T cells, CD8+ T cells and Th17 cells, among others. When compared to reductionist approaches, such as single strain probiotics, the company says this form of treatment can “shift the gut ecosystem.”

Microbiota play a critical role in numerous diseases
The gut microbiome is a symbiotic community of trillions of microbes, including bacteria, viruses and fungi. Each person has a distinct microbiome, and research indicates that the microbiome plays an important role in numerous diseases, including IBD, which affects more than 3.5 million people worldwide and is growing in prevalence, the researchers note. IBD is a chronic disease that is marked by periods of remission followed by flare-ups in which the disease becomes active.

For this study, distinguished as the “most comprehensive analysis to date of human microbiome interactions during IBD,” researchers from Harvard T.H. Chan School of Public Health and the Broad Institute of MIT followed 132 participants for one year and compared Crohn's disease and ulcerative colitis patients to a control group of participants that did not have IBD. 

Participants provided stool samples every two weeks, blood samples approximately once a quarter and a set of colon biopsies at the start of the study for analysis. In total, 2,965 stool, biopsy and blood samples were analyzed with an unprecedented suite of molecular, cellular and clinical tools to understand the detailed biochemistry of the disease.

These detailed measurements made it easy to observe and confirm findings from previous studies, such as a reduction in overall gut ecological diversity and the gain and loss of specific "pro-" and "anti-inflammatory" microbes during disease, the researchers elaborate.

Significantly, the suite of tools deployed for this study allowed researchers to determine the reasons for the changes. The results show that during periods of disease activity, people with IBD had fewer microbially-derived chemicals, which they speculate could be due to a combination of factors, including less beneficial microbial metabolism, poorer nutrient absorption, greater water or blood levels in the bowels, and more urgent bowel movements. These factors decreased the overall stability of the gut microbial ecosystem, leading to more episodes of improper immune responses and overreaction to the normal gut microbiome among IBD patients.

Specifically, during periods of disease activity, people with IBD had higher levels of polyunsaturated fatty acids, including adrenate and arachidonate. The researchers also discovered that nicotinuric acid was found almost exclusively in the stool of patients with IBD and that levels of vitamins B5 and B3 were particularly depleted in the gut of people with IBD.

The team also found that bile acids – a set of compounds made by humans but chemically modified by gut microbes – were disrupted during IBD, in tandem with molecular regulation in groups of microbes. These included a group of bacteria related to the genus Subdoligranulum that are carried by almost everyone, but are depleted during inflammation, and which have not been previously isolated or characterized.

Overall, the findings are said to provide the “most detailed snapshot to date of the microbiome in people with IBD, during active and non-active disease states.” 

“Given how tightly connected the microbiome is with our health and wellbeing, these results shed some light on how we might avoid the problems that arise when this relationship goes awry, and how we might be better stewards of these lifelong companions,” says Jason Lloyd-Price, who worked on the study while a research scientist at Harvard Chan School and the Broad Institute and was lead author of the paper.

By Benjamin Ferrer