Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And today, we're highlighting circadian rhythms and gastrointestinal health. Joining me is Dr. Keith Summa. He's an Assistant Professor of Gastroenterology and Hepatology in the Department of Medicine at Northwestern Medicine.

Dr. Summa, it's a pleasure to have you join us today. This is such a fascinating topic, so I can't wait to delve into this. How do peripheral clocks in organs like the liver, intestines, and pancreas synchronize with the master clock in the brain? And what happens when they fall out of sync? What kinds of things do we notice?

Dr. Keith Summa: Thank you, Melanie. It's a pleasure to be here and to talk about this topic. The peripheral clocks in organs throughout the body synchronize with the master clock in the brain through a variety of mechanisms. For example, there can be a direct neural connection through nerves such as the vagus nerve, which can communicate with different organs in the body and influence the peripheral clocks in those tissues.

There can be hormonal connections through hormones that are released in a time of day-dependent manner that can then act upon different organs to influence the clocks in those tissues. Two examples would be melatonin, which is a hormone secreted by the pineal gland, which signals to the body that it's dark outside. This can help set the time in the clocks in different tissues, as well as work to improve our sleep-wake cycle. Another example is cortisol, which is released in the morning. Again, this can serve a function to help communicate the time to different clocks in peripheral tissues throughout the body. Third, the central clock in the brain sets a rhythm of core body temperature. This rhythm of body temperature can be used to fine tune clocks in different tissues and peripheral organs throughout the body. And then, finally, the master clock in the brain helps to regulate behaviors that can influence peripheral clocks.

These can include the sleep-wake cycle, feeding and fasting cycles, social activity, exercise. All of these behaviors can then input into peripheral clocks in different organs throughout the body. What happens when they fall out of sync is that the functioning of these different organs can become disorganized and less efficient. And that can lead to increased risk of diseases from developing as well as poor overall function. I like to think of the circadian clock system as orchestrating a symphony. When things are all in sync, everything is ticking together in harmony, and things are working optimally. If that synchrony falls out of sync due to disruptions of the clock in different tissues, that can create a chaotic situation where things aren't working optimally in the way that they should.

Melanie Cole, MS: Dr. Summa, in your article you wrote about flying and jet lag. And I'm just curious, when you're discussing this with us about synchronizing and things falling out of sync, when you talk about that, does that also go together with the fact that when people travel, certain bowel issues, constipation, diarrhea, those things can sync up with that so that maybe you don't need to use the bathroom, or maybe you do. It's almost like it figures out where you are in that time.

Dr. Keith Summa: Yes, absolutely. GI symptoms and GI issues are a very common occurrence in people that are experiencing jet lag. And what's going on is there is now a desynchronization between the external time, the sunrise and sunset at the location that you've landed with the internal time, the body's internal rhythms, and that desynchronization can manifest with GI symptoms such as diarrhea or constipation because that synchrony between the internal and external time is lost, and that can manifest with these GI symptoms. Another perhaps more common occurrence of this situation occurs when the schedule on free days, for example, during the weekend is different from that during work days or school days during the week. And if there is a mismatch between your schedule during work or during school, with that during the weekend on free days, that can create a situation that we call social jet lag, where there is shift in the internal clock relative to your behavior, and that can also manifest with GI problems.

Melanie Cole, MS: Wow, this is just such an interesting topic, and we're learning so much more about it. Explain the role of the circadian rhythms in metabolic processes. You just touched on it a bit, but how these disruptions might contribute to conditions like obesity and diabetes, because we are learning more and more about sleep and obesity and diabetes and that connection there. So, go over that for us.

Dr. Keith Summa: Yes. This is exciting area of investigation. There have been a number of epidemiologic studies linking sleep problems and circadian rhythm disruption, such as experienced by shift workers with an increased risk of metabolic diseases, such as obesity and diabetes. And we're beginning to learn more about the specific role that the circadian clock system is playing in contributing to this increased risk that is observed.

What we're finding is that the circadian clock system helps control key metabolic processes involved in energy regulation and in glucose sensitivity. And so, disruptions of the circadian clock system causing that loss of synchronization that we talked about, that can manifest with alterations in energy regulation. That can favor the excess storage of energy from consumed food that can lead to weight gain and obesity. Similarly, disruptions in the clock system can impact how different tissues are sensitive to insulin and able to store glucose in response to insulin. That change in the glucose sensitivity over time can lead to increased blood glucose levels and an increased risk of developing diabetes.

Melanie Cole, MS: Along those lines then, how does the circadian disruption affect intestinal permeability and, this is so interesting, what role does alcohol play in that process?

Dr. Keith Summa: What we found studying different models of circadian rhythm disruption and sleep deprivation is that the gut epithelial barrier can become disrupted. And that can lead to increased intestinal permeability, which means that the epithelial barrier in the intestine becomes leaky to pro-inflammatory products such as bacterial components that are in the gut. They can leak across that barrier and get into the intestine and into the portal system and affect the liver. That increase in intestinal permeability can promote inflammation. And we think that it can increase the risk of developing inflammatory bowel diseases, as well as liver disease, in particular, alcoholic liver disease. And the impact of circadian disruption on the intestine is augmented or increased by alcohol. So, I often think of it as the circadian rhythm disruption is a second hit that can increase susceptibility to challenges like alcohol or a high fat Western diet. And that can lead to worsening inflammation and worsening pathology when those two factors are working together.

Melanie Cole, MS: Dr. Summa, tell us some of the most significant findings from your research on clock genes in mice. Give us a little bit of an overview of that research and its impact on our overall health.

Dr. Keith Summa: Well, I just highlighted, I think, one of most significant findings that we have, is that the intestinal epithelial barrier is disrupted by circadian rhythm disruption. We have also found that in animal models of circadian rhythm disruption and sleep loss, there is an increased susceptibility to colitis, an inflammation in the colon that is similar to what is observed in types of inflammatory bowel disease in humans. And we've also found that circadian rhythm disruption can lead to shifts in the gut microbiome, predominantly leading to a decrease in the overall diversity of the gut microbiome. And we think that those changes to the microbiome can also impact susceptibility to inflammation in the gut and in the liver.

Melanie Cole, MS: Wow. So, I'd like you to take these findings, everything we've just been discussing, and translate them. Take us from bench to bedside. So, how our growing understanding, what you're telling us here today of circadian rhythms and peripheral clocks, how is that going to influence our future approaches to diagnosing and treating complex disorders? We're talking about depression, inflammatory bowel disease, as you've mentioned, metabolic syndrome, and even the potential clinical implications of your findings for intestinal and liver diseases, as you were just saying, when we're talking about these disrupted circadian rhythms.

Dr. Keith Summa: Well, I think there is a lot of potential for translating these findings from the bench to the bedside to help our patients. Over the short term, I think that this research helps us with risk stratification for patients and trying to understand which individuals are at higher risk for having worsening disease or failing to respond to treatments like we hope that they will.

So, over the short term, it helps us understand which patients may be at higher risk relative to others, which may influence our treatment decisions and our monitoring plan. Similarly, it does provide us with an ability to talk with patients about things that they can do, behavioral and lifestyle modifications, to help support their circadian rhythms, improve their sleep wake cycles, and basically try to provide that level of organization to help support healthy circadian rhythms within the gut and other peripheral organs to help protect against flares of disease activity. I have found that this can be a helpful thing to talk with patients because it can give some agency for things that patients can do themselves to help impact their disease in the setting of what can often be an overwhelming situation and trying to deal with these complicated, complex, and often severe diseases.

Over the longer term, I think that this line of investigation has the potential to provide new insights into mechanisms of disease development. If we can understand how disrupted sleep and disrupted circadian rhythms are impacting molecular pathways of inflammation that impact disease development and progression, we may be able to elucidate new targets for treatments or new approaches to treatments, for example, by looking at the time of day that a medicine is given to try to improve our treatment of the diseases that are affecting these patients. So, those are some of the ways in which I think that this line of investigation is helping to improve both the short-term prospects for patients as well as the longer term approaches to treatment.

Melanie Cole, MS: There are such broad implications for immune function, and as you said, the beginnings of disease and identifying these things. This is really such a fascinating topic and so exciting for a time in your field to be able to look into this and see future implications. I'd like you to tell other providers your key takeaways, what you want them to take away from this type of research, because it really can affect the way that so many practitioners help their patients.

Dr. Keith Summa: Well, I think the biggest takeaway that I can recommend is to think about time of day and think about sleep. These are challenges in the environment that we live in, where we have access to screens and electricity that can disrupt our sleep, disrupt our circadian rhythms. We live in a society where we spend more time indoors than our ancestors did. We get less light during the day, we get more exposure to light at night. So, the society we live in really presents challenges to having healthy sleep and circadian rhythms. And that can influence people's risk for disease and people's overall health. So, I would encourage providers to talk with their patients about sleep and about their schedules. It's something that may influence their disease risk as well as their overall health and their overall quality of life.

Melanie Cole, MS: Great advice. Thank you so much, Dr. Summa, for joining us today and sharing these studies and your incredible expertise in this area. To refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/gastroenterology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole. Thanks so much for tuning in today.