R Balfour Sartor, MD, on New Insights Into the Microbiome and IMIDs

In this video, Dr Sartor discusses the role of bacteria and other organisms in the microbiome and how a variety of therapies, from biologic therapies to fecal microbiota transplantation, may work to alleviate dysbiosis and effectively treat immune-mediated inflammatory diseases from Crohn disease to psoriasis, as he explained at the Interdisciplinary Autoimmune Summit.

R. Balfour Sartor, MD, is the Midget Distinguished Professor of Medicine and Microbiology and Immunology at the University of North Carolina at Chapel Hill.

TRANSCRIPT:

Dr. Balfour Sartor:  Good afternoon, I am Balfour Sartor, University of North Carolina. I'm a physician scientist in the Gastroenterology and Hepatology Division. My specialty is Crohn's disease and ulcerative colitis management as well as basic mechanisms of immune microbial interactions.

This afternoon, I discussed new insights into the microbiome and the immune-mediated inflammatory diseases. We coexist with a huge number of bacteria, viruses, and fungi that are at least as numerous as our cells in our body. Some people say outnumber by tenfold.

These bacteria eat what we eat. They are predominantly in the intestine, oral cavity, and any mucosal surface as well as the skin. They are very important in maintaining homeostasis, both in the intestine and the immune function of the body.

In the intestine, they are most prevalent in the colon, where they are predominantly anaerobic as opposed to the aerobic bacteria of the upper GI tract and the mixed aerobes and anaerobes in the mouth cavity. The mucosal surfaces, of course, they are predominantly aerobic bacteria.

The importance of these bacteria is that they are metabolically active and they interact with epithelial surfaces as well as the immune response. Because the bacteria are present from birth, we have adapted to these bacteria and they have adapted to us.

They are extremely important in mediating immune responses as well as metabolic products feeding the intestinal cells and to some extent, skin. In a normal individual, there is a balance of beneficial and detrimental bacteria, with the beneficial bacteria winning out. These stimulate protective immune responses and give valuable protective metabolic products, such as short-chain fatty acids that are the primary metabolic fuel of the colonocyte.

However, in many inflammatory diseases —including Crohn's disease, ulcerative colitis, pouchitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and to some extent, multiple sclerosis — there is an abnormal balance of beneficial and detrimental bacteria. And in this case, the detrimental bacteria outstrip the beneficial bacteria that are characteristically decreased in the so-called dysbiosis of inflammation.

These gut bacteria obviously influence gut intestinal inflammation, but they even have a role in systemic inflammation, like arthritis and skin manifestations such as psoriasis, in particular.  Their characteristic transport mechanisms are selectively home to these regions through adhesion molecules and integrins that can be blocked therapeutically. In the intestine, these bacteria will stimulate Th1 and Th17 immune responses that then can influence arthritis. In the intestine, these bacteria will stimulate Th1 and Th17 immune responses that then can influence arthritis.

There are several strategies that one can use to therapeutically correct the dysbiosis that is associated with inflammation. One is to replace the entire microbiome, such as a fecal microbial transplant, or FMT.

The second is to use selective antibiotics, or phages, or medications to block uptake of aggressive bacteria. Conversely, you can restore the missing protective bacteria or those bacterial functions, such as short-chain fatty acids, with defined products.

Finally, one strategy would be to create a less hostile environment, to alter the diet to remove toxic metabolites and metabolites that stimulate the growth of these aggressive bacteria.

FMTs have been widely used and are the first-line therapy now in treatment of recurrent Clostridium difficile. This is FDA-approved, but all other indications are still under IND strategies and in clinical trials. There's some evidence that in ulcerative colitis, FMT can be effective, but there is a strong donor effect, in that some donors are more effective than others, and some recipients are more responsive to FMT. We don't quite know how to match the optimal donor with the optimal recipient.

Another problem with FMT was that they can transmit antibiotic-resistant bacteria. There was a New England Journal article showing that antibiotic-resistant E. coli could be transmitted and lead to death in immunosuppressed patients. So there are theoretic problems with FMT that could be improved by using subsets of protective bacteria that are very well-defined.

This approach has the theoretic and practical advantages of being able to avoid any aggressive bacteria in the FMT. It also is a more verified product, where you get rid of the differences between donors that exist in FMT. There are some theoretic advantages. There are trials going on with these purified bacteria but have not yet been FDA-approved.

A study with a group of spores that are predominantly Clostridia that in combination with antibiotics have been shown to be effective in ulcerative colitis.

I think there's great opportunities to improve upon FMT and I think the final frontier is in diet. If we could avoid foods such as high fructose diets, high sucrose diets, that stimulate the growth of E. coli and Enterobacteriaceae such as klebsiella, then increase the fiber that increases protective bacteria and their metabolic activities, such as short-chain fatty acids, that we could move forward in a very physiologic manner.

To me, the path forward to improve current techniques to restore a healthy microbiota in IBD, psoriasis, psoriatic arthritis, and multiple sclerosis, and perhaps rheumatoid arthritis, is to develop an individualized approach to measure what is missing in a dysbiotic patient's microbiota, and then selectively replace those missing or dysfunctional components. Then, concentrate on protective resident species that have a good chance of colonizing and functioning in the intestine, as opposed to currently available probiotics that do not persist in the intestine.

Refined fecal transplants try to determine which donors could have greater efficacy and which recipients might be more responsive, and then try to match those and extend their duration of effectiveness.

Then, perhaps determine improved dietary components, perhaps in conjunction with an FMT or with a live biotherapeutic product or the selected bacterial replacement, and then finally target outcomes based on the metabolic functions—do a metabolomic analysis of the patient.

So I think there's great opportunities to manipulate the microbiome. I would predict that this microbiome replacement strategy to correct dysbiosis will be used as an adjunctive therapy to corticosteroids and biologic therapies and could be very important in maintaining remission after induction of remission with an aggressive immune-based therapy.

This could be a potentially more physiologic and less expensive, less toxic approach in long-term immunosuppression. I think that there are boundless opportunities for manipulating the microbiota, we just need to be smarter in how we approach this type of therapy. Thank you.