On March 30 a series of speakers made clear that maternal nutrition interventions must start earlier, beginning in the preconception period, to achieve better birth outcomes. The symposium was called “Do We Need Preconception Nutrition Interventions to Improve Birth Outcomes Beyond the Prevention of Neural Tube Defects?”
Janet King of UC-Berkeley and Davis began with a review of the evidence related to maternal nutrition in the preconception period. She explained that a woman's preconception nutritional status has an impact on fetal growth, affecting both linear growth and birthweight. One mechanism for this relationship is through the placenta, which responds to undernutrition with altered expression and activity of nutrient transporters, increased oxidative stress, epigenetic modification of placental genes, and abnormal villous branching. Maternal nutritional status, in turn, can be influenced by a number of factors, including the inter-pregnancy interval and maternal age.
Next, speakers presented two examples of interventions targeting maternal nutrition during the preconception period. Usha Ramakrishnan of Emory University and Phuong Nguyen of Thai Nguyen University (Viet Nam) spoke about a study in Viet Nam, while Caroline Fall of the University of Southampton (UK) described a project in India. In Viet Nam, mothers were given micronutrient supplements in pill form. In India, the research team developed 70 recipes for micronutrient-rich snacks, which were then delivered to women six days a week. The study in Viet Nam observed no impact on birth outcomes. Results from India indicated that birthweight was higher in treatment than control groups, but this difference was not significant. Still, these studies represented an important starting point in the relatively under-studied area of preconception nutrition interventions.
Finally, Luz María DeRegil of Micronutrient Initiative spoke about the research and policy gaps related to preconception nutrition. She emphasized the need for more data on interventions, pointing out that while a great deal of evidence exists for some interventions, such as salt iodization, many others still need to be rigorously evaluated. In particular, a need exists for research on the most effective delivery platforms and on strategies for demand creation. This should include delivery platforms for adolescent friendly care, in order to encourage adolescent mothers to access health and nutrition services.
In terms of policy, she pointed out that the importance of preconception nutrition has been recognized by institutions such as the Food and Agriculture Organization and the World Health Organization, which together released the Rome Declaration on Nutrition in November 2014 committing to “develop policies, programmes and initiatives for ensuring healthy diets throughout the life course … including … before and during pregnancy.” However, this commitment can be extended further by individual governments, which can support women to improve their diets and nutritional status.
Although the speakers in the session focused primarily on maternal undernutrition in middle- and low-income countries, one commenter noted that the issue of overnutrition also deserves attention, especially when it occurs in combination with micronutrient deficiencies. In either case, the importance of women's nutrition before and during pregnancy for improved birth outcomes seems clear.
Historically, immunology and metabolism have been distinct disciplines. However in recent decades we have learned that metabolic diseases such as obesity and type 2 diabetes result in major changes in inflammation and the immune response. Conversely, it has also become clear that certain behaviors and properties of lymphocytes are regulated by internal metabolic processes. Thus the new field of immunometabolism has emerged to examine the crosstalk between immune and metabolic processes. Speakers at the symposium “Diet and Immunometabolism,” co-sponsored by the Nutritional Immunology and Obesity RIS, highlighted the role of nutrients and metabolites in inflammatory processes on March 31.
While we may traditionally think of iron's role in anemia and fetal development, it is also required for proper immune function and adipogenesis. Elevated serum ferritin levels are associated with type 2 diabetes, gestational diabetes, and metabolic syndrome. Excess iron also induces lipolysis and insulin resistance. Dr. Alyssa Hasty from Vanderbilt University School of Medicine presented data from mouse models indicating that iron homeostasis is disrupted during obesity. Iron is traditionally stored in the liver, however during obesity it appears that iron levels decrease in the liver and increase in adipocytes.
These changes may be related to changes in macrophage populations, which are important mediators of adipose tissue inflammation. Hasty identified two distinct macrophage populations based on their iron content. Some macrophages have high iron content which allows them to be isolated using a magnet while others have low iron content. Lean animals have both types of macrophages. However obese animals have increased levels of macrophages with low iron content.
This indicates that iron levels are changing in both adipocyte and macrophage populations during obesity and suggests that the ability of macrophages to sequester iron may be impaired. Further study is needed to identify the mechanisms of crosstalk between macrophages and adipocytes and examine potential functional consequences.
“A calorie is a calorie, but the body's physiological response to that calorie might be different depending on the circadian phase the body is exposed to,” said Frank Sheer, PhD, an assistant professor of medicine at Harvard Medical School. Sheer spoke during ASN's scientific symposium titled “Is ‘When' We Eat As Important As ‘What' We Eat?—Chronobiological aspects of food intake.” He opened his discussion by asking why we should care about circadian biology, and then pointed to its possible influence on metabolic processes, meal timing, and disease risk. He explained that an internal “circadian clock”—present in nearly all the body's cells—regulates the body's rhythms based on feedback from the brain. We can uncouple those rhythms and choose to be awake, but at a cost, possibly increasing our risk of some chronic diseases, like type 2 diabetes.
Jonathan Johnston, PhD, an associate professor at University of Surrey, “flipped the question on its head,” so to speak, and asked what effect meal timing might have on the body's internal clock. Johnston explained that circadian rhythms are endogenous and self-sustaining even without external cues, like light and darkness. “Clocks are everywhere,” Johnston said, “and they function like an orchestra.” All the “musicians”—the various clocks—have to be synchronized to function properly, he said. Johnston's data, gleaned from gene expression studies in human adipose tissue, suggest that modifying meal times might help synchronize the body's clocks, a possible treatment for the circadian dyssynchrony commonly observed with shift work, jet lag, blindness, and sleep disorders.
“Humans are the only species that disobeys their biological clocks,” said Fred Turek, PhD, a professor at Northwestern University, and the downstream effects might be enormous. We have become “night creatures,” he said, and he and his colleagues are wondering how that affects human health. Turek pointed out that at least 10 to 30 percent of gene expression in the human body is under circadian control including genes in tissues like the brain, liver, and muscle—key players in metabolism—and likely influences disease risk, gut permeability, and the gut microbiota. He suggested that science is at a tipping point with regard to circadian medicine and health, adding that the field of circadian biology is growing and spans many different disciplines, including immunology, oncology, cardiology, and nutrition. “I think it's the next frontier in medicine,” Turek said.
Jose Ordovás, PhD, a professor at Tufts, explained that circadian rhythms extend beyond 24-hour cycles to monthly and seasonal patterns, a phenomenon now ingrained in human physiology. Ordovás suggested that humans' ancestral genes were more like the genes of the laboratory animals he studies, which respond to regular cycles of light and dark. Migration away from humans' equatorial origins likely has altered human circadian biology and, in fact, circadian clocks now vary depending on geographical location. Ordovás speculated on the potential application of circadian biology in personalized or precision medicine as a means to identify those at risk for nutritional disease, and added, “Know your genome and act accordingly.”
W. Allan Walker, MD, and Emeran Mayer, MD chaired a symposium during ASN's Scientific Sessions and Annual Meeting on March 30 that considered the role the gut microbiome plays in human behavior.
Mark Lyte, PhD, MS, a professor at Texas Tech University, provided insights into aspects of gut-brain communication pathways. He introduced the idea that gut bacteria, as neuroendocrine organisms, are more interactive with their human hosts than previously believed. Lyte then pointed out that the gut is highly innervated, and information flows in a bi-directional but asymmetrical fashion between the gut and the brain, with as much as 90 percent of the information flowing from the gut. He suggested that neuroendocrine chemicals naturally present in foods might influence gut bacteria responses, and mechanisms that were previously considered immunological might be neuroendocrinal instead. The take-home message, Lyte said, was that these food-derived neurochemicals, when absorbed in gut, likely interact with the microbiota. In response, the microbiota produce neurochemicals that affect behavior and cognition in a sort of feedback loop. He cautioned that much of the data are correlational, and causation cannot be assigned.
Sarkis Mazmanian, PhD, California Institute of Technology, focused his remarks on specific molecular communications between the gut and brain. He explained that our bodies are in contact with trillions of microbes. “This microbial fingerprint has effects on many aspects of our biology,” said Mazmanian. He noted that in recent decades, the prevalence of autism spectrum disorder (ASD) has increased dramatically, and he presented data demonstrating that in rodents, maternal immune activation during pregnancy yields offspring with ASD and dysbiosis, suggesting a possible gut-microbiome-brain connection in ASD.
Premysl Bercik, MD, a gastroenterologist and associate professor at McMaster University, noted that while individuals with inflammatory bowel disorders commonly have abnormal gut function and low-grade inflammation, they also experience psychiatric comorbidities such as depression, stress, and anxiety. The trigger for this chain of events has not been identified, Bercik said, but some have hypothesized that infections or abnormal gut flora might be responsible. He then presented data from animal models that demonstrate the bi-directional communication between the gut and brain, and described recent research indicating that both microbial and host factors influence behavior.
Mayer, a professor at the David Geffen School of Medicine at UCLA, began his presentation with a historical perspective on the perceived gut-brain connection, which dates back several millennia. He then described notable limitations to using rodent models to study the gut-brain connection due to structural differences between rodent and human brains, and added that the germ-free mouse, a common model for understanding gut microbiome function, introduces many confounders into the research due to its altered metabolism. Mayer presented data that indicate that pre- and post-natal stress alters the gut microbiome in animals, as evidenced by both behavioral and biological changes, and he raised the idea that the gut microbial organization might influence brain structure. Attempts to modulate behavior with probiotics are promising, Mayer said, because intake blunts the reactivity of several internal organs, including those in the gut. Mayer concluded his presentation by cautioning that although enthusiasm to extrapolate findings from rodent models to human conditions including obesity, autism, and others is high, many questions remain about the role the gut microbiome plays in human health.
Tuesday's minisymposium 'Nutrition and Inflammation' covered a wide range of topics and research designs from clinical, lab, and public health perspectives.
Starting with clinical research, Wendy Ward of Brock University (Canada) presented on associations of dietary intake with periodontal healing. She explained that 42% of adults in the US are affected by periodontal disease, which is characterized by inflammation of tissues around the teeth that can eventually lead to loss of alveolar bone. One treatment is the mechanical removal of bacteria below the gum line through sanative therapy. Dr. Ward's group found that higher dietary intakes of fruits and vegetables, β-carotene, vitamin E, and α-linolenic acid were associated with greater healing following sanative therapy.
Taking a more public health-oriented perspective, Mercedes Sotos Prieto of Harvard University spoke about the development of a healthy lifestyle score (HLS) and its association with inflammatory markers among Puerto Rican adults in Boston. The HLS included five components: diet, physical activity, smoking, social network and support, and sleep. Dr. Sotos Prieto found that a 20-unit increase in the HLS was associated with a decrease in the inflammatory biomarkers IL-6 and TNF-α when adjusted for a number of covariates. These in turn were associated with obesity and hypertension but not with diabetes or heart disease.
Presentations from Yaw Addo and Leila Larson of Emory University also had clear public health implications. They looked at biomarkers of iron and vitamin A status, respectively, and their relationship with biomarkers of inflammation. First, Dr. Addo explained that transferrin receptor was strongly associated with α-1 acid glycoprotein (AGP) in women of reproductive age across six countries, though the magnitude of the association varied by country. Next, Ms. Larson showed that retinol binding protein (RBP) was significantly associated with both C-reactive protein (CRP) and AGP among preschool children in Liberia. Both of these analyses suggested that it may be important to account for inflammation, particularly with RBP, where adjusting for inflammation through linear regression decreased the prevalence of vitamin A deficiency by almost 20 percentage points.
Moving to lab studies, Marie-Caroline Michalski of the University of Lyon (France) presented research on the effects of dietary lipids on plasma endotoxins and lipopolysaccharides (LPS), which contribute to low-grade inflammation. She showed that in a sample of normal weight and obese men, ingestion of a higher-fat test meal led to postprandial endotoxemia only in obese subjects. Qiaozhu Su of the University of Nebraska then presented data showing that the cAMP responsive element binding protein H (CREBH), which is activated by the inflammatory cytokine TNF-α, induces expression of apolipoprotein B. This in turn increases secretion of very low density lipoproteins (VLDL) and may play a role in hepatic steatosis, hyperlipidemia, and insulin resistance. Finally, Sadiq Umar of Washington State University showed that thymoquinone, a compound derived from Nigella sativa, or black cumin, inhibits TNFα-induced production of the inflammatory cytokines IL-6 and IL-8 as well as the pro-inflammatory mediator ASK1.
Given the associations between inflammation and many chronic diseases, we will likely hear a great deal more about these topics in years to come.
Robert Waterland, PhD, an associate professor at Baylor College of Medicine, described nutritional influences on human developmental epigenetics. Waterland defined epigenetics as “mitotically heritable stable alterations in gene expression potential that are not caused by changes in DNA sequence.” Multiple factors likely contribute to epigenetic changes, including cytosine methylation, histone modification, auto-regulatory transcription factors, and non-coding RNAs, Waterland pointed out, and they tend to work in a synergistic fashion to influence gene transcription. Waterland said he is particularly interested in DNA methylation because methylation requires dietary donors and cofactors, which is influenced by nutritional factors. He presented data demonstrating that periconceptual maternal nutrition status predicts hypomethylation in a mother's infant. These changes are stable and maintained over a lifetime, Waterland said, and may point to evidence of metabolic imprinting as an adaptive response to early nutrition.
“We live in a microbial world,” said Dingding An, PhD, a researcher at Boston Children's Hospital. An elaborated on the role of early life gut microflora in immune system development, and explained that microbial exposure begins at birth and influences our risk for chronic diseases such as inflammatory bowel disease, asthma, arthritis, and autism later in life. Many early-life factors impact the makeup of the gut microbial population in particular, such as nutrition, hygiene, and antibiotic use. An presented data indicating that some gut microbes enhance immune cell maturation and immune response. But the timing of microbial exposure is critical, An added, because later exposure diminishes the response, indicating that key windows of regulation have been missed.
Deborah Sloboda, PhD, an associate professor at McMaster University, provided insights into the impacts of fructose consumption during pregnancy. Fructose is a monosaccharide present in honey, maple syrup, and fruit sugar, and is widely available in processed foods. Fructose consumption differs by sex and age, Sloboda said, with highest consumption reported among lower socioeconomic status females during their reproductive years. This is important, Sloboda said, because “the early-life environment plays a very big role in determining health and disease risk later in life.” Her data from animal models indicate that high fructose intake during pregnancy induces changes in the offspring's metabolic response. Taurine supplementation reversed fructose-induced adverse metabolic programming, Sloboda said, but not in the presence of a high fat diet, emphasizing the importance of correctly identifying the population in need of intervention.
Growing up in the now well-studied Swedish village Överkalix strongly influenced the research of Lars Bygren, MD, PhD, a professor at University of Umea. Bygren, who addressed the topic of transgenerational outcomes associated with paternal nutrition, explained that human responses to early-life exposures, especially in males, have the potential to impact development for multiple generations. In particular, exposure to high food availability during slow-growth periods negatively affects the health of subsequent generations, and could explain the present day prevalence of many chronic diseases. Byrgen said data from other studies, including the Taiwan betel nut study and the ALSCAP study, lend support to these conclusions.
How does one estimate the prevalence of anemia in a population? Historically, this has been a fairly straightforward matter of testing hemoglobin levels and comparing them to set cutoff figures. However, as we learn more about the physiological effects of infection and inflammation, the validity of our estimates is called into question.
Monday's symposium on the Biomarkers Reflecting Inflammation and Nutrition Determinants of Anemia (BRINDA) project highlighted some of these issues and potential approaches to address them. Parminder Suchdev of the Centers for Disease Control and Emory University began with an overview. He explained that the immune response triggers inflammation, which leads to temporarily decreased serum zinc and retinol and increased ferritin, transferrin receptor, and hepcidin. Although we know that these nutrients and biomarkers are affected by the inflammatory response, there is no widely accepted approach to effectively account for inflammation when analyzing and interpreting micronutrient data.
In order to address this gap, the BRINDA project team has been analyzing data from 15 countries representing all six WHO regions. Sorrel Namaste of Helen Keller International presented the key findings. Using C-reactive protein (CRP) and α-1 acid glycoprotein (AGP) as biomarkers of inflammation, they found that the prevalence of inflammation varied by country but was, on average, approximately 20% based on CRP and 40% based on AGP. Different methods of adjusting for CRP and AGP in the data analysis produced varying results, with a linear regression method being the most successful. These findings indicated that it is necessary to measure both CRP and AGP and to adjust for them in the analysis phase.
Next, Grant Aaron of Global Alliance for Improved Nutrition presented preliminary findings related to preschool aged children. In the sample, the burden of anemia was approximately 45%. Among children with anemia, 30% of the anemia was attributable to iron deficiency (unadjusted for inflammation). The age of the child, presence of inflammation, and anthropometric measures were associated with anemia in a majority of countries. Using an external correction factor, the proportion of anemia attributable to iron deficiency was adjusted to 35% for this age group.
Finally, Ken Brown of the Bill & Melinda Gates Foundation shared his interpretation of the findings. He emphasized the need for these biomarkers to establish the presence and magnitude of the problem, identify high risk sub-groups, and measure their response to interventions. This will require addressing practical challenges relating to specimen collection, analysis, and interpretation. He also pointed out that the need to collect biomarkers of any potential adverse effects of interventions. Ultimately, he encouraged the BRINDA team to make specific recommendations that other researchers can follow.
Overall, a major conclusion of the project thus far is that accounting for inflammation is necessary in order to improve the validity of anemia estimates. In acting on this conclusion, it will be important for researchers to ensure consistency in the parameters that are measured and to strengthen coordination between programs, evaluators and the academic community to build the evidence base.
The Tuesday issue of Nutrition Notes Daily is live, featuring research reporting advice, carotenoids, resistant starch, and a photo montage.
Read the second issue for the latest news from ASN's Scientific Sessions & Annual Meeting. Don't miss the photos at the back!
A symposium chaired by Bahram Arjmandi, PhD, RD, and Carmen Castaneda-Sceppa, MD, PhD, provided insights into the etiology and pathophysiology of osteosarcopenic obesity, and presented suggestions for pharmacological and dietary treatment strategies.
Jasminka Ilich-Ernst, PhD, RD, a professor at Florida State University, outlined the problem and scope of osteosarcopenic obesity, a term first coined in 2012. Characterized by the coexistence of three distinct musculoskeletal disorders—osteopenia/osteoporosis, sarcopenia, and obesity—osteosarcopenic obesity is a complex condition, for which the proof-of-concept was established only recently.
A major concern with osteosarcopenic obesity, Ilich-Ernst said, lies in age-related fat redistribution and subsequent infiltration into bone and muscle. Typically bone, muscle, and fat progenitor cells differentiate in a balanced distribution to enable normal tissue development. But with aging, a sedentary lifestyle, poor nutrition, and low-grade inflammation, differentiation patterns become altered and fat production predominates.
Whereas current nutritional and lifestyle management recommendations address the individual components of osteosarcopenic obesity, they do not address the collective triad. Ilich-Ernst suggested adhering to current recommendations to achieve peak bone mass before age 30, gain and maintain adequate muscle mass, and maintain a health weight, but she added that increasing dietary protein to 25 percent of total energy and limiting carbohydrate consumption to approximately 40 percent of total energy might further reduce risk of developing osteosarcopenic obesity.
Further insights into the interconnected nature of bone, muscle, and fat were provided by Clifford J. Rosen, MD, a professor of medicine at Tufts University and research scientist at the Maine Medical Center Research Institute. Rosen explained that the three tissues derive from a single progenitor cell type, and their responses to various cytokines, hormones, and regulatory input, primarily the sympathetic nervous system, are similar.
He then described newly identified “beige,” or brown-like, adipocytes, which contain more mitochondria and are more thermogenic than classic white adipocytes. Beige adipocytes share a common progenitor cell with smooth muscle. As such, they can be viewed as a sort of “hybrid” between fat and muscle cells. Intermittent cold exposure induces beige adipogenesis, a process referred to as “browning,” and promotes weight loss by increasing sympathetic tone—a potential non-pharmacological approach to body fat loss.
However, Rosen noted, whereas sympathetic tone enhances fat loss, it uncouples the process of bone remodeling, promoting bone loss. He added that many of the new classes of drugs that target beige adipogenesis might have similar, deleterious off-target effects on bone.
Ronenn Roubenoff, MD, MHS, of Novartis Institutes for Bone Research, and a professor of medicine and nutrition at Tufts University, compared the effects of dietary versus pharmacological approaches to treating sarcopenia. Sarcopenia, Roubenoff said, is an age-related loss of muscle mass due to type II muscle fiber atrophy. He said that preventing sarcopenia might increase life span and improve quality of life in older adults.
Although some research suggests increasing dietary protein intake might reduce muscle wasting, few data support changing current recommendations, Roubenoff said. In addition, the muscle-sparing effects of dietary protein differ in women versus men. Whereas women benefit from increased intake, men (who experience a U-shaped curve in response to intake) benefit from more moderate intake.
Roubenoff added that muscle, unlike other organs, doesn't senesce; rather, it remains plastic, providing the potential for older adults to regain muscle mass and function. However, muscle in older adults exhibits “anabolic resistance”—an inability to integrate and build muscle. Emerging pharmacological approaches target this resistance to reverse muscle wasting.
Finally, Wayne Campbell, PhD, a professor of nutrition science at Purdue University, described the differential effects of dietary protein intake during weight loss on bone, muscle, and fat. Specifically, Campbell addressed the question of how older adults can purposefully lose weight without compromising musculoskeletal function.
Campbell and his colleagues analyzed NHANES data from 1999-2004, a period that included dual energy X-ray absorptiometry data. They partitioned the data based on thresholds of the Recommended Dietary Allowance regarding bone health, and noted that whereas inadequate protein intake had an adverse effect on bone health in adults over age 50, high protein had variable effects. Campbell then described his research with whey supplementation and noted that groups that consumed higher amounts of a whey protein supplement lost more fat than groups consuming lesser amounts. However, they experienced no change in bone status, consistent with the epidemiological data.
At a minimum, Campbell said, adults should consume adequate protein. But he added that high dietary protein intake during weight loss has a positive effect on body composition, inducing greater fat loss while maintaining lean muscle mass. In addition, he noted that high protein intake has variable effects, depending on protein type. In particular, whereas protein from dairy and plant sources likely provides greater benefit to bone, protein from non-dairy animal sources likely benefits soft tissue.