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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

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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

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Research Uncovers Details about How Gut Microbes Influence the Immune System

Source: Memorial Sloan Kettering - On Cancer
Date: 04/22/2020
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The microscopic organisms that live in our intestines perform many jobs to keep us healthy, such as helping our bodies digest nutrients from food. They keep harmful microbes under control and prevent them from taking over the gut, and also play a role in regulating the immune system.

Researchers at Memorial Sloan Kettering are studying the connections between gut microbes and human health. In a study published April 15 in Nature, an MSK team uncovered new findings about an important relationship: the way that gut microbes promote the formation of a type of immune cell called regulatory T cells (Tregs).

Tregs help keep powerful immune responses in check. They are crucial for preventing autoimmunity, when the immune system mistakenly attacks the body. Tregs also play a role in cancer: Cancer is more likely to develop when malfunctioning Tregs lead to chronically inflamed tissue. This is seen in conditions such as inflammatory bowel disease (IBD).

Focusing on the Microbe–T Cell Connection

“Life in all mammals, including humans, is impossible without regulatory T cells,” says the study’s senior author, Alexander Rudensky, Chair of the Immunology Program in the Sloan Kettering Institute and a Howard Hughes Medical Institute investigator. “This study builds on previous research from our lab and others that looked at how these cells are made and why they are so important.

“It’s already been shown that disturbance of the microbial community in the gut is associated with autoimmune and inflammatory diseases, like IBD,” he adds. “These findings have illustrated the importance of the relationship between the microbes that live in our guts and our immune systems.”

To better understand this relationship, Dr. Rudensky and his team study how different microbes in the gut affect the production of Tregs that protect against inflammation and autoimmune conditions. They do this by looking at the molecules that microbes make to carry out their metabolic functions. Then they study how those metabolites in turn influence the manufacturing of Tregs.

In the experiments, the investigators concentrated on a class of metabolites called secondary bile acids. These are produced by gut microbes. Bile acids help the digestion of dietary fats.

Members of Dr. Rudensky’s team focused on a type of gut bacteria belonging to a group called Bacteroides and engineered them to produce a particular bile acid, called isoDCA. They exposed naive T cells, which had not yet developed into a specific T cell type, to isoDCA during the process of their activation. They found that isoDCA caused the immature T cells to become Tregs.

Ultimately, these findings could lead to a bacterial-based therapy for the treatment of IBD associated with imbalanced microbes and diminished Treg activity. (Currently, IBD is treated with anti-inflammatory drugs, which can have many side effects.) But Dr. Rudensky says much more work is needed before this kind of treatment could be tested. Many parts of the process are still not well understood. In addition, researchers would have to do extensive testing in mice before designing a clinical trial. “We plan to continue exploring the possibility of using metabolic products from microbes for the treatment of inflammatory disorders,” he says.

The two first authors on the paper were research fellow Clarissa Campbell and research associate Peter McKenney in Dr. Rudensky’s lab. Investigators in MSK’s Donald B. and Catherine C. Marron Cancer Metabolism Center, including the center’s director, Justin Cross, also contributed to the research.

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Gut microbe movements regulate host circadian rhythms

Source: Cell Press
Date: 12/01/16
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Even gut microbes have a routine. Like clockwork, they start their day in one part of the intestinal lining, move a few micrometers to the left, maybe the right, and then return to their original position. New research in mice now reveals that the regular timing of these small movements can influence a host animal’s circadian rhythms by exposing gut tissue to different microbes and their metabolites as the day goes by. Disruption of this dance can affect the host. The study appears December 1 in Cell.

“This research highlights how interconnected the behavior is between prokaryotes and eukaryotes, between mammalian organisms and the microbes that live inside them,” says Eran Elinav, an immunologist at the Weizmann Institute of Science, who led the work with co-senior author Eran Segal, a computational biologist also at the Weizmann. “These groups interact with and are affected by each other in a way that can’t be separated.”

The new study had three major findings:

  • The microbiome on the surface layer of the gut undergoes rhythmical changes in its “biogeographical” localization throughout the day and night; thus, the surface cells are exposed to different numbers and different species of bacteria over the course of a day. “This tango between the two partners adds mechanistic insight into this relationship,” Elinav says.
  • The circadian changes of the gut microbiome have profound effects on host physiology, and unexpectedly, they affect tissue that is far away from the gut, such as the liver, whose gene expression changes in tandem with the gut microbiome rhythmicity. “As such,” adds Elinav, “disturbances in the rhythmic microbiome result in impairment in vital diurnal liver functions such as drug metabolism and detoxification.”
  • The circadian rhythm of the host is deeply dependent on the gut microbiota oscillations. Although some circadian machinery in the host was maintained by its own internal clock, other components of the circadian clock had their normal rhythms destroyed. Most surprising, another set of genes in the host that normally exhibit no circadian rhythms stepped in and took over after the microbial rhythms were disrupted.

Previous work by Elinav and Segal revealed that our biological clocks work in tandem with the biological clocks in our microbiota and that disrupting sleep-wake patterns and feeding times in mice induced changes in the microbiome in the gut.

“Circadian rhythms are a way of adapting to changes in light and dark, metabolic changes, and the timing of when we eat,” says Segal. “Other studies have shown the importance of the microbiome in metabolism and its effect on health and disease. Now, we’ve shown for the first time how circadian rhythms in the microbiota have an effect on circadian rhythms in the host.”

The investigators say their work has potential implications for human health in two important ways. First of all, because drugs ranging from acetaminophen to chemotherapy are metabolized in the liver, understanding — and potentially being able to manipulate — the circadian rhythms of our microbiota could affect how and when medications are administered.

Second, understanding more about this relationship could help to eventually intervene in health problems like obesity and metabolic syndrome, which are more common in people whose circadian rhythms are frequently disrupted due to shift work or jet lag.

“What we learned from this study is that there’s a very tight interconnectivity between the microbiome and the host. We should think of it now as one supraorganism that can’t be separated,” Segal says. “We have to fully integrate our thinking with regard to any substance that we consume.”

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Newly discovered gut organism protects mice from bacterial infections

Source: Cell Press
Date: 10/06/16
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While bacteria are often stars of the gut microbiome, emerging research depicts a more complex picture, where microorganisms from different kingdoms of life are actively working together or fighting against one another. In a study published October 6 in Cell, scientists reveal one example: a newly discovered protist that protects its host mice from intestinal bacterial infections.

“This was a serendipitous finding, but an important one,” says senior author Miriam Merad, a Professor of Oncological Sciences and of Medicine at the Icahn School of Medicine at Mount Sinai. “This study shows how vital it is to go beyond bacteria when studying the microbiome.”

The investigators made the discovery when they realized that mice that had been bred at their own facility had a greater number of immune cells in the gut than mice purchased from an outside vendor. Graduate student Aleksey Chudnovskiy, the study’s first author, together with postdoctoral fellow Arthur Mortha, decided to figure out why that was the case. When they performed an intestinal cleanse on the two groups of mice, they were surprised to find that the mice from the Mount Sinai facility had flagellated protozoa living in their guts. DNA sequencing revealed that the microorganism was a new protozoan parasite, which they named Tritrichomonas musculis (T. mu).

Further investigations showed that when this protist was given to the mice that didn’t have it, they, too, had an increase in the number of immune cells in their guts and also increased inflammatory cytokines. The researchers set out to discover the underlying mechanism. They found that T. mu activates the inflammasome in the gut epithelial cells of the mice, which in turn led to the activation of cytokines. They also found that dendritic cells were required to induce inflammation.

To determine whether colonization of T. mu in the gut affected the mice’s ability to fight off infection, they infected mice with Salmonella and found that the animals that had T. mu as part of their microbiome were very resistant to Salmonella infection. “The protective effect of this species is very striking,” Chudnovskiy says.

T. mu was found to be an ortholog of Dientamoeba fragilis, a parasite that’s found in the guts of many humans, but the researchers don’t know if D. fragilis also has a protective effect. It’s something they plan to study. “People from industrialized countries traveling to emerging countries are more susceptible to intestinal infection than the indigenous population,” Merad explains. “It’s possible that protists, which are known to be common in emerging countries, contribute to the protective effect against intestinal pathogenic infections.”

She adds: “The fight against pathogens determined the survival of the human species, and those with stronger immune systems are the ones who survived. It is likely that the microbiome is a big part of the evolutionary process. Thus, identifying those commensals that confer immune strength in exposed communities should help identify novel therapeutics.”

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Twin study finds that gut microbiomes run in families

Source: Cell Press
Date: 05/11/16
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A genome-wide association analysis of over 1,000 twins in the UK supports that some parts of our microbiomes are inherited and shaped–not through a spread of microbes from parent to child, but through our genes. The results, revealing new examples of heritable bacterial species–including those related to diet preference, metabolism, and immune defense–appear May 11 in Cell Host & Microbe‘s special issue on the “Genetics and Epigenetics of Host-Microbe Interactions.”

“We set out to find out about human genes that are implicated in the regulation of the gut microbiome, and we found some that are,” says senior author Ruth Ley, an Associate Professor in the Department of Microbiology at Cornell University and the study’s senior author. One connection they were able to make was between the LCT gene, which is involved in making the enzyme that helps the body digest dairy, and a type of microorganism called Bifidobacterium, which is commonly used in probiotics. They also found links between specific gut bacteria blood pressure and self/non-self recognition.

“Based on our research, we identified more than a dozen microbes with known links to health that are heritable,” says Ley, also director of the Department of Microbiome Science at the Max Planck Institute for Developmental Biology in Tübingen, Germany. “These microorganisms are environmentally acquired, but the genome also plays a part–by determining which microorganisms are more dominant than others.”

The investigators analyzed the gut microbiomes of 1,126 pairs of twins who were part of the TwinsUK Study. This multiyear research effort, which includes a total of 12,000 twins, is looking at a number of diseases and conditions. By including data from both identical and fraternal twins who were raised together, the study seeks to account for both environmental and genetic contributions.

The twins in the current study had already had their genomes analyzed, and 1.3 million small genetic variations (also known as single-nucleotide polymorphisms or SNPs) were known for each participant. The investigators used the genome-wide association approach to look for connections between genetic variations between twin pairs and certain bacterial types that were present and stable in the study subjects.

“The overall numbers in this study were still small for genome-wide association analysis, but they help validate some of the findings we’ve seen in smaller studies,” Ley says. The analysis confirmed earlier findings that several other types of bacteria are also heritable, but specific genes connected to those differences were not found. “This type of study opens up many questions but doesn’t give us a lot of answers yet,” Ley says. “It gives us lots of ideas to study.”