The Microbiome and Inflammatory Bowel Disease: Driver or Passenger?

An Interview with Dr. Ashwin Ananthakrishnan

Dr. AshwinAhswin Ananthakrishnan is a gastroenterologist at Massachusetts General Hospital and performs innovative research focusing on the epidemiology and outcomes of inflammatory bowel diseases. Here he discusses with the Center of Microbiome Informatics and Therapeutics the relationship between inflammatory bowel disease and the microbiome.


What is Inflammatory Bowel Disease?

So Inflammatory Bowel Disease (IBD) refers to one of two chronic immune mediated diseases: Ulcerative Colitis or Crohn’s Disease. The common characteristics involve inflammation somewhere along the gastrointestinal tract. Ulcerative Colitis involves just the colon, whereas Crohn’s Disease can involve anywhere from your mouth to your anus.

These diseases typically have their onset during teenage years, or the 20s and 30s, and are also viewed as life-long diseases. It’s possible to have excellent control and not have the disease impact your life at all, and that’s our goal with treatments. But they are not diseases that are typically considered cured by the existing medications that we have. They are also characterized by progression that under-treated or untreated disease can lead to bowel damage that can then result in hospitalization, surgeries, or other disabling symptoms.

What role does the Microbiome have in IBD?

I think there’s potential for it to be involved in a number of different ways. Clinical studies so far have looked at the differences between the microbiome of IBD and non-IBD patients and observed reduced bacterial diversity in people with IBD. However, the degree to which that is driven by inflammation and the degree that the microbiome changes drive the inflammation is still not clearly known. We recognize that there are some potentially protective bacteria, like firmicutes that may protect against inflammation in a subset of people, like those with Crohn’s disease. We also recognize that there could be some bacteria that could be drivers of inflammation for example, Adherent-invasive E. coli in people who have ileal Crohn’s.

Additionally, I think that what we know about the microbiome has the potential to inform our care going forward in that we recognize there are a number of different environmental influences that affect Crohn’s and Ulcerative Colitis.

But we don’t yet know the mechanism how these environmental factors affect the disease, and the microbiome promises to be an important window into that process. For example, there’s an evolution in thinking that diet is an important determinant of both incident disease and how the disease behaves, but we don’t know the mechanism. One mechanism that may be involved is the microbiome which we know is exquisitely sensitive to both long-term and short-term diet. Environmental factors could be modifying the microbiome or affect how your intestinal immune system responds to such influences, which then either trigger a flare of your Crohn’s or Ulcerative Colitis, or make you develop the diseases if you’re otherwise predisposed.

So what needs to be studied to potentially improve the disease outcome?

I think there are several different ways forward. We recognize that there is a lot of variation in the microbiome and that looking cross-sectionally across people is only informative to a particular extent. We need to look at changes that are happening over time in a person. It’s critically important for studies to look into how they can capture changes that occur before the event of interest. When you’re looking at microbiome changes once the outcome has already occurred, then it becomes the question of the chicken or the egg – which came first? If the microbiome changes are the consequence of inflammation, then the patterns are useful to know but do not directly help treatment. Whereas if the microbiome is truly what is driving the inflammation then this would be evidence for targeting those changes to prevent the outcome such as the development of Crohn’s or Ulcerative Colitis. It’s critically important for future of studies to be able to look at that.

So if we knew the microbiome caused the inflammation, would the next step be to prescribe more Fecal Microbiota Transplants(FMT) for individuals?

I don’t think we would necessarily prescribe more FMTs. This is where we can be smarter about treatments. If you look at the current state of microbiome directed treatments for Crohn’s and Ulcerative Colitis, most of them have modest, or no effectiveness. That could in part be because we’ve been very broad in our hammers used to target the nails. We’re either using broad spectrum antibiotics that target both beneficial and harmful bacteria or restoring the microbiome through FMTs in a random fashion without knowing what does and doesn’t need to be replaced. There is growing data that the specificity of the donor including the presence of specific communities, may be important in treating inflammation. Similarly, we’ve been using sort of very broad and nonselective groups of probiotics.

That’s why if you ask, “what has targeting the microbiome has helped?”, I think the answer is very little. But that’s not a reflection of the microbiome not being a good target, but rather how we’ve been targeting changes in the microbiome. Once, we have more granular longitudinal studies we’ll be able to better tailor our microbiome therapeutics.

Just as a corollary, if you look at immune suppressant treatments, we’re moving away from broad sort of immunosuppressants like steroids or thiopurines, to agents that are targeting specific mechanisms of inflammation like anti-TNF agents, anti-integrin therapies, and those that direct against chemokines and cytokines. We need something parallel in the microbiome; moving from broad therapies to more focused treatments.

We are also recognizing the need to understand how changes in the microbiome can be brought on by changing your behavior. Changes in diet could change the microbiome in a beneficial fashion and help you get control of your disease. So instead of taking the medication, you’re modifying your diet to achieve the same outcome. I think that’s the sort of a goal we’re all hoping to incorporate in our practice.

2 thoughts on “The Microbiome and Inflammatory Bowel Disease: Driver or Passenger?”

  1. william Bauske says:

    I must disagree with you that microbiome treatments have not shown efficacy in IBD, the efficacy has been unreliable, some people have experianced improvement to nothing to cure. Dr Borodys study in 2003 show 6 UC patients completely cured with patient follow of 25 years later. There is one report of one case of Crohn’s also being completely cured with patient follow up 13 years post FMT. These official reports should not be ignored or downplayed, more research is absolutely needed.

  2. William Bauske says:

    It is only in my opinion that the intestinal environment of IBD patients is more hospitable to pathogens then it is to the healthy microbes, this presents a big challenge to successful FMT. Many variables are involved in this, but unless these variables are addressed in further studies, we will just see more of the same unreliability of any of these previous protocols, and potential for falsely concluding there is no hope for FMT in IBD, that’s one thing I’m concerned about. The good bacteria are just not going to “stick” down there unless we start to reliably manipulate patients diet, donor diet, inflammation and a standardized concentration of bacteria. It’s almost just as likely or more likley we will add new pathogens in IBD with full spectrum FMT then we will be able to restore the “theoretical” missing bacteria. We really gotta try to narrow down these essential ones and deliver in high enough dose for long enough and I don’t think I’m really saying anything original here, I just haven’t heard any specific plans for anyone to actually do this yet. Although there is researcher who plans to try full spectrum FMT capsules in crohn’s and 1-2 companies trying a selected mix of bacteria for UC.

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