Seema Bhatnagar, PhD, Associate Professor of Anesthesiology at the University of Pennsylvania talks about ways to fight depression and future possibilities.
Interview conducted by Ivanhoe Broadcast News in October 2019.
What were the results of the study that you conducted?
BHATNAGAR: Broadly speaking, our results showed that the gut microbiome reflects an individual’s experience of stressful events. And not just broadly that all individuals respond to stress the same way, but that there are unique differences in the gut that reflect individual vulnerability or resilience to the effects of stress. So that was the novel finding of the study.
What were you looking at as a marker for that individual reaction to it?
BHATNAGAR: We’ve done work in the past to look at how animals, in this case, cope with repeated social stress. Animals that are more passive in coping with stress show more – we call vulnerability because they exhibit behaviors that are more associated with a helpless, depressive-type state and a more anxious state in a number of behavioral tests. And what – our goal was to follow up on previous work where we’d shown that inflammatory processes in the brain and the brain region called the ventral hippocampus underlie the vulnerability. So if you reduce the inflammatory processes, you reduce vulnerability. And we were asking about the role of the gut microbiome because the gut microbiome is a major source of immune inflammatory molecules, some of which can access the brain. We asked whether there were differences in the gut microbiome between animals that become resilient or vulnerable to stress and whether the gut microbiome contributes to those differences – what’s the role of the gut microbiome in producing vulnerability or resilience to stress?
And if you had to just sort of lay out a path for how that happened – sort of a which came first, the chicken or the egg routine?
BHATNAGAR: Right. We did look at the microbiome before stress was administered because we’re looking at the microbiome sample through fecal matter. And we were able to get that before we stressed the animals, and there was no differences in microbiome pre-existing. So it’s the experience of stress that has to happen first. There may be pre-existing differences that we couldn’t detect and pre-existing differences in the brain that we don’t know about, but the stress happens, it influences the gut, and then the gut microbiota start changing and they – likely, they communicate with the brain, and then a loop happens with the gut and the brain communicating with each other as stress continues.
How do you break that chain or that loop? How can people take this information and apply it in real life?
BHATNAGAR: Right. In a context where there are stressful life events and we believe these inflammatory processes are important both in the gut and the brain, and you want to reduce inflammatory processes. I think the best advice anyone could give is to maintain a healthy body – sleep, exercise, stress reduction techniques. There are a number of probiotics people like to take, and there’s anecdotal evidence that it works for some people, but there’s not a lot of experimental evidence. There is accumulating evidence that prebiotic substances that actually promote the growth of certain types of bacteria – those might be a better way to kind of promote a healthy gut. There’s also a newer concept of postbiotics, products of bacteria that may also be useful. I should caution thought that for all these substances that are targeting our guts, we need much more study of which are the most effective and improving health.
You found out that different kinds of stress impacted them differently – and in their case, it would be territorial – you know, whatever they’re worried about. We worry about different things. Would that be applicable? I know that’s a broad jump to human beings.
BHATNAGAR: The reason we used social stress is it takes advantage of the natural behavior of rodents. Rodents have social dominance hierarchies. What we’re doing is studying behaviors that occur naturally anyway in the rodents. For people, stressors in the social domain, in our social relationships are probaby the biggest source of stress. in that sense, you’re working with the same systems in rodents that underlie social kinds of stressors in people most likely.
The study also referenced this might be applicable in vitro – which, again, is a direction that a lot of medicine is taking. When do you maybe see that happening or what does that look like right now?
BHATNAGAR: There’s a couple of avenues that you could pursue in research that could take you in the in vitro direction. One is to try and grow bacterial populations in culture and look at the products they produce, and then you can maybe look at whether you could use those products to enhance health. There are some technical difficulties in growing specific kinds of bacterial strains, so we’re not there yet in terms of being able to grow very specific strains of bacteria. Another approach to in vitro would be to take brain cells in culture and sort of look at whether those products enter the brain, and what are their actions on brain cells? So that could be done in vitro.
So the gut bacteria, as it relates to depression, is the middle step in that process. Is that kind of what I’m hearing?
BHATNAGAR: That would be what our data suggest. Certain bacteria in the gut promote inflammation in the hippocampus, which leads to behaviors that are relevant for depression.
We hear all the time, destress your life, don’t be stressed – which is impossible for almost everyone. So some real advice for people on both impacting their gut bacteria, reducing inflammation, and minimizing stress.
BHATNAGAR: I would say a lot of these will be up to the individual. The kinds of regimens they can adhere to. Stress reduction techniques. A lot of people use mindfulness training – meditation, yoga. Exercise in general is very stress-reducing. A balanced diet. And I think, in this day and age, getting sufficient sleep – that varies by the individual, but lack of sleep in and of itself can have inflammatory-promoting properties. So definitely want to try and get sufficient sleep.
And the last question is the mechanics of the actual study if you’ll give me some data on how many and that type of thing.
BHATNAGAR: The study took two to three years to complete. We used different cohorts of animals. We can’t do a full study in one cohort, there’s only so much space we have, there’s only so much manpower, and so we run groups of animals. What we end up doing by doing that is having sort of replicates of cohorts that get the same kinds of treatment. And the group sizes in neuroscience and behavioral neuroscience tend to be between 8 to 10 to 12 animals. That gives us sufficient statistical power to be confident in our results.
How does a mouse show that they’re depressed?
BHATNAGAR: What we look at are behaviors that have been validated using antidepressant drugs. They’re very well-validated behaviors that are widely used. And we look at behaviors that make sense from the depression perspective in humans. So animals become helpless, they show despair, they show passive coping, they essentially give up in certain situations. And those are the kinds of behaviors that, when you give antidepressant drugs, are reduced. So that’s how we validate these tests and say, OK, these tests are getting at behaviors that are relevant to depression in humans, and test animals in those kinds of paradigms.
What is passive coping?
BHATNAGAR: Well, in animals passive coping is essentially being submissive in a situation where you’re being attacked. In people, there are strong data to support that passive coping to life stressors has detrimental effects on health particularly cardiovascular health. But one thing we have to remember is that it’s not that active coping is always good and passive coping is always bad. There are certain situations where it may make sense to be a passive coper and being actively coping is going to be detrimental. So in this particular paradigm, that’s what we found. There’s a lot of human data also suggesting that passive coping is not good for your health, so that is consistent. But not every – not in every situation is passive coping bad or active coping good. Within the context of the study, passive coping produced vulnerability to stress.
END OF INTERVIEW
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