News Round-up

 

The Gut Microbiome’s Supersized Role in Shaping Molecules in Our Blood

ISB researchers show which blood metabolites are associated with the gut microbiome, genetics, or the interplay between both – findings have promising implications for guiding targeted therapies.

The nearly 200-year-old phrase “you are what you eat” has some new evidence. ISB researchers have found that the gut microbiome, including what we feed it, is largely responsible for the variation in circulating blood metabolites across people. This knowledge will help guide targeted interventions designed to alter the composition of the human blood metabolome. The findings have been published in Nature Metabolism.

“We know that person-to-person variation in the blood metabolome – the small molecules found in the bloodstream that can interact with all the systems of our body – can tell us a lot about health and disease status. Figuring out what governs this variation is a necessary step that gets us closer to precision approaches to healthcare,” said Dr Sean Gibbons, an ISB faculty member and co-corresponding author of the paper.

The research team examined 930 blood metabolites that were present in more than 1,500 individuals. Over 60% of the detected metabolites were significantly associated with either host genetics or the gut microbiome. “Notably, 69% of these associations were driven solely by the microbiome, with 15% driven solely by genetics and 16% were under hybrid genetic-microbiome control,” said ISB Senior Research Scientist Dr. Christian Diener, lead author of the study. Diener and co-lead author Chengzhen Dai analysed the de-identified metabolomic, genomic, and microbiome data from consenting patients in a consumer scientific wellness program.

They found that the blood metabolite variation explained by the microbiome was largely independent of the variation explained by the genome, even for hybrid metabolites that were significantly associated with both genetics and microbes. Additionally, certain metabolite-microbe associations were only significant in individuals with specific genetic backgrounds, indicating a nuanced interplay between the microbiome and host genetics in shaping the blood metabolome.

These new findings are promising for a couple of reasons. First, the high number of microbiome-specific metabolites suggests that much of our blood metabolome could be modified through dietary, probiotic, and other lifestyle interventions. Second, metabolites that are under stricter genetic control may not be responsive to lifestyle modification, making them targets for pharmacological interventions that directly target host pathways.

“A deeper understanding of the determinants of the blood metabolome will provide us with a window into how these circulating metabolite levels can be engineered and optimised for health,” said Dr. Andrew Magis, co-corresponding author of the paper. “Understanding which circulating small molecules fall predominantly under host versus microbiome control will help guide interventions designed to prevent and/or treat a range of diseases.”

^{This research was supported by the National Institutes of Health under award number R01DK133468, as well as by funds from Dr. Gibbons’ Washington Research Foundation Distinguished Investigator Award. The content published in Nature Metabolism is solely the responsibility of the paper’s authors and does not necessarily represent the official views of the National Institutes of Health.
About ISB: Institute for Systems Biology (ISB) is a Seattle-based non-profit biomedical research organization. We focus on some of the most pressing issues in human health, including aging, brain health, cancer, COVID-19, and many infectious diseases. ISB is an affiliate of Providence, one of the nation’s largest not-for-profit health care systems. Follow us at www.isbscience.org and on YouTube, Facebook, LinkedIn and Twitter.
Paper: Genome–microbiome interplay provides insight into the determinants of the human blood metabolome. Nature Metabolism; https://doi.org/10.1038/s42255-022-00670-1}

 

Food Industry Shows ‘Stalled Progress’ to Reduce Salt Intakes

Excess salt consumption* increases the risk of high blood pressure and is thought to be responsible for at least 2.5 million deaths worldwide each year, mostly from strokes and cardiovascular disease (World Health Organization). Reducing salt intake is therefore a public health priority. Since 2003, the UK Government has set a series of voluntary targets to encourage the food industry to reformulate products to contain less salt. These targets are not legally-binding, and it has been unclear how much progress has been made in recent years.

To investigate this, researchers from Oxford University assessed whether the amount of salt in a range of different foods sold in supermarkets had changed between 2015 and 2020. The study was based on the nine grocery food categories that contribute the most to adults’ salt intake in the UK. For each year, the analysis included approximately 8,000-9,500 food products from 400 different brands.

Key findings:

• The average salt content of all food products in the study fell by 5%, from 1.04 g per 100 g in 2015, to 0.99 g per 100 g in 2020, although this was not statistically significant
• The biggest reductions were seen in breakfast cereals (-16%) and processed beans, potatoes and vegetables (-11%), but there was no change for bread (-2%) and ready meals (+1%). None of these changes were statistically significant
• The categories with the highest salt content in 2020 were savoury snacks (1.6 g per 100 g on average) and cheese (1.6 g per 100 g). Products with more than 1.5 g salt per 100 g are classed as ‘high’ in salt¹
• The total volume of salt sold from all food products decreased from 2.41 g per person per day in 2015, to 2.25 g in 2020: a reduction of 0.16 g per person (6.7%). Most of the salt sold came from three categories: bread (24%), meat, seafood and alternatives (19%), and cheese (12%)
• For certain products (ready meals, pizzas and soups) the volume of salt sold increased, with any reduction of salt content offset by rising sales
• Overall, there has been little change in the average salt content and total volume of salt sold from these foods.

The study did not include table salt or salt consumed at restaurants, cafes, or fast foods, hence the total volume of salt consumed per person will be much higher.

According to the research team, several reasons may explain why little recent progress has been made to reduce salt in food products. Reformulating food products can be technically challenging, especially where salt acts as a preservative; there can be consumer resistance to low salt varieties; and there has been a recent shift in focus by industry and policy makers towards sugar and calorie reduction instead.

Lead author of the study, Dr Lauren Bandy (Nuffield Department of Primary Care Health Sciences, Oxford University) said: “Our results demonstrate that overall progress to reduce salt intake has stalled. Voluntary targets alone may be insufficient to achieve the Government’s target of a population salt intake of less than 6 g per day and additional policy measures might be needed to achieve further progress. This could include mandatory reporting of salt sales by manufacturers to improve transparency – as has been called for in the National Food Strategy.”

Professor Graham MacGregor, Professor of Cardiovascular Medicine and Chairman of Action on Salt (who were not directly involved in the study), said: “Reducing salt is the most cost-effective measure for lowering blood pressure and reducing the number of people suffering and dying from strokes, heart disease and life changing disabilities. The UK was once considered world-leading in our approach to salt reduction, but this paper and many others before it makes it clear that the voluntary approach is no longer fit for purpose. Failing to deliver on such a simple and effective public health strategy will have undoubtedly resulted in needless death and suffering, and should serve as a wakeup call to the Prime Minister** that her focus should be on the people she was elected to serve.”

The nine categories of food products included in the analysis were: bread; breakfast cereals; butter and spreads; cheese; meat, seafood and alternatives; processed beans, potatoes and vegetables; ready meals, soup and pizza; sauces and condiments; and savoury snacks.

Information on the salt content of foods was sourced from two databases that collect product information (including nutrient composition data) from the websites of the leading UK supermarkets. One of these platforms, foodDB,² was built by Oxford University researchers and collects information on around 120,000 products each week within the UK. Retail sales data were obtained from Euromonitor International, a private market research company that is representative of the whole packaged food market.

<sup>*Adults are recommended to consume no more than 6g of salt a day (2.4g sodium), around 1 teaspoon.
**At the time this story was written Liz Truss was Prime Minister.
The study ‘Changes in the salt content of packaged foods sold in supermarkets between 2015-2020 in the United Kingdom: A repeated cross-sectional study’ has been published in PLOS Medicine: https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004114
References: 1. www.nhs.uk/live-well/eat-well/food-guidelines-and-food-labels/how-to-read-food-labels/;
2. www.ndph.ox.ac.uk/food-ncd/research/fooddb</sup>

 

 

Genetic Variant Found that Predisposes People to Slimness Carried by 60% of Europeans

Researchers from the Spanish National Cancer Research Centre (CNIO) and the IMDEA Food Institute have discovered that those who have a certain version of a gene involved in cell nutrition tend to accumulate less fat.

But "this association does not mean that people with this genetic variant can overeat without getting fat," says Alejo Efeyan (CNIO), senior co-author of the paper together with Ana Ramirez de Molina (IMDEA Food).

The work is published in Genome Biology. It represents a breakthrough in the understanding of the genetic components of obesity, which may pave the way to future anti-obesity treatments, the authors say.

How much do genes influence our body weight? For the general population this influence is estimated in 20%, according to studies that in recent years have analysed the complete genome of tens of thousands of individuals. In other words, "lifestyle, such as eating habits and exercise, have a great impact, but genetic factors also exert an influence," explains researcher Nerea Deleyto-Seldas from the Spanish National Cancer Research Centre (CNIO).

Some of these genetic factors are already known. Nearly a hundred genetic variants that moderately increase the probability of having a high Body Mass Index (BMI, a common indicator of being overweight or suffering from obesity) have already been identified. CNIO and IMDEA Food researchers have identified a new one. Their work is published in the journal Genome Biology, with Nerea Deleyto-Seldas (CNIO) and Lara P. Fernandez, from the IMDEA Food Institute, as first co-authors.

Genetic variants are slightly different versions of a gene, and most often do not result in visible changes in the body. But this specific variant does: it affects the amount of fat the body stores, and the authors of the new study show that it is particularly prevalent in Europe. It is estimated to be present in almost 60% of the European population.

For Alejo Efeyan, head of the CNIO's Metabolism and Cell Signalling Group, "the finding is a step forward in the understanding of the genetic components of obesity." Ana Ramirez de Molina, director of the IMDEA Food Institute, believes that "a deep knowledge of the involvement of the cellular nutrient-sensing pathway in obesity may have implications for the development and application of personalised strategies in the prevention and treatment of obesity."

Genetics and clinical data from 790 volunteers

Overweight and obesity are defined by an abnormal or excessive accumulation of fat that affects health. To find genetic variants that influence the phenomenon, and the associated metabolic alterations, a team from IMDEA Food Institute collected genetic material and data such as body weight, BMI, total and visceral fat, muscle mass, waist and hip circumferences, among others, from 790 healthy volunteers.

Researchers studied the possible associations of these parameters with 48 genetic variants, selected based on their potential functional relevance. They detected a "significant correlation between one of these variants in the FNIP2 gene and many of these obesity-related parameters," explains the study, which has just been published in the scientific journal Genome Biology.

Demonstration in animal models

The CNIO team then studied the effect of this variant in mice genetically-engineered to express it. "We found that mice with this variant, which in people is associated with leanness, have between 10% and 15% less fat than their non-carrier counterparts," explains Efeyan.

In humans, the effect of this variant cannot be isolated from that of the many other genetic and environmental variables that influence the physical constitution, so it is impossible to estimate precisely the strength of its effect. But given that the influence of genetics on obesity does not exceed 20%, the contribution of the variant now identified is necessarily small.

For this reason, researchers use terms like predisposition or tendency: "It is not at all the case that people with this genetic variant can overeat without getting fat," Efeyan clarifies.

The animals genetically modified for this study showed no other alterations or differences. "The observations in mice are very striking, because many of these studies are typically limited to reporting associations in the human population; in this paper we show that changing a single letter in the entire mouse genome replicates what we observed in the human variant," Efeyan continues.

Related to what the cell 'eats'

This variant is present in a gene that participates in a signalling pathway that tells the cell what nutrients are available. Why a small genetic change affects the tendency to be lean now needs to be studied.

The goal for the future is to "better understand the molecular basis of the effects of this genetic variant, i.e. what is happening biochemically to the cell," adds Nerea Deleyto. "We need to improve the genetic tools to dissect when the functional consequences of this variant are important in the organism, for example, during the fat development," she stresses.

The finding also raises questions for other areas of science, such as what evolutionary pressures favoured the selection of this variant and when it occurred.

^{Paper: Folliculin-interacting protein FNIP2 impacts on overweight and obesity through a polymorphism in a conserved 3′ untranslated region. Genome Biology; https://doi.org/10.1186/s13059-022-02798-5.}

 

 

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