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.

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.

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.

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

Gut microbes respond differently to foods with similar nutrition labels

Source: Cell Press
Date: 06/12/2019
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Foods that look the same on nutrition labels can have vastly different effects on our microbiomes, report researchers in a paper publishing June 12 in the journal Cell Host & Microbe. The researchers’ observations of participants’ diets and stool samples over the course of 17 days suggested that the correlation between what we eat and what’s happening with our gut microbes might not be as straightforward as we thought. This adds an increased level of complexity to research focused on improving health by manipulating the microbiome.

“Nutrition labels are human-centric,” says senior author Dan Knights (@KnightsDan), of the Department of Computer Science and Engineering and the BioTechnology Institute at the University of Minnesota. “They don’t provide much information about how the microbiome is going to change from day to day or person to person.”

In the study, the investigators enrolled 34 participants to record everything they ate for 17 days. Stool samples were collected daily, and shotgun metagenomic sequencing was performed. This allowed the researchers to see at very high resolution how different people’s microbiomes, as well as the enzymes and metabolic functions that they influence, were changing from day to day in response to what they ate. It provided a resource for analyzing the relationships between dietary changes and how the microbiome changes over time.

“We expected that by doing this dense sampling–where you could see what people were eating every single day and what’s happening to their microbiome–we would be able to correlate dietary nutrients with specific strains of microbes, as well as account for the differences in microbiomes between people,” Knights says. “But what we found were not the strong associations we expected. We had to scratch our heads and come up with a new approach for measuring and comparing the different foods.”

What the researchers observed was a much closer correspondence between changes in the diet and the microbiome when they considered how foods were related to each other rather than only their nutritional content. For example, two different types of leafy greens like spinach and kale may have a similar influence on the microbiome, whereas another type of vegetable like carrots or tomatoes may have a very different impact, even if the conventional nutrient profiles are similar. The researchers developed a tree structure to relate foods to each other and share statistical information across closely related foods.

Two people in the study consumed nothing but Soylent, a meal replacement drink that is popular with people who work in technology. Although it was a very small sample, data from these participants showed variation in the microbiome from day to day, suggesting that a monotonous diet doesn’t necessarily lead to a stable microbiome.

“The microbiome has been linked to a broad range of human conditions, including metabolic disorders, autoimmune diseases, and infections, so there is strong motivation to manipulate the microbiome with diet as a way to influence health,” Knights concludes. “This study suggests that it’s more complicated than just looking at dietary components like fiber and sugar. Much more research is needed before we can understand how the full range of nutrients in food affects how the microbiome responds to what we eat.”

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This work was supported by General Mills Inc.

Cell Host & Microbe, Johnson et al.: “Daily longitudinal sampling reveals personalized diet-microbiome associations.” https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(19)30250-1

Clinical trial shows alternate-day fasting a safe alternative to caloric restriction

Source: Cell Press
Date: 08/27/2019
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In recent years there has been a surge in studies looking at the biologic effects of different kinds of fasting diets in both animal models and humans. These diets include continuous calorie restriction, intermittent fasting, and alternate-day fasting (ADF). Now the largest study of its kind to look at the effects of strict ADF in healthy people has shown a number of health benefits. The participants alternated 36 hours of zero-calorie intake with 12 hours of unlimited eating. The findings are reported August 27 in the journal Cell Metabolism.

“Strict ADF is one of the most extreme diet interventions, and it has not been sufficiently investigated within randomized controlled trials,” says Frank Madeo, a professor of the Institute of Molecular Biosciences at Karl-Franzens University of Graz in Austria. “In this study, we aimed to explore a broad range of parameters, from physiological to molecular measures. If ADF and other dietary interventions differ in their physiological and molecular effects, complex studies are needed in humans that compare different diets.”

In this randomized controlled trial, 60 participants were enrolled for four weeks and randomized to either an ADF or an ad libitum control group, the latter of which could eat as much as they wanted. Participants in both groups were all of normal weight and were healthy. To ensure that the people in the ADF group did not take in any calories during fast days, they underwent continuous glucose monitoring. They were also asked to fill in diaries documenting their fasting days. Periodically, the participants had to go to a research facility, where they were instructed on whether to follow ADF or their usual diet, but other than that they lived their normal, everyday lives.

Additionally, the researchers studied a group of 30 people who had already practiced more than six months of strict ADF previous to the study enrollment. They compared them to normal, healthy controls who had no fasting experience. For this ADF cohort, the main focus was to examine the long-term safety of the intervention.

“We found that on average, during the 12 hours when they could eat normally, the participants in the ADF group compensated for some of the calories lost from the fasting, but not all,” says Harald Sourij, a professor at the Medical University of Graz. “Overall, they reached a mean calorie restriction of about 35% and lost an average of 3.5 kg [7.7 lb] during four weeks of ADF.”

The investigators found several biological effects in the ADF group:

* The participants had fluctuating downregulation of amino acids, in particular the amino acid methionine. Amino acid restriction has been shown to cause lifespan extension in rodents.

  • They had continuous upregulation of ketone bodies, even on nonfasting days. This has been shown to promote health in various contexts.
  • They had reduced levels of sICAM-1, a marker linked to age-associated disease and inflammation.
  • They had lowered levels of triiodothyronine without impaired thyroid gland function. Previously, lowered levels of this hormone have been linked to longevity in humans.
  • They had lowered levels of cholesterol.
  • They had a reduction of lipotoxic android trunk fat mass–commonly known as belly fat.

“Why exactly calorie restriction and fasting induce so many beneficial effects is not fully clear yet,” says Thomas Pieber, head of endocrinology at the Medical University of Graz. “The elegant thing about strict ADF is that it doesn’t require participants to count their meals and calories: they just don’t eat anything for one day.”

The investigators point to other benefits that ADF may have, compared with continuous calorie restriction. Previous studies have suggested calorie-restrictive diets can result in malnutrition and a decrease in immune function. In contrast, even after six months of ADF, the immune function in the participants appeared to be stable.

“The reason might be due to evolutionary biology,” Madeo explains. “Our physiology is familiar with periods of starvation followed by food excesses. It might also be that continuous low-calorie intake hinders the induction of the age-protective autophagy program, which is switched on during fasting breaks.”

Despite the benefits, the researchers say they do not recommend ADF as a general nutrition scheme for everybody. “We feel that it is a good regime for some months for obese people to cut weight, or it might even be a useful clinical intervention in diseases driven by inflammation,” Madeo says. “However, further research is needed before it can be applied in daily practice. Additionally, we advise people not to fast if they have a viral infection, because the immune system probably requires immediate energy to fight viruses. Hence, it is important to consult a doctor before any harsh dietary regime is undertaken.”

In the future, the researchers plan to study the effects of strict ADF in different groups of people including people with obesity and diabetes. They also plan to compare ADF to other dietary interventions and to further explore the molecular mechanisms in animal models.

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The research was primarily funded by the Austrian Science Fund; the Austrian Federal Ministry of Education, Science and Research; the University of Graz, and the field of excellence program BioHealth. Additional funding and declarations of interests can be found in the study.

Cell Metabolism, Stekovic, Hofer, and Tripolt et al.: “Alternate day fasting improves physiological and molecular markers of aging in healthy, non-obese humans.” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30429-2

Researchers alter mouse gut microbiomes by feeding good bacteria their preferred fibers

Source: Cell Press
Date: 09/19/2019
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Humans choose food based on the way it looks, smells, and tastes. But the microbes in our guts use a different classification system–one that is based on the molecular components that make up different fibers. In a study published September 19 in the journal Cell, investigators found particular components of dietary fiber that encourage growth and metabolic action of beneficial microbes in the mouse gut.

The research aims to develop ways to identify compounds that can enhance the representation of health-promoting members of the gut microbial community. The goal is to identify sustainable, affordable dietary fiber sources for incorporation into next-generation, more nutritious food products.

“Fiber is understood to be beneficial. But fiber is actually a very complicated mixture of many different components,” says senior author Jeffrey Gordon, a microbiologist at the Washington University School of Medicine in St. Louis. “Moreover, fibers from different plant sources that are processed in different ways during food manufacturing have different constituents. Unfortunately, we lack detailed knowledge of these differences and their biological significance. We do know that modern Western diets have low levels of fiber; this lack of fiber has been linked to loss of important members of the gut community and deleterious health effects.”

The researchers started by testing 34 food-grade fiber preparations, many purified from byproducts of food manufacturing such as peels from fruits and vegetables that are thrown out during production of processed foods and drinks. They used mice initially raised under sterile conditions and then colonized with human gut microbes. The animals were fed a high-fat, low-fiber diet representative of diets typically consumed in the United States, with or without different types of supplemental fibers. The goal was to identify those fibers that were best at boosting the levels of key fiber-degrading bacterial species and promoting the expression of beneficial metabolic enzymes in the microbiome.

Since the mice had been colonized with a defined collection of human gut bacteria with sequenced genomes, the researchers knew all the genes that were present in their model human gut microbial community. This allowed them to perform a comprehensive, high-resolution proteomics study of all bacterial proteins whose expression changed in response to the different fiber types they tested. Combining these results with genetic screens, they were able to identify particular fiber sources, their bioactive molecular components, and the bacterial genes that increased for different Bacteroides species when they encountered different fibers. They focused on Bacteroides because members of this group of bacterial species contain genes responsible for metabolizing dietary fiber that are not present in the human genome.

For the second phase of the study, the investigators wanted to determine how different members of the microbial community interact with each other as they dine on dietary fiber. First author Michael Patnode, a postdoctoral fellow in Gordon’s lab, developed fluorescently labeled artificial food particles with different types of bound carbohydrates from different fibers. Collections of these nutrient-containing particles were fed to mice colonized with defined microbial communities containing different combinations of Bacteroides species.

“We were excited to see how these ‘biosensors’ could be used to assess the processing of particular fiber components by particular bacterial species,” Patnode says. By feeding these particles to mice that either carried or did not carry a dominant fiber-consuming species, the authors found that subordinate species were waiting in line to step up and consume the fiber.

“We had suspected there might be competition going on among the different strains and that some would be stronger competitors than others,” Patnode says. Proteomics analyses and genetic screens confirmed that there was a hierarchy of fiber consumption among the species present in this model bacterial community.

Gordon explains that “it’s important to understand how the presence of a particular organism affects the dining behavior of other organisms–in this case, with regard to different fibers. If we are going to develop microbiota-directed foods aimed at providing benefits to human health, it’s important to find ways to determine which food staples will be the best source of nutrients and how the microbiota will respond.”

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This work was supported by the National Institutes of Health, Mondelez International, and the U.S. Department of Energy. Gordon is a co-founder of Matatu, Inc., a company characterizing the role of diet-by-microbiota interactions in animal health. Elements of this report are the subject of patent applications that are currently being submitted.

Cell, Patnode et al.: “Interspecies competition impacts targeted manipulation of human gut bacteria by fiber-derived glycans” https://www.cell.com/cell/fulltext/S0092-8674(19)30899-2

Pilot study finds time-restricted eating has benefits for people at risk for diabetes

Source: Cell Press
Date: 12/05/2019
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Previous studies have looked at employing time-restricted eating (TRE), a form of intermittent fasting, as a way to lose weight and improve health measures such as blood sugar and blood pressure in mice and healthy people. But in a study publishing December 5 in the journal Cell Metabolism, researchers for the first time looked at the effects of TRE in people who had been diagnosed with metabolic syndrome and therefore were at a higher risk of diabetes, heart disease, and stroke. The investigators found that when participants restricted their eating to 10 hours or less over a period of 12 weeks, they lost weight and some symptoms of metabolic syndrome improved.

“There has been a lot of discussion about intermittent fasting and what time window people should eat within to get the benefits of this kind of diet,” says co-corresponding author Satchidananda Panda, a Professor at the Salk Institute. “Based on what we’ve observed in mice, a 10-hour time window seems to convey these benefits. At the same time, it’s not so restrictive that people can’t follow it long-term.”

Metabolic syndrome is characterized by having three or more of five specific risk factors: high fasting blood sugar, high blood pressure, high triglyceride levels, low HDL (“good”) cholesterol, and abdominal obesity. People with metabolic syndrome are at greatly increased risk of developing more severe health problems, including diabetes, heart disease, and stroke.

“As a preventive cardiologist, I try to work with my patients and encourage them to make lifestyle changes, but it is very hard to get them to make lasting and meaningful changes,” says co-corresponding author Pam Taub, a cardiologist and Associate Professor of Medicine at the University of California San Diego School of Medicine. “When someone has been diagnosed with metabolic syndrome, this is a critical window for intervention. Once people become diabetic or are on multiple medications such as insulin, it’s very hard to reverse the disease process.”

In the study, 19 individuals with metabolic syndrome were recruited to participate in a program of TRE for three months. They were told they could decide what time to eat and how much to eat as long as all food consumption occurred within a 10-hour window. Most of the people in the study were obese and 84% were taking at least one medication, like a statin or antihypertensive.

At the end of the 12 weeks, the participants had an average of a 3% reduction in their weight and body mass index (BMI) and a 3% reduction in abdominal/visceral fat. Many also had reductions in cholesterol and blood pressure and improvements in fasting glucose.

Participants in the study used an app created by Panda called myCircadianClock (mCC) to log the times they ate and also to track their sleep. They also wore activity monitors that measured their sleeping and waking patterns and a glucose monitor that continuously tracked their glucose levels.

“We told people that they could choose when they ate their meals, as long as they remained within the 10-hour window,” Panda says. “We found that universally, they chose to eat breakfast later, about two hours after waking, and to eat dinner earlier, about three hours before going to bed.” He notes that in addition to the improvements seen in body weight and measures of metabolic syndrome, 70% of the participants also reported an increase in sleep satisfaction or in the amount they slept.

Taub says that the participants, about half of whom were already her patients, also reported generally having more energy, and some were able to have their medications lowered or stopped after completing the study. Overall, they told her that the plan was easier to follow than counting calories or embarking on an exercise program. More than two-thirds of participants continued with TRE for up to a year after the study was over, at least part of the time, she says.

Based on this pilot study, Taub and Panda have already begun a randomized, controlled clinical trial funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to confirm the benefits of TRE in people with metabolic syndrome. They plan to recruit more than 100 participants–half for each arm. They also intend to conduct additional research to look at other physiological responses to TRE, including effects on the mitochondria in skeletal muscle and changes in liver function.

For anyone considering trying TRE, Taub recommends they first consult with a physician. This is especially important for anyone with metabolic syndrome who is already taking medication, she notes. “Any time someone is losing weight, they need to check with their doctor about whether their medications need to be adjusted,” she says. “For instance, if a patient is on blood pressure medications and they lose a significant amount of weight their blood pressure medication needs to be lowered.”

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This study was funded by a University of California San Diego Public Health Pilot Grant, an American College of Cardiology (ACC)/Merck Research Fellowship Award, a Larry L. Hillblom Foundation Postdoctoral Fellowship, a Salk Women in Science Fellowship, the Department of Homeland Security, the Department of Defense, the Leona M. and Harry B. Helmsley Charitable Trust, the Robert Wood Johnson Foundation, and the National Institutes of Health.

Cell Metabolism, Wilkinson et al.: “Ten-hour time-restricted eating reduces weight, blood pressure, and atherogenic lipids in patients with metabolic syndrome” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30611-4

Food Safety during COVID-19: What People with Cancer Should Know

Source: Memorial Sloan Kettering
Date: 04/21/2020
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During the COVID-19 pandemic, we’ve been told to wash our hands frequently, sanitize surfaces, and not touch our faces. On top of that, conflicting reports are circulating online about how to safely handle the food that we’re bringing into our homes.

The challenges of safely buying groceries and getting takeout may be even greater for people with cancer and cancer survivors, who often have weakened immune systems. This makes it harder for their bodies to fight off infections, including COVID-19. It’s important that people with cancer closely follow steps to protect themselves while still getting proper nutrition.

Memorial Sloan Kettering clinical dietitian Cara Anselmo offers guidance for people with cancer and their families on how to carefully get and prepare food during the COVID-19 pandemic.

What safety measures should you take while grocery shopping?

If you are in active treatment for cancer or you have a weakened immune system because of a cancer history or other medical conditions, it’s better to have someone else in your household or a neighbor or friend go to the store for you, or use a delivery service. That’s the most important way you can avoid exposure to COVID-19 or other infectious germs.

But if you do have to go to the store, here are some important tips:

  • Take a grocery list. Before you go, figure out exactly what you need so you can get in and get out fast. This also helps minimize the number of shopping trips.
  • Bring sanitizing wipes to disinfect the handle of the shopping cart or basket.
  • Don’t browse with your hands. When you are at the store, avoid touching food or other products that you don’t intend to buy.
  • Cover your face with a scarf or cloth mask. (In early April, the Centers for Disease Control and Prevention recommended that all Americans wear a face covering to protect themselves from COVID-19.) If you need to adjust your mask, be careful not to touch the part that touches your face.
  • Check to see if your store has special hours for people who are immunocompromised and read the store’s policies on how many shoppers are allowed inside at once. While you are in the store, be careful to maintain a proper distance of six feet from others.

Do you need to disinfect your groceries after bringing them into your home?

At this time, experts are not aware of COVID-19 being spread by food or food packaging. But it’s still important to carefully wash your hands before and after grocery shopping. You should also wash your hands after putting your groceries away.

If you are concerned about the surfaces of packages, you can use disinfectant products to wipe them off. Fresh fruits and vegetables should be carefully washed with running water. Never use Lysol or bleach on fruits and vegetables, since the chemicals could be ingested.

How can you safely get takeout or food delivery from restaurants?

A lot of the advice for grocery shopping is the same for getting takeout or delivery: You should wash your hands before and after touching bags and food packages from restaurants, and before eating.

If you are picking up takeout, make sure you maintain safe distances. If you are getting delivery, pay in advance and ask the delivery person to leave the food outside your door to minimize person-to-person contact.

With either takeout or delivery, you should always transfer food to your own plates and dishes.

People whose immune systems are compromised by cancer or cancer treatment should be careful about eating certain foods from restaurants. This includes things like prepared salads, cut fruit, and deli meats. This is important to avoid food poisoning and not specifically because of COVID-19.

Do you have tips for healthy eating during the COVID-19 pandemic?

If you can’t get fresh produce, frozen or canned fruits and vegetables can be just as healthy. If you normally buy organic foods and you are not able to get them, don’t worry. Organic foods are not necessarily healthier or safer than conventional foods.

In this time of stress and uncertainty, it’s especially important to practice mindful eating. That means you should only eat when you’re hungry. Don’t eat so much that you feel too full. Do the best you can to include plenty of fruits and vegetables, but give yourself permission to eat what tastes good and feels good in your body. There’s no such thing as a perfect diet.

Some dietary supplements are claiming that they improve your immune function and offer protection against COVID-19. What do we know about these products?

Some of these products may be dangerous and potentially even life-threatening. The government has issued warning letters to many companies making these claims about their products.

There have been claims that some familiar supplements, including vitamin C and zinc, may “boost” your immune system. Some studies show that these supplements stimulate the immune system, but the evidence is inconclusive. They can also lead to unwanted effects.

Make sure you talk to your doctor, nurse, or registered dietitian before taking any supplements. Some of these products may also interfere with cancer treatment.

The best way to keep your immune system strong is to eat a balanced diet, limit alcohol, stay hydrated, manage stress, stay as physically active as you can, and get enough sleep.

During this difficult time, many people may be struggling to put food on the table. What are some good resources for MSK patients and their families?

MSK’s Food to Overcome Outcome Disparities program connects patients with a variety of emergency food resources. This includes a food pantry that MSK operates for patients and their families. If you would like more information, you can discuss it with your MSK care team or call MSK’s nutrition office at 212-639-7312.

New York City is offering three free meals per day for both children and adults, with pickup at more than 400 sites. People who are age 60 and older and need assistance can also get home-delivered meals

Artificial sweeteners combined with carbs may be more harmful than those sweeteners alone

Source: Cell Press
Date: 03/03/2020
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The influence of artificial sweeteners on the brain and ultimately metabolism has been hotly debated in recent years. Some studies have found adverse effects on blood sugar and insulin levels, while others have not. In a study publishing March 3 in the journal Cell Metabolism, researchers say the discrepancies in these studies may be due to how the sweeteners are consumed–or, more specifically, what they are consumed with.

Investigators report that the artificial sweetener sucralose seems to have no negative impact on its own, but when it is consumed with a carbohydrate, it induces deleterious changes in insulin sensitivity and decreases the brain’s response to sweet taste as measured by fMRI.

“When we set out to do this study, the question that was driving us was whether or not repeated consumption of an artificial sweetener would lead to a degrading of the predictive ability of sweet taste,” says senior author Dana Small, a neuroscientist who is a professor of psychiatry and the director of the Modern Diet and Physiology Research Center at Yale University. “This would be important because sweet-taste perception might lose the ability to regulate metabolic responses that prepare the body for metabolizing glucose or carbohydrates in general.”

The trial enrolled 45 volunteers between the ages of 20 and 45 who didn’t normally consume low-calorie sweeteners. All of them were of healthy weight and had no metabolic dysfunction. Other than consuming seven beverages in the lab over a two-week period, they didn’t make any changes to their diet or other habits. The investigators conducted studies on the volunteers before, during, and after the testing period, including performing fMRI scans to look at changes in the brain in response to sweet tastes, as well as other tastes like salty and sour. They also measured taste perception and did an oral glucose tolerance test to look at insulin sensitivity.

The sweeteners were consumed as fruit-flavored beverages with added sucralose, or with table sugar for comparison. In what was intended to be a control group: some of the volunteers had the carbohydrate maltodextrin added to their sucralose drinks. The researchers chose maltodextrin, a non-sweet carbohydrate, to control for the calories of sugar without adding more sweet taste to the beverage. Surprisingly, it was this control group that showed changes in the brain’s response to sweet taste and the body’s insulin sensitivity and glucose metabolism. Given the surprising result, the researchers added a second control group, in which the participants drank beverages with maltodextrin alone. They found no evidence that consuming maltodextrin-containing beverages over the seven-day period alters insulin sensitivity and glucose metabolism.

“Perhaps the effect resulted from the gut generating inaccurate messages to send to the brain about the number of calories present,” Small says. “The gut would be sensitive to the sucralose and the maltodextrin and signal that twice as many calories are available than are actually present. Over time, these incorrect messages could produce negative effects by altering the way the brain and body respond to sweet taste.”

She notes that a subset of the previous studies of artificial sweeteners have involved mixing the sweeteners with plain yogurt, adding carbohydrates from the yogurt and leading to the same effects seen here as with the maltodextrin. This could explain why previous findings about artificial sweeteners have been in conflict with each other.

Small says that her team began doing similar studies in adolescents, but they ended the trial early when they saw that two of the kids who were getting the sucralose-carbohydrate combination had their fasting insulin skyrocket.

“Previous studies in rats have shown that changes in the ability to use sweet taste to guide behavior can lead to metabolic dysfunction and weight gain over time. We think this is due to the consumption of artificial sweeteners with energy,” she notes.

Future studies will look at whether other artificial sweeteners, as well as more natural sweeteners like stevia, have the same effects as sucralose. Small expects that many of them will. “It’s hard to say, because we still don’t fully understand the mechanism,” she concludes. “That’s also something we hope to study further, especially in mice.”

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This work was supported by the National Institutes of Health.

Cell Metabolism, Dalenberg et al.: “Short-term consumption of sucralose with, but not without, carbohydrate impairs neural and metabolic sensitivity to sugar” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30057-7