Developing biomarkers for gut and neurological, cognitive functioning associations in children


In this Contemporary Pediatrics interview, Rob Knight, PhD, discusses translating adult studies into children to determine gut microbiome biomarkers, and how they are associated with neurological and cognitive conditions.

This interview is the last installment of a 3-part series with Rob Knight, PhD, Wolfe Endowed Chair in Microbiome Science at Rady Children's Hospital-San Diego, discussing the potential associations between gut microbiomes and neurological, and cognitive functioning in children, how it is being researched, and the potential role it can play in the future. Click here to view part part 1; click here to view part 2.

Transcript (edited for clarity):

Contemporary Pediatrics®:

After an association between the gut microbiome and neurological or cognitive functioning has been made, what could next steps be?

Rob Knight, PhD:

Once you see an association, you want to know what the mechanism is so that you can do something about it. One area where we think this very rapid prospects for success is taking studies that have been done in adults and then translating them rapidly into children. That's the focus of our microbiome theme at Rady Children's, where initially we're starting with, with 1 project, a major depressive disorder, and a second project on cancer where in both of these situations, there have been a lot of studies and adults, there hasn't been a lot of work done on kids. We think the fundamentals are going to be very good for developing new biomarkers. The second step is usually biomarker discovery and the reason why that's important is that a lot of therapies are only effective for a subset of patients, and often the number needed to treat (NNT) is quite large and even for things like selective serotonin reuptake inhibitor (SSRIs), for example, many patients don't benefit from the first SSRI, or the second or even the third. And so if you can detect a microbiome signature, to either see what's happening with the patient on an intake, or after the first few days on a particular medication, to be able to determine "will this medication ultimately work for this patient," that can be really important for avoiding those months and months and frustration of applying a treatment that's not going to work. That's the focus of the 2 studies that I mentioned. Ultimately, when you know the mechanism, you can come up with completely new therapeutic targets, but unlike companion diagnostics, where the regulatory pipeline is quite short, for new therapeutic, often it's a gap of 20 or 30 years, between when you have the new mechanism and when you're able to come up with a compound that's fully FDA approved and marketable. So, we think being able to use companion diagnostics to make existing drugs, much more effective for more people, is going to be a much better short-term pathway to addressing these issues. I also want to emphasize the role of food. So in adults, and this hasn't been done in children yet, to my knowledge, even though most of the guidelines suggest that the same foods that are healthy for adults are also healthy for children, the Mediterranean diet in the SMILES study, was shown to be quite effective for major depressive disorder, with about 30% of subjects responding and was about equal to standard of care, non-pharmaceutical interventions like group therapy. So, I think there's a tremendous amount of potential for designing dietary interventions that are perhaps in general, like the Mediterranean diet, or perhaps very specific to an individual, where we may be able to improve management of a lot of diseases that way, as well as with more traditional pharmaceutical or non-pharmaceutical interventions. But what we have to do for dietary response, as well as for drug response, is to understand that individual variation that leads to those differences, and there's been billions of dollars spent working first in the human genome where we're all 99.9% identical. And we only have about that we only have about 20,000 genes, but far less has been spent has been spent looking for those keys in the microbiome, where you and I are probably 90% different and we have millions of genes, not tens of thousands like in our human genome. So, for that reason, I think there's tremendous potential to go after that individual variability and to use the microbiome to do it. There's also the point that it's very hard to change your genome If you find that you have other risk allele, you're not going to, like CRISPR-cas9 it out, but on the other hand, your microbiome, you absolutely have changed dramatically from the time you were born to the present and you continue to change it. What we see in projects like the American Gut Project, which I cofounded, is that over the long term, like 6 months to a year, you radically reshape your microbiome, depending on the diet you're eating. That's what makes your microbiome look like a different person's right, there's nothing you can do in a week, short of surgery that's going to make your microbiome was like someone else's surgery or antibiotics. But over the long term, that's how you powerfully reshape all those microbial genes in a way that we think is going to have a really durable impact on your health. In kids, the potential is much more because most of that microbiome changes happening in early life, and so if we can instill a good microbiome and good habits early on, that can be totally transformative for all these conditions we're talking about, including neurological and mental health conditions.

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