March 9

Gut Microbiome Could Predict Drug Response In RA

A recent study shows how gut microbiome can explain variations in response to drugs like Methotrexate.

If you’ve ever wondered why some people do well on methotrexate and some others don’t, or if you’ve been on methotrexate once and done well and then in the future you don’t seem to respond. Then those variables could be, at least in part, a result of your gut microbiome.

This study just published on the 8th of February 2021 in Nature Reviews Rheumatology Journal. The researchers found and demonstrated for the first time that oral methotrexate can be metabolized by the human gut microbiota, and suggests that the gut microbiome could have value in predicting response to the drug, which is well known to vary in patients with rheumatoid arthritis. So how did they find out that this actually occurred? What they did is they used metabolomics platforms and found that methotrexate levels remained after XP varying incubation. These samples correlated with the magnitude of future clinical response, suggesting a possible direct effect of the gut microbiome on methotrexate metabolism and treatment outcomes. And the first time I read that, I had to think about what that actually meant, and what this is saying is that after they studied the post-digestive samples of how methotrexate remained almost after, I guess, the ash after the wood has been burnt in a fire. They found that the more that the methotrexate had been broken down or metabolized by the gut microbiome, the more likely those individuals were going to do well on the drug. And so they then went and applied another level of intelligence to this. They then used machine learning based on the metagenomics data and developed a microbiome-based model which predicted the response of methotrexate based on their microbiome sample. By doing so, they then studied a new group of people who had just been diagnosed with rheumatoid arthritis, and correctly to an accuracy of 80% predicted whether or not these patients would respond or not respond well to methotrexate.

So this is really, really fascinating and just to summarize this, so that it sinks in a little better because it did take me a few goes thinking this through. What we have is now evidence that the microbiome plays a role in the breakdown of methotrexate. The amount that the microbiome gets involved or had the capacity to metabolize methotrexate impacts how well someone will respond to the drug, and it’s so predictable to an accuracy of 80% that someone’s microbiome will tell researchers using this machine-learned software how well they’ll do on methotrexate. This really reinforces once again, we need to have a really, really good, diverse microbiome. Not just if we want to take methotrexate, but one could hypothesize that other drugs may also be influenced by the gut microbiome as well. We don’t just want that for the purposes of our drug responding capacity, we also want it directly because an improved microbiome gives us an improved outcome with rheumatoid arthritis. One way we can do that is simply to go onto a plant-based diet.

In this medical journal, a study called “The impact of vegan diets on gut microbiota an update on the clinical implications”. In the abstract it says, We report on the health benefits of a vegan diet for metabolic syndrome, cardiovascular disease and rheumatoid arthritis concerning relevant impacts from the gut microbiota. They draw upon a few studies inside this literature review going back a few years at 53 patients with R.A. who were previously on an omnivorous diet. The study found significant changes to the intestinal flora after patients shifted to a vegan diet for one year. Their fecal flora or microbiome was different between patients with high improvement and low improvement, which indicated the gut profiles are associated with disease activity. This is crucial, the better the microbiome, the less disease activity.

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Another study with 43 patients which were randomized into two groups, one consuming an uncooked vegan diet and another on an omnivorous diet for just a month. Significant changes in the fecal flora with this decreased disease activity were noted in the vegan group, but not in the omnivorous group. This confirmed the connection between a vegan diet, fecal microbiome, microbial flora, and disease activity in our patients. And a third example reported similar results from a controlled single-blind trial with a vegan diet. So we can definitely go on a plant-based diet and expect our symptoms to improve based on the quite fast response that our gut microbiome has to that increased fiber intake and reduction of animal products.

Another way to improve your microbiome is just to become more active. In a study published on 12th of May 2020 in the Journal of International Society of Sports Nutrition. This literature review was done on how athletes have different and better microbiomes than those people who are inactive. The conclusion of this literature review said that the typical features that are associated with those who exercise a lot include a higher abundance of health-promoting bacterial species in their microbiome, increased microbial diversity, functional pathways, and microbial associated metabolites, stimulation of bacterial abundance that can modulate mucosal immunity and improved barrier functions. Let me just pause there to emphasize this last section. Improved barrier functions are crucial when you have an autoimmune disease because the mechanism of the leaky gut is playing a big role in the underlying cause, the disease itself. This is crucial, especially for those of us with autoimmunity.

The study conclusion continues in comparison to sedentary controls, Athletes have increased fecal metabolites and improved overall health unless overtrained or what they call in Red S and Red S turns out to be when you’re exercising with insufficient calories or if you’re training without sufficient rest. The conclusion is also positive if you’re currently not exercising, because, in sedentary individuals, exercise appears to positively modulate the composition and metabolic capacity of the human gut microbiota. If you’re not doing too much, but then you begin to exercise, then you can positively influence the microbiome. Another way that we can influence the microbiome is to get better sleep. We see here in this study called Gut Microbiome Diversities Associated with Sleep Physiology in Humans published in 2019, they found the total microbiome diversity was positively correlated with increased sleep efficiency and total sleep time and was negatively correlated with wake after sleep onset. You can also reduce your stress because in this study, stress, depression, diet, and the gut microbiota human bacteria interactions at the core of psychoneuroimmunology and nutrition. This study said that stress and depression can reshape the gut and bacteria’s composition through stress hormones, inflammation and autonomic alterations.

What have we learned? We have learned that methotrexate is influenced by how your gut bacteria portfolio looks and that we can improve our microbiome through a vegan diet, having more exercise, getting better sleep, and reducing stress.

If you’re looking for a program that can do all of those things, then head over to where you’ll be able to follow a systematic approach to improving your microbiome through the influence of all of those aspects of life. A 360-degree approach to improved health and improved microbiome and consequently less rheumatoid arthritis activity. Thank you very much, see you soon.

Clint Paddison

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  1. Great podcast Clint
    Just a quick question does that apply to injectable methotrexate as well most likely not, but I have still have to add the question as I am not sure.

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