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Cancer has an obesity-related risk factor, and it depends on sex and cancer type

Source: Cell Press
Date: 6/12/2023
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Obesity has been previously linked to an increased risk of cancer, but most studies have not differentiated the risks between male and female patients. A new study published June 12 in the journal Cancer Cell takes a closer look at this connection. The investigators report that both overall fat accumulation and fat distribution in different parts of the body confer different cancer risks depending on sex. Additionally, the risks vary across cancer types, like colorectal, esophageal, and liver cancer.

“Doctors and scientists are aware that obesity increases cancer risk, but this connection is less well known to members of the public,” says first author Mathias Rask-Andersen, a researcher at Uppsala University in Sweden. “These observations are important for risk assessment and to gain a deeper understanding of adiposity-related disease risks.”

“An important aspect of obesity-associated disease risk is the distribution of fat in different compartments of the body,” says senior author Åsa Johansson, also of Uppsala University. “Fat stored in the abdomen is considered more pathogenic compared to subcutaneous fat. In addition, the amount of fat stored in different compartments, as well as the rates of most cancers, is known to differ between females and males. These facts motivated a careful sex-stratified analysis of adiposity-related cancer risk.”

The investigators used data from the UK Biobank, a cross-sectional cohort of 500,000 U.K. residents aged between 37 and 73 who were recruited between 2006 and 2010 and then followed for a mean time of 13.4 years. Among the data collected from participants in the database were details about the distribution of fat in their bodies and whether they developed cancer.

The researchers used Cox proportional hazards modeling to identify the associations between the levels and distribution of fat in the participants’ bodies at the time of the initial assessment and their later rates of cancer. The team found that all cancer types except brain, cervical, and testicular cancers are associated with at least one obesity-related trait.

In female patients, the strongest links between overall fat accumulation and cancer were in gallbladder cancer, endometrial cancer, and esophageal adenocarcinoma. In males, the strongest links between overall fat accumulation and cancer were in breast cancer, hepatocellular carcinoma, and renal cell carcinoma. In terms of fat accumulation and distribution, there were differential effects between sexes on colorectal, esophageal, and liver cancer. For instance, a larger proportion of fat stored in the abdomen was associated with esophageal squamous cell carcinoma in females, but not in males. Additionally, body fat accumulation was associated with a high risk for hepatocellular carcinoma in males, an effect that was not present in females.

“We were surprised to see that there appeared to be a difference in the effect of obesity on cancer risk, not only between males and females, but also between post- and pre-menopausal females,” Johansson says. “Most remarkable, obesity is only a risk factor for breast cancer after menopause, probably due to the change in estrogen production in association with menopause.”

The investigators note limitations to this study, especially that it was limited largely to British White participants, which make up almost 95% of the UK Biobank. They explain that their findings may differ from or may not be applicable to other ethnicities. They also say that because participants were older, the results are likely not directly transferable to younger populations.

They plan to do additional studies to help develop a complete understanding of the molecular mechanisms underlying these findings. Future work will also focus on genetic and environmental risk factors for cancer, which are not static but differ across a person’s lifespan. This includes taking a closer look at the variation in the effects of obesity before and after menopause.

“Given the rapidly increasing rates of obesity globally, obesity is now the fastest-growing risk factor for overall cancer risk,” Rask-Andersen says. “Measures to prevent and reduce the occurrence of obesity and being overweight are therefore highly motivated. However, it is important to consider that reducing weight does not eliminate the risk of cancer. There are still many individual risk factors that play a much larger impact on specific types of cancer, such as smoking for lung cancer and exposure to sun for skin cancer.”

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Combining time-restricted eating and HIIT improves health measures in women with obesity

Source: Cell Press
Date: 10/4/2022
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Both time-restricted eating (TRE) and high-intensity interval training (HIIT) have been shown to improve cardiometabolic health in people who are overweight and at risk of serious disease. Now a randomized, controlled trial has tested whether combining these two approaches is more effective than either of them on their own. The results, publishing in the journal Cell Metabolism on October 4, show that the combination improved the average long-term glycemic control compared to a no-intervention control group and induced 2-fold greater reductions in fat mass and visceral fat area compared with each intervention in isolation.

“Isolated TRE and HIIT have received increasing attention for being effective and feasible strategies for at-risk populations,” says senior author Trine Moholdt, head of the Exercise, Cardiometabolic Health, and Reproduction Research Group at Norwegian University of Science and Technology (NTNU). “We wanted to compare the effects of the combination of TRE and HIIT with their isolated effects and to determine whether TRE and HIIT would act synergistically in improving health in individuals with risk for cardiometabolic disease. This finding highlights the importance of changing both dietary and physical activity habits for individuals who wish to rapidly improve their health and lower their disease risk.”

The trial had four arms: HIT alone, TRE alone, the TRE-HIIT combination, and a control group. A total of 131 women were enrolled, with 32 or 33 in each arm. All of them had overweight or obesity and had risk factors for cardiometabolic diseases like type 2 diabetes and cardiovascular disease. TRE was defined as consuming all daily calories within a 10-hour time window. HIIT was defined as exercise done at 90% of maximum heart rate for 35 minutes, three times per week. The exercise sessions were supervised by the investigators, and the participants were asked to log their first and last calories every day.

The interventions lasted for 7 weeks. Several measures were taken both before and after the study, including the participants’ blood pressure, body mass index, fat and cholesterol levels in the blood, and several measures of blood glucose and insulin levels.

The researchers found that the participants who combined TRE and HIIT were able to improve their average long-term glycemic control measured as HbA1c. They were also able to effectively reduce fat mass and visceral fat and increase their cardiorespiratory fitness measured as peak oxygen uptake. However, there were no statistically significant differences in blood lipids, appetite hormones, or vital signs after any of the interventions compared with the control group.

Another important finding from the study was that adherence to the study was high. “High adherence rates are important,” says first author Kamilla La Haganes, a PhD student at NTNU. “Adherence rates to general lifestyle recommendations are low, and our diet-exercise strategies may serve as an alternative.” After the study was completed, 18 participants from the control group also chose to try one of the study interventions.

“We recommend this kind of program for people who wish to have a relatively simple way of changing diet and exercise habits and improving their health,” Moholdt says. “TRE is a less tedious and time-efficient method to lose weight compared with daily calorie counting, and HIIT is tolerable and safe for previously sedentary individuals and can be completed within 30-40 minutes.”

A limitation of the study was that the intervention period was only 7 weeks; longer-term investigations are needed to determine effects and feasibility for longer periods of time. The study also took place during COVID-19 lockdowns, which affected the participants’ lifestyles and could have influenced the results.

The researchers are currently inviting the participants back for follow-up testing 2 years after they completed the study to find out if they have continued with the interventions. They also plan to determine whether the combination of TRE and HIT will induce the same health benefits and have equally good adherence rates in a completely home-based setting. That study will include both men and women. “Together, these two new studies will tell us more about the long-term feasibility and also the possibility for implementation in a real-world setting,” Haganes says. “Additionally, we can investigate if there are any sex differences in response to these interventions.”

This research is supported by the Liaison Committee for Education, Research and Innovation in Central Norway, the EFSD/Novo Nordisk Foundation Future Leaders Awards Programme, the Norwegian University of Science and Technology (NTNU), and by a Novo Nordisk Foundation Challenge Grant.

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Time-restricted eating reduces cardiovascular health risks associated with shift work for firefighters

Source: Cell Press
Date: 10/4/2022
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Shift work has been linked to a number of health problems, including higher rates of diabetes, heart attacks, and other cardiometabolic diseases. But despite the known risks, little research has been done to identify lifestyle interventions that could help prevent these concerns. A new randomized, controlled clinical trial, published October 4 in Cell Metabolism, found that time-restricted eating (TRE) could be safely practiced in shift workers. Additionally, the researchers found that TRE provided benefits to participants who had indications of cardiometabolic disease. Called the Healthy Heroes Study, the intervention focused on San Diego firefighters.

“Shift work is much more common than many people think, affecting workers in a range of different fields as well as parents of newborn babies,” says co-corresponding author Satchidananda Panda, a professor at the Salk Institute and holder of the Rita and Richard Atkinson Chair. “Not only does shift work contribute to an increased burden of disease in our society, but it makes it hard for people with existing conditions like diabetes and cardiovascular disease to manage them.”

“Within the confines of shift work, there are many lifestyle interventions that can potentially optimize the health of shift workers,” says co-corresponding author Pam Taub, a cardiologist and professor in the University of California San Diego School of Medicine’s Division of Cardiovascular Medicine. “However, there are very few research studies on this population. Our study sheds light on one way that we can help this population.”

Panda and Taub have collaborated on research into TRE for several years. In January 2020, they published a study in Cell Metabolism that found that restricting the time of eating to 10 hours a day reduced body weight and improved blood pressure and cholesterol levels in people with metabolic syndrome. In the current study, they focused on TRE in shift workers. The trial recruited San Diego firefighters, who work 24-hour shifts. There were 137 firefighters ultimately enrolled in the study; 70 followed TRE, eating all of their meals within a 10-hour time window, and 67 were in the control group. All participants were encouraged to follow a Mediterranean diet that was rich in fruits, vegetables, whole grains, and healthy fats. The subjects were followed for 12 weeks.

One barrier to conducting research studies with shift workers has been the subjects’ inability to come to the lab during regular business hours. The researchers got around this by going to the fire stations to apply wearable devices on the participants to collect their activity, sleep, and blood glucose levels. They also customized an app that allowed the firefighters to log their food and sleep and answer study surveys; the app also enabled the researchers to send study materials and to guide the participants on following the recommended lifestyle.

The investigators found that for the firefighters, following a time-restricted eating pattern was both safe and feasible. The subjects didn’t report any problems with concentration, reaction times, or other issues. Their quality of life generally improved.

“Overall, firefighters are a pretty healthy group of people, but we found that for those who had underlying cardiometabolic risk factors like high blood pressure, high cholesterol, and hyperglycemia, there was some benefit to TRE, especially in terms of improvement in glucose levels and blood pressure,” Taub says. “Even those who were healthy with no underlying cardiomeatabolic risk factors had improvements in quality of life and in VLDL, which is a form of bad cholesterol.”

Taub and Panda say they would like to conduct similar research on other shift workers, especially healthcare workers, but it’s difficult to get funding for such studies.

“Humans have been living with circadian rhythms for at least 200,000 years, and these rhythms clearly have a profound effect on us,” Panda says. “Shift workers, whether they are astronauts or custodians, are vital to our society. It’s time to think about how we might help them improve their health.”

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Front-loading calories early in the day reduces hunger but does not affect weight loss

Source: Cell Press
Date: 9/9/2022
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There’s the old saying in dieting that one must “breakfast like a king, lunch like a prince, and dine like a pauper,” based on the belief that consuming the bulk of daily calories in the morning optimizes weight loss by burning calories more efficiently and quickly. But according to a new study publishing September 9 in Cell Metabolism, whether a person eats their largest meal early or late in the day does not affect the way their body metabolizes calories. However, people who ate their largest meal in the morning did report feeling less hungry later in the day, which could foster easier weight loss in the real world.

“There are a lot of myths surrounding the timing of eating and how it might influence either body weight or health,” says senior author Professor Alexandra Johnstone, a researcher in the field of appetite control at the Rowett Institute, University of Aberdeen, Scotland. “This has been driven largely by the circadian rhythm field. But we in the nutrition field have wondered how this could be possible. Where would the energy go? We decided to take a closer look at how time of day interacts with metabolism.”

In this study, the investigators recruited healthy subjects who were overweight or obese to have their diets controlled and their metabolisms measured over a period of time; 16 men and 14 women completed the study. Each participant was randomly assigned to eat either a morning-loaded or an evening-loaded diet for four weeks. The diets were isocaloric, with a balance of 30% protein, 35% carbohydrate, and 35% fat. After a washout period of one week in which calories were balanced throughout the day, each participant crossed over to the opposite diet for four weeks. In that way, each participant acted as their own study control.

Throughout the study, the subjects’ total daily energy expenditures were measured using the doubly labelled water method, an isotope-based technique that looks at the difference between the turnover rates of the hydrogen and oxygen of body water as a function of carbon dioxide production. The primary endpoint of the study was energy balance measured by body weight. Overall, the researchers found that energy expenditures and total weight loss were the same for the morning-loaded and evening-loaded diets. The subjects lost an average of just over 3 kg (about 7 pounds) during each of the four-week periods.

The secondary end points were subjective appetite control, glycemic control, and body composition. “The participants reported that their appetites were better controlled on the days they ate a bigger breakfast and that they felt satiated throughout the rest of the day,” Johnstone says. “This could be quite useful in the real-world environment, versus in the research setting that we were working in.”

One limitation of the study is that it was conducted under free-living conditions rather than in the lab. Additionally, certain metabolic measurements were available only after breakfast and not after dinner.

Johnstone notes that this type of experiment could be applied to the study of intermittent fasting (also called time-restricted eating), to help determine the best time of day for people following this type of diet to consume their calories.

The group plans to expand its research into how the time of day affects metabolism by conducting studies similar to the one described here in subjects who do shift work. It’s possible these individuals could have different metabolic responses due to the disruption of their circadian rhythms. “One thing that’s important to note is that when it comes to timing and dieting, there is not likely going to be one diet that fits all,” Johnstone concludes. “Figuring this out is going to be the future of diet studies, but it’s something that’s very difficult to measure.”

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Researchers call for a focus on fitness over weight loss for obesity-related health conditions

Source: Cell Press
Date: 9/20/2021
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The prevalence of obesity around the world has tripled over the past 40 years, and, along with that rise, dieting and attempts to lose weight also have soared. But according to a review article publishing September 20 in the journal iScience, when it comes to getting healthy and reducing mortality risk, increasing physical activity and improving fitness appear to be superior to weight loss. The authors say that employing a weight-neutral approach to the treatment of obesity-related health conditions also reduces the health risks associated with yo-yo dieting.

“We would like people to know that fat can be fit, and that fit and healthy bodies come in all shapes and sizes,” says co-author Glenn Gaesser of the College of Health Solutions at Arizona State University. “We realize that in a weight-obsessed culture, it may be challenging for programs that are not focused on weight loss to gain traction. We’re not necessarily against weight loss; we just think that it shouldn’t be the primary criterion for judging the success of a lifestyle intervention program.”

“This is especially important when you consider the physiological realities of obesity,” says co-author Siddhartha Angadi of the School of Education and Human Development at the University of Virginia. “Body weight is a highly heritable trait, and weight loss is associated with substantial metabolic alterations that ultimately thwart weight loss maintenance.”

Obesity is associated with a number of health conditions, including cardiovascular disease, diabetes, cancer, and problems with the bones and joints. But weight cycling, commonly called yo-yo dieting, is also associated with health problems, including muscle loss, fatty liver disease, and diabetes. The authors say that by focusing on fitness rather than weight loss, people can gain the benefits of exercise while avoiding the risks associated with weight cycling.

Current public health guidelines recommend that adults accumulate 150-300 minutes per week of moderate-intensity physical activity (the intensity equivalent to walking at casual-to-brisk pace) or 75-150 minutes per week of vigorous-intensity physical activity (the intensity equivalent to jogging or running). “But it’s important to note that the benefits of exercise are dose dependent, with the biggest benefits coming from just moving out of the couch-potato zone to doing at least some moderate-intensity activity,” Gaesser says. “It’s also important to emphasize that physical activity can be accumulated throughout the day. For example, multiple short walks during the day (even as short as two to ten minutes each) are just as beneficial as one long walk for health benefits.”

In the review, the authors cite recent research focused on the magnitude of mortality risk reduction associated with weight loss compared to that associated with an increase in physical activity or cardiorespiratory fitness. The risk reduction associated with increasing fitness and physical activity was consistently greater than that associated with intentional weight loss. They also looked at the magnitude of reduction in the risk markers of cardiovascular disease that are associated with either weight loss or increased physical activity. They used meta-analyses from several studies done over a range of time periods and across a broad geographical area. “Science has generally supported the main points proposed in Big Fat Lies, a book on this topic that I first published in 1996,” Gaesser notes.

The researchers acknowledge limitations in the existing body of research, including the fact that this field is heavily reliant on epidemiological studies that do not definitively establish cause and effect, and note that only large, randomized, controlled clinical trials can fully examine the outcomes of using a fitness-focused approach to optimize cardiometabolic mortality risk in people who are obese. “Collectively, however, these epidemiological studies demonstrate strong and consistent associations, and this is why meta-analyses can be useful,” Angadi says. “In the case of physical activity and fitness, the epidemiological evidence is supported by a large body of experimental studies and randomized controlled trials that have established plausible mechanisms for the consistent findings in epidemiological studies.”

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Translating Discoveries Into Better Treatments for IBD

Source: Brigham and Women's Hospital
Date: 5/16/2022
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Current treatments for inflammatory bowel disease (IBD) can help manage the disease’s effects, but improved treatments are desperately needed. To develop those treatments, it’s important to understand the underlying biological causes that drive different forms of IBD, including Crohn’s disease and ulcerative colitis.

Scott B. Snapper, MD, PhD, a physician-scientist in the Crohn’s and Colitis Center within the Division of Gastroenterology, Hepatology and Endoscopy at Brigham and Women’s Hospital, has devoted his research to this topic—both in the lab and the clinic. His current work focuses on determining the causes of IBD and employing novel animal models as well as direct human studies, including early-stage clinical trials, to study it.

“Since I began my research career, my goal has always been to better understand these diseases,” says Dr. Snapper, who trained as a microbiologist and immunologist in addition to training as a gastroenterologist. “All of that work has been leading up to developing new therapeutics.”

Mouse Models Reveal Disease Mechanisms

When Dr. Snapper started his research, there was a need for better animal models for studying IBD. One reason was that most cases of IBD are caused by numerous genetic factors. He realized that by studying the rare cases caused by single genes, he could pull apart the mechanisms that contribute to these conditions in more common cases as well.

“We use these rare examples to help us understand the cellular and molecular mechanisms and the host-microbial interactions that occur in all people who get Crohn’s disease and ulcerative colitis,” he says.

The first mouse model he worked with was one for Wiskott-Aldrich syndrome, a rare monogenic disease characterized by abnormal immune system function, among other issues. All the mice with the disease developed IBD. Today, there are more than 60 mouse models for studying different forms of IBD.

The Snapper Laboratory employs a number of basic, translational and clinical research strategies to understand and define not only the constituents but also the mechanisms that regulate intestinal homeostasis as it pertains to gastrointestinal health and IBD. Among the ongoing projects in his lab are the study of intestinal epithelial cells, immune cells and cytokines as well as translational work using humanized mice. This research is laying the foundation for the development of clinical trials.

Decoding the Underlying Causes of IBD

Among the findings that have come out of Dr. Snapper’s lab are that some cases of IBD presenting in very young children are caused by the absence of the interleukin-10 receptor.

“Patients lacking this receptor make a lot of the cytokine interleukin-1,” says Dr. Snapper, who is also chief of the Division of Gastroenterology, Hepatology and Nutrition and director of the Inflammatory Bowel Disease Center at Boston Children’s Hospital. “We’ve shown in early studies that in these patients, you can ameliorate much of their disease by blocking interleukin-1.”

Dr. Snapper says that this treatment has served as a bridge to offering bone marrow transplants for children with this rare immunodeficiency syndrome. He also notes ongoing efforts to identify subsets of all IBD patients with an enhanced interleukin-1 signature who might benefit from IL-1 blockade.

Research employing several mouse models of IBD, including the murine model of the Wiskott-Aldrich syndrome, has revealed another underlying mechanism of IBD, this one related to regulatory T cells.

“We’ve found in a novel humanized mouse model of IBD that you can expand regulatory T cells by giving low doses of interleukin-2 and improve disease,” Dr. Snapper says. This work has been used for treating graft-versus-host disease in patients who have undergone bone marrow transplants, but studies in mice suggest it could be an effective treatment for IBD as well.

Applying Lab Findings to Clinical Trials

At the 2021 Digestive Disease Week conference, Dr. Snapper and Brigham colleagues including Jessica R. Allegretti, MD, MPH, Vanessa Mitsialis, MD, Matthew J. Hamilton, MD, and Joshua R. Korzenik, MD, presented the results from an open-label, single-arm, phase 1b/2a trial that looked at whether subcutaneously administered, low-dose interleukin-2 is safe and results in a biological response. The study, which enrolled 26 patients with ulcerative colitis, showed that this treatment was well-tolerated, and was associated with a biological response and the expansion of regulatory T cells in patients with moderate to severely active ulcerative colitis.

“This treatment led to clinical improvement in more than 50% of the patients and complete remission in about a quarter of them,” Dr. Snapper says. “These are patients who had already failed multiple drugs.”

A new early-stage study has enrolled eight patients to look at whether expanding regulatory T cells with interleukin-2 can provide the same benefit in people with Crohn’s disease.

Outside of his clinical trials, Dr. Snapper was instrumental in establishing the Very Early Onset Inflammatory Bowel Disease (VEO-IBD) Consortium, an international group of investigators studying IBD in young children. The group includes scientists from North America, Europe, Australia, South America, Israel and the Middle East who are all focused on these efforts.

The VEO-IBD Consortium has identified numerous genetic defects that cause IBD and has developed novel therapeutic approaches. The group has received support from a number of philanthropies, including the Helmsley Charitable Trust and the National Institutes of Health, as well as support from the pharmaceutical and biotechnology industries.

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The Science of Eating Well: MSK Research Focuses on Nutrition after a Stem Cell Transplant

Source: Memorial Sloan Kettering - On Cancer
Date: 03/28/2018
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People who have stem cell and bone marrow transplants face many challenges. One obstacle that is often overlooked is the difficulty that many of them have eating well during and after the transplant process.

Now there is a new focus on nutrition during transplants, especially at Memorial Sloan Kettering. In fact, MSK researchers are leading work showing the role that a healthy diet plays in recovery. They are developing unique ways to help people who are having transplants maintain good nutrition.

We spoke with Marissa Buchan, a research nutritionist who works exclusively with the bone marrow transplant team, about how MSK is using science to ensure that patients have proper nutrition.

Why is it so hard for people undergoing transplants to eat a healthy diet?

There are several reasons why it’s challenging to eat a healthy diet while having a transplant. One is that they generally just don’t feel well, which decreases their appetite. On top of that, they often experience side effects of the treatments they are given, such as nausea, vomiting, diarrhea, or sores in the mouth and throat that can make eating difficult or painful.

Another big problem is that people undergoing transplants often report that their sense of taste has changed. Chemotherapy can affect the taste buds and other cells inside the mouth. This is something that we’ve known about for a while, but no one has ever done research to quantify it or to figure out what to do about it.

Can a change in taste be measured?

We’re starting to look at it. As far as we know, we’re the first ones ever to do so. Sergio Giralt [Chief of MSK’s Adult Bone Marrow Transplant Service], myself, and several others are conducting a study to measure which specific tastes are upset in people undergoing autologous transplants [transplants using their own blood stem cells].

We’re giving patients taste tests and using chemistry techniques to measure which flavors seem to have changed. Certain flavors may be lost. Others may become stronger. These changes can happen right away or down the road. Not only do we not know which specific flavors are involved but no one has ever studied how long it takes for these problems to get better. We also measure other factors related to taste, such as the amount of saliva produced and the bacteria in the mouth.

We don’t have any answers yet, but we’re starting to get good information. Our hope is that we can find new ways to develop a personalized diet for each person based on their individual taste changes and symptoms.

Why is maintaining good nutrition during a transplant so important?

I am currently leading a study to understand how diet affects the microbiota. This is the balance of microbes that live in the intestinal tract. I presented what I’ve found so far at the American Society for Blood and Marrow Transplantation’s annual meeting in February 2018.

Earlier studies done at MSK showed that the makeup of gut bacteria had a huge impact on outcomes after transplant. This included relapse, survival, and the development of graft-versus-host disease (GVHD). GVHD is a potentially fatal side effect in which the new blood cells attack the patient’s tissues. For example, the team found that if people maintain the naturally occurring intestinal bacteria Blautia, they are less likely to develop GVHD. The researchers discovered that Blautia is sensitive to the antibiotics that people are given during the course of treatment. It also declines in those who aren’t eating.

Our latest research is digging deeper into the role of nutrition in the maintenance of a healthy, diverse microbiota. We have found that people who eat fewer calories have decreased diversity in their intestinal flora. This decline happens even if they are not taking antibiotics. Our discovery shows the importance of maintaining a varied diet after a transplant. This practice can keep the gut active and preserve important flora, like Blautia.

What is MSK doing to change the way people who have transplants eat?

Because transplants increase the risk of infection, in the past we’ve recommended a low-microbial diet. This meant very few fruits and vegetables. Everything had to be well cooked. But our nutrition team came to realize that this diet was unnecessarily restrictive. After much review, we changed our official dietary recommendations last summer.

Our transplant patients are now allowed to eat raw fruits and vegetables, as long as they’re washed well. This diet gives them more options to maintain a healthy, varied diet while still emphasizing food safety to minimize the risk of foodborne illnesses.

In addition, nutrition has become an integral part of care at MSK. Everyone on the care team is focused on getting patients to eat, since they realize how important it is. During the transplant process, we tell patients that eating is one of their jobs.

Bone health can be a problem for some survivors. We recommend diets that are high in calcium, vitamin D, and other nutrients.

Other survivors may have changes in their metabolism that lead to diabetes or obesity. Our clinical dietitian-nutritionists and other experts can work with them to help maintain a healthy diet and lifestyle.

What’s your favorite recipe to give someone who is recovering from a stem cell transplant?

Our nutrition service has developed a whole menu of smoothies and other healthy recipes for people having cancer treatment, depending on their symptoms. One smoothie that’s especially good for people with GVHD is the apple pie smoothie.

These smoothie recipes are great for anyone having cancer treatment. In particular, those who may be experiencing nausea or diarrhea as a side effect of chemotherapy may find them helpful.

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Study in Mice Suggests Lactose in the Diet Feeds Dangerous Gut Bacteria When the Immune System Is Compromised

Source: Memorial Sloan Kettering - On Cancer
Date: 11/29/2019
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Infections with the Enterococcus bacterium are a major threat in healthcare settings. They can lead to inflammation of the colon and serious illnesses such as bacteremia and sepsis, as well as other complications.

Enterococcus infections are particularly risky for people having stem cell and bone marrow transplants (BMTs) to treat blood cancer. Studies have suggested that high levels of Enterococcus increase the incidence of graft-versus-host disease (GVHD), a potentially fatal condition in which immune cells from the donor’s stem cells attack the recipient’s organs.

Now, an international team led by scientists from Memorial Sloan Kettering has shown for the first time that foods containing lactose, a sugar that’s naturally found in milk and dairy products, help Enterococcus thrive in the gut, at least in mice. They also studied changes in the bodies of people having BMTs. The study was published November 29 in Science.

“These findings hint at a possible new way to reduce the risk of GVHD as well as dangerous infections,” says MSK physician-scientist and GVHD expert Jonathan Peled. “But they are still preliminary, and it’s too early to suggest cutting out lactose in the diets of people undergoing BMTs or other hospitalized patients who are at risk from Enterococcus.”

Focusing on the Microbiota

For several years, Dr. Peled and Marcel van den Brink, head of MSK’s Division of Hematologic Malignancies, have been studying the relationship between GVHD and microbiota — the community of microorganisms that inhabit the body. The two of them are co-senior authors of the new study.

Their previous research has shown that when harmless strains of microbes are wiped out, often due to treatment with antibiotics, Enterococcus and other harmful types of bacteria can take over due to lack of competition. As part of the new study, which included analysis of microbiota samples from more than 1,300 adults having BMTs, the team confirmed the link between Enterococcus and GVHD.

The investigators conducted further Enterococcus research in cell cultures and in mice. “Mouse models are very helpful for understanding the mechanisms in the gut that lead to GVHD,” says Dr. van den Brink, who is also Co-Director of the Parker Institute for Cancer Immunotherapy at MSK and leads a lab in the Sloan Kettering Institute’s Immunology Program. “We studied mice that had been given BMTs and found that the cells lining their intestines, called enterocytes, were no longer able to make lactase, the enzyme that breaks down lactose. The high levels of undigested lactose in turn led to a total domination of Enterococcus. It was shocking to see how one type of bacteria completely takes over.”

Dr. van den Brink adds that on top of the defective enterocytes, the loss of competing healthy strains of bacteria caused by antibiotic treatment makes problems in the gut even worse. “It’s a double whammy,” he says.

A Trip to the Pharmacy Leads to a Surprising Discovery

To study whether higher lactose levels were boosting the growth of Enterococcus, or whether the connection was only a coincidence, visiting researcher and first author Christoph Stein-Thoeringer went to the pharmacy to buy Lactaid®. These lactase-containing pills break down lactose, helping people who are lactose intolerant to eat dairy products without side effects.

The researchers discovered that when lactase was added to lab cultures of Enterococcus, the bacterial growth was blocked. So, they began to feed lactose-free chow to lab mice that had been given BMTs and found that mice on the special diet were protected against Enterococcus domination.

“We’re not suggesting this is a cure for GVHD,” Dr. van den Brink says. “But it appears to be an important modulator.”

The investigators have not yet tested the new findings in humans, but existing data suggests that the same connection between lactose and Enterococcus seen in the mice may be at play in people who have had BMTs. “We know which gene variants are associated with being lactose intolerant,” Dr. Peled notes. “We looked at our records and found that people who had these gene variants tended to have a harder time clearing Enterococcus from their guts than others did.”

He adds that many BMT recipients become temporarily lactose intolerant, likely due to the loss of enterocytes caused by chemotherapy. “We are considering doing a trial in which people eat a lactose-free diet or take Lactaid during their cancer treatment to see if the growth of Enterococcus is blocked,” Dr. Peled says.

A Global Effort

Another important aspect of the new study is that it didn’t just look at people treated at MSK. It also included patient samples from Duke University School of Medicine in Durham, North Carolina; Hokkaido University in Sapporo, Japan; and University Hospital Regensburg in Germany. Researchers from those three institutions also contributed to the Science paper.

“Researchers who study the microbiome know that the environment in which a person lives is a major factor,” Dr. van den Brink says. “We’ve made a major effort to collect samples from all over the world, so we know that when we find common features, they are likely to hold up worldwide.”

This work was supported by the German Research Foundation, a Young Investigator-Award from the American Society of Bone Marrow Transplantation, the Lymphoma Foundation, the Susan and Peter Solomon Divisional Genomics Program, the Parker Institute for Cancer Immunotherapy at MSK, the Sawiris Foundation, the Society of MSK, an MSK Cancer Systems Immunology Pilot Grant, the Empire Clinical Research Investigator Program, Seres Therapeutics, the Japan Society for the Promotion of Science, the Center of Innovation Program from Japan Science and Technology, a Conquer Cancer Foundation Young Investigator Award/Gilead Sciences, and more than a dozen National Institutes of Health grants (R01-CA228358, R01-CA228308, P30 CA008748, P01-CA023766, R01-HL125571, R01-HL123340, P01-AG052359, U01 AI124275, R01 AI032135, AI095706, U01 AI124275, KL2 TR001115-03, 2P30AG028716-11, R01CA203950-01, 1R01HL124112-01A, R01 CA203950-01).

Dr. Peled reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from DaVolterra. Dr. van den Brink has received research support from Seres Therapeutics; has consulted, received honorarium from, or participated in advisory boards for Seres Therapeutics, Flagship Ventures, Novartis, Evelo, Jazz Pharmaceuticals, Therakos, Amgen, Magenta Therapeutics, WindMIL Therapeutics, Merck & Co. Inc., Acute Leukemia Forum (ALF), and DKMS Medical Council (Board). He also has IP licensing with Seres Therapeutics and Juno Therapeutics and stock options from Smart Immune.

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Two studies explore whether time of day can affect the body’s response to exercise

Source: Cell Press
Date: 04/18/2019
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Two papers appearing April 18 in the journal Cell Metabolism confirm that the circadian clock is an important factor in how the body responds to physical exertion. The studies focused on different components of exercise, thereby complementing each other. Based on this work alone, it’s too early to say when the best time is for you to go for a jog. But at least in the lab, exercise in the evening seems to be more productive, although human lifestyles are much more complicated and so this area of research is only just beginning.

“It’s quite well known that almost every aspect of our physiology and metabolism is dictated by the circadian clock,” says Gad Asher of the Department of Biomolecular Sciences at the Weizmann Institute of Science, who is senior author of one of the studies. “This is true not only in humans but in every organism that is sensitive to light. We decided to ask whether there is a connection between the time of day and exercise performance.”

“Circadian rhythms dominate everything we do,” adds Paolo Sassone-Corsi of the Center for Epigenetics and Metabolism at the University of California, Irvine, who is senior author of the other paper. “Previous studies from our lab have suggested that at least 50% of our metabolism is circadian, and 50% of the metabolites in our body oscillate based on the circadian cycle. It makes sense that exercise would be one of the things that’s impacted.”

Both research teams looked at the association between time of day and exercise performance primarily in mice. Because mice are nocturnal, one thing they had to do was translate mouse timing to human timing, by distinguishing between the active phase and resting phase of the mice rather than using numbers on the clock.

Asher’s group started by putting mice in treadmills at different times of day within their active phase. They examined the exercise capacity of mice upon different exercise intensities and regimens and found that overall exercise performance is substantially better (about 50% on average and more in some protocols) in the “mouse evening” (toward the end of their active time) compared to the morning hours. These daily differences were diminished in mice that had mutant clocks–supporting a potential role of the clock in the observed variance in exercise performance.

To identify a potential determinant of daily variance in exercise performance, they applied high-throughput transcriptomics and metabolomics on muscle tissue. The researchers found that in response to exercise in the “mouse evening,” there were higher levels of a metabolite called ZMP (5-aminoimidazole-4-carboxamide ribonucleotide). ZMP is known to activate metabolic pathways that are related to glycolysis and fatty acid oxidation through activation of AMPK, which is a master cellular metabolic regulator. Therefore, it is likely to contribute to the increased exercise capacity in the evening. “Interestingly, ZMP is an endogenous analog of AICAR [aminoimidazole carboxamide riboside], a compound that some athletes use for doping,” Asher says.

The researchers also studied 12 humans and found similar effects. Overall, the people in the study had lower oxygen consumption while exercising in the evening compared with the morning; this translated to better exercise efficiency.

Sassone-Corsi’s team also put mice on treadmills, but they had a different approach. Using high-throughput transcriptomics and metabolomics to look at a wide range of possible factors, they characterized the changes in the mice’s muscle tissue that occur in response to exercise. This allowed them to look at processes like glycolysis (which contributes to sugar metabolism and energy production) and lipid oxidation (fat burning).

They found that a protein called hypoxia-inducible factor 1-alpha (HIF-1α) plays an important role and that it is activated by exercise in different ways depending on the time of day. HIF-1α is a transcription factor that is known to stimulate certain genes based on oxygen levels in tissue. “It makes sense that HIF-1α would be important here, but until now we didn’t know that its levels fluctuate based on the time of day,” Sassone-Corsi says. “This is a new finding.”

Based on the work from the UC Irvine team, exercise seemed to have the most beneficial impact on the metabolism at the beginning of the active phase phase (equivalent to late morning in humans) compared with the resting phase (evening).

The researchers note that even though circadian clocks have been conserved throughout evolution, translating the findings to humans is not so straightforward. One reason is that humans have more variation in their chronotypes than mice living in a lab. “You may be a morning person, or you may be a night person, and those things have to be taken into account,” Sassone-Corsi says.

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Cell Metabolism, Ezagouri, Zwighaft, and Sobel et al.: “Physiological and Molecular Dissection of Daily Variance in Exercise Capacity” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30141-X DOI: 10.1016/j.cmet.2019.03.012

This study was supported by the European Research Council and an EMBO Young Investigator Award. It was also supported by Fonds de Dotation AGIR pour les Maladies Chroniques and a fellowship from the Placid Nicod Foundation.

Cell Metabolism, Sato et al.: “Time of Exercise Specifies the Impact on Muscle Metabolic Pathways and Systemic Energy Homeostasis” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30183-4 DOI: 10.1016/j.cmet.2019.03.013

This study was supported by the Novo Nordisk Foundation, the Swedish Diabetes Foundation, the Swedish Research Council, the National Institutes of Health, INSERM, and the Della Martin Foundation.

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Controlled study links processed food to increased calorie consumption

Source: Cell Press
Date: 05/16/2019
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Experts have long suspected that increased consumption of processed foods over the past 50 years has been a primary driver of the obesity epidemic. But because studying dietary habits is complicated, it’s been difficult to make a direct connection.

On May 16 in the journal Cell Metabolism, researchers report results from the first randomized, controlled trial that directly compared differences in calorie consumption and weight gain between an ultra-processed and an unprocessed diet. The team found that even when the two diets were matched for the amount of presented carbohydrates, fat, sugar, salt, and calories, people consumed more food and gained weight on an ultra-processed diet.

“I was surprised by the findings from this study, because I thought that if we matched the two diets for components like sugars, fat, carbohydrates, protein, and sodium, there wouldn’t be anything magical about the ultra-processed food that would cause people to eat more,” says lead author Kevin Hall, a section chief in the Laboratory of Biological Modeling at the National Institute of Diabetes and Digestive and Kidney Diseases within the National Institutes of Health. “But we found that, in fact, people ate many more calories on the ultra-processed diet, and this caused them to gain weight and body fat.”

The study enrolled 20 healthy volunteers who were admitted to the NIH’s Metabolic Clinical Research Unit for a month. Each participant was given either an ultra-processed diet or an unprocessed diet for two weeks, and then switched. The participants were given three meals a day and had access to bottled water and either ultra-processed or unprocessed snacks throughout the day. They were told they could eat as much as they wanted, and the quantities they consumed were measured.

The researchers used the NOVA food classification system, which categorizes foods according to the extent and purpose of processing, to develop the two diets. For example, one ultra-processed breakfast consisted of Honey Nut Cheerios, whole milk with added fiber, a packaged blueberry muffin, and margarine; an unprocessed one was a parfait made with plain Greek yogurt, strawberries, bananas, walnuts, salt, and olive oil and apple slices with fresh-squeezed lemon. Participants reported that both diets tasted good and were satisfying, eliminating food preference as a factor.

During the two weeks that they were given ultra-processed food, the people in the study consumed an average of 508 calories more per day, compared with the days they got unprocessed food. Two weeks on the ultra-processed diet resulted in an average weight gain of two pounds, compared with an average weight loss of two pounds for the two weeks on the unprocessed diet. The volunteers gained body fat on the ultra-processed diet and lost it on the unprocessed diet.

Metabolic testing revealed that when participants ate the ultra-processed diet, they expended more energy than when they ate the unprocessed diet, but not enough to make up for the increased number of calories they consumed. Because the participants were healthy and the testing period lasted only a month, the investigators didn’t see significant differences in other measures of health, such as liver fat or blood glucose.

The researchers have several hypotheses for why the people on the ultra-processed diet consumed more food.

When people were on the ultra-processed diet, they ate faster. “There may be something about the textural or sensory properties of the food that made them eat more quickly,” Hall says. “If you’re eating very quickly, perhaps you’re not giving your gastrointestinal tract enough time to signal to your brain that you’re full. When this happens, you might easily overeat.”

Another hypothesis is the role of solid foods versus beverages. To balance the dietary fiber and match the calorie density of the overall diets, drinks were added to the ultra-processed meals, such as juice and lemonade, that had added fiber. But some researchers believe that beverages don’t contribute to satiety the same way that solid foods do. So, the higher calorie density of the solid foods in the ultra-processed diet could have led people to increase their overall calorie intake.

A third factor could be that although the diets were matched as closely as possible, the unprocessed diet contained slightly more protein, about 15.6% of calories versus 14% for the ultra-processed diet. “It could be that people ate more because they were trying to reach certain protein targets,” Hall says.

Future studies will try to account for these factors and explore the possible mechanisms behind the increase in calorie consumption.

The investigators note one important limitation of the study: because all the food was prepared for the participants, it didn’t take into account how convenient they were to make or how much they cost.

“We know there are a lot of factors that contribute to why someone might choose an ultra-processed meal over an unprocessed one,” Hall says. “For people in lower socio-economic brackets especially, we need to be mindful of the skills, equipment, knowledge, and expense needed to create unprocessed meals.”

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This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

Cell Metabolism, Hall et al.: “Ultra-processed diets cause excess calorie intake and weight gain: An inpatient randomized controlled trial of ad libitum food intake” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30248-7