Microplastics make their way from the gut to other organs

It's happening every day. From our water, our food and even the air we breathe, tiny plastic particles are finding their way into many parts of our body.

But what happens once those particles are inside? What do they do to our digestive system?

In a recent paper published in the journal Environmental Health Perspectives, University of New Mexico researchers found that those tiny particles -- microplastics -- are having a significant impact on our digestive pathways, making their way from the gut and into the tissues of the kidney, liver and brain.

Eliseo Castillo, PhD, an associate professor in the Division of Gastroenterology & Hepatology in the UNM School of Medicine's Department of Internal Medicine and an expert in mucosal immunology, is leading the charge at UNM on microplastic research.

"Over the past few decades, microplastics have been found in the ocean, in animals and plants, in tap water and bottled water," Castillo, says. "They appear to be everywhere."

Scientists estimate that people ingest 5 grams of microplastic particles each week on average -- equivalent to the weight of a credit card.

While other researchers are helping to identify and quantify ingested microplastics, Castillo and his team focus on what the microplastics are doing inside the body, specifically to the gastrointestinal (GI) tract and to the gut immune system.

Over a four-week period, Castillo, postdoctoral fellow Marcus Garcia, PharmD, and other UNM researchers exposed mice to microplastics in their drinking water. The amount was equivalent to the quantity of microplastics humans are believed to ingest each week.

Microplastics had migrated out of the gut into the tissues of the liver, kidney and even the brain, the team found. The study also showed the microplastics changed metabolic pathways in the affected tissues.

"We could detect microplastics in certain tissues after the exposure," Castillo says. "That tells us it can cross the intestinal barrier and infiltrate into other tissues."

Castillo says he's also concerned about the accumulation of the plastic particles in the human body. "These mice were exposed for four weeks," he says. "Now, think about how that equates to humans, if we're exposed from birth to old age."

The healthy laboratory animals used in this study showed changes after brief microplastic exposure, Castillo says. "Now imagine if someone has an underlying condition, and these changes occur, could microplastic exposure exacerbate an underlying condition?"

He has previously found that microplastics are also impacting macrophages -- the immune cells that work to protect the body from foreign particles.

In a paper published in the journal Cell Biology & Toxicology in 2021, Castillo and other UNM researchers found that when macrophages encountered and ingested microplastics, their function was altered and they released inflammatory molecules.

"It is changing the metabolism of the cells, which can alter inflammatory responses," Castillo says. "During intestinal inflammation -- states of chronic illness such as ulcerative colitis and Crohn's disease, which are both forms of inflammatory bowel disease -- these macrophages become more inflammatory and they're more abundant in the gut."

The next phase of Castillo's research, which is being led by postdoctoral fellow Sumira Phatak, PhD, will explore how diet is involved in microplastic uptake.

"Everyone's diet is different," he says. "So, what we're going to do is give these laboratory animals a high-cholesterol/high-fat diet, or high-fiber diet, and they will be either exposed or not exposed to microplastics. The goal is to try to understand if diet affects the uptake of microplastics into our body."

Castillo says one of his PhD students, Aaron Romero, is also working to understand why there is a change in the gut microbiota. "Multiple groups have shown microplastics change the microbiota, but how it changes the microbiota hasn't been addressed."

Castillo hopes that his research will help uncover the potential impacts microplastics are having to human health and that it will help spur changes to how society produces and filtrates plastics.

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Parkinson's Disease: New theory on the disease's origins and spread

The nose or the gut? For the past two decades, the scientific community has debated the wellspring of the toxic proteins at the source of Parkinson's disease. In 2003, a German pathologist, Heiko Braak, MD, first proposed that the disease begins outside the brain. More recently, Per Borghammer, MD, with Aarhus University Hospital in Denmark, and his colleagues argue that the disease is the result of processes that start in either the brain's smell center (brain-first) or the body's intestinal tract (body-first).

A new hypothesis paper appearing in the Journal of Parkinson's Disease on World Parkinson's Day unites the brain- and body-first models with some of the likely causes of the disease-environmental toxicants that are either inhaled or ingested. The authors of the new study, who include Borghammer, argue that inhalation of certain pesticides, common dry cleaning chemicals, and air pollution predispose to a brain-first model of the disease. Other ingested toxicants, such as tainted food and contaminated drinking water, lead to body-first model of the disease.

"In both the brain-first and body-first scenarios the pathology arises in structures in the body closely connected to the outside world," said Ray Dorsey, MD, a professor of Neurology at the University of Rochester Medical Center and co-author of the piece. "Here we propose that Parkinson's is a systemic disease and that its initial roots likely begin in the nose and in the gut and are tied to environmental factors increasingly recognized as major contributors, if not causes, of the disease. This further reinforces the idea that Parkinson's, the world's fastest growing brain disease, may be fueled by toxicants and is therefore largely preventable."

Different pathways to the brain, different forms of disease

A misfolded protein called alpha-synuclein has been in scientists' sights for the last 25 years as one of the driving forces behind Parkinson's. Over time, the protein accumulates in the brain in clumps, called Lewy bodies, and causes progressive dysfunction and death of many types of nerve cells, including those in the dopamine-producing regions of the brain that control motor function. When first proposed, Braak thought that an unidentified pathogen, such as a virus, may be responsible for the disease.

The new piece argues that toxins encountered in the environment, specifically the dry cleaning and degreasing chemicals trichloroethylene (TCE) and perchloroethylene (PCE), the weed killer paraquat, and air pollution, could be common causes for the formation of toxic alpha-synuclein. TCE and PCE contaminates thousands of former industrial, commercial, and military sites, most notably the Marine Corps base Camp Lejeune, and paraquat is one of the most widely used herbicides in the US, despite being banned for safety concerns in more than 30 countries, including the European Union and China. Air pollution was at toxic levels in nineteenth century London when James Parkinson, whose 269th birthday is celebrated today, first described the condition.

The nose and the gut are lined with a soft permeable tissue, and both have well established connections to the brain. In the brain-first model, the chemicals are inhaled and may enter the brain via the nerve responsible for smell. From the brain's smell center, alpha-synuclein spreads to other parts of the brain principally on one side, including regions with concentrations of dopamine-producing neurons. The death of these cells is a hallmark of Parkinson's disease. The disease may cause asymmetric tremor and slowness in movement and, a slower rate of progression after diagnosis, and only much later, significant cognitive impairment or dementia.

When ingested, the chemicals pass through the lining of the gastrointestinal tract. Initial alpha-synuclein pathology may begin in the gut's own nervous system from where it can spread to both sides of the brain and spinal cord. This body-first pathway is often associated with Lewy body dementia, a disease in the same family as Parkinson's, which is characterized by early constipation and sleep disturbance, followed by more symmetric slowing in movements and earlier dementia, as the disease spreads through both brain hemispheres.

New models to understand and study brain diseases

"These environmental toxicants are widespread and not everyone has Parkinson's disease," said Dorsey. "The timing, dose, and duration of exposure and interactions with genetic and other environmental factors are probably key to determining who ultimately develops Parkinson's. In most instances, these exposures likely occurred years or decades before symptoms develop."

Pointing to a growing body of research linking environmental exposure to Parkinson's disease, the authors believe the new models may enable the scientific community to connect specific exposures to specific forms of the disease. This effort will be aided by increasing public awareness of the adverse health effects of many chemicals in our environment. The authors conclude that their hypothesis "may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal-prevention."

In addition to Parkinson's, these models of environmental exposure may advance understanding of how toxicants contribute to other brain disorders, including autism in children, ALS in adults, and Alzheimer's in seniors. Dorsey and his colleagues at the University of Rochester have organized a symposium on the Brain and the Environment in Washington, DC, on May 20 that will examine the role toxicants in our food, water, and air are playing in all these brain diseases.

Read more at Science Daily

From the first bite, our sense of taste helps pace our eating

When you eagerly dig into a long-awaited dinner, signals from your stomach to your brain keep you from eating so much you'll regret it -- or so it's been thought. That theory had never really been directly tested until a team of scientists at UC San Francisco recently took up the question.

The picture, it turns out, is a little different.

The team, led by Zachary Knight, PhD, a UCSF professor of physiology in the Kavli Institute for Fundamental Neuroscience, discovered that it's our sense of taste that pulls us back from the brink of food inhalation on a hungry day. Stimulated by the perception of flavor, a set of neurons -- a type of brain cell -- leaps to attention almost immediately to curtail our food intake.

"We've uncovered a logic the brainstem uses to control how fast and how much we eat, using two different kinds of signals, one coming from the mouth, and one coming much later from the gut," said Knight, who is also an investigator with the Howard Hughes Medical Institute and a member of the UCSF Weill Institute for Neurosciences. "This discovery gives us a new framework to understand how we control our eating."

The study, which appears Nov. 22, 2023 in Nature, could help reveal exactly how weight-loss drugs like Ozempic work, and how to make them more effective.

New views into the brainstem

Pavlov proposed over a century ago that the sight, smell and taste of food are important for regulating digestion. More recent studies in the 1970s and 1980s have also suggested that the taste of food may restrain how fast we eat, but it's been impossible to study the relevant brain activity during eating because the brain cells that control this process are located deep in the brainstem, making them hard to access or record in an animal that's awake.

Over the years, the idea had been forgotten, Knight said.

New techniques developed by lead author Truong Ly, PhD, a graduate student in Knight's lab, allowed for the first-ever imaging and recording of a brainstem structure critical for feeling full, called the nucleus of the solitary tract, or NTS, in an awake, active mouse. He used those techniques to look at two types of neurons that have been known for decades to have a role in food intake.

The team found that when they put food directly into the mouse's stomach, brain cells called PRLH (for prolactin-releasing hormone) were activated by nutrient signals sent from the GI tract, in line with traditional thinking and the results of prior studies.

However, when they allowed the mice to eat the food as they normally would, those signals from the gut didn't show up. Instead, the PRLH brain cells switched to a new activity pattern that was entirely controlled by signals from the mouth.

"It was a total surprise that these cells were activated by the perception of taste," said Ly. "It shows that there are other components of the appetite-control system that we should be thinking about."

While it may seem counterintuitive for our brains to slow eating when we're hungry, the brain is actually using the taste of food in two different ways at the same time. One part is saying, "This tastes good, eat more," and another part is watching how fast you're eating and saying, "Slow down or you're going to be sick."

"The balance between those is how fast you eat," said Knight.

The activity of the PRLH neurons seems to affect how palatable the mice found the food, Ly said. That meshes with our human experience that food is less appetizing once you've had your fill of it.

Brain cells that inspire weight-loss drugs

The PRLH-neuron-induced slowdown also makes sense in terms of timing. The taste of food triggers these neurons to switch their activity in seconds, from keeping tabs on the gut to responding to signals from the mouth.

Meanwhile, it takes many minutes for a different group of brain cells, called CGC neurons, to begin responding to signals from the stomach and intestines. These cells act over much slower time scales -- tens of minutes -- and can hold back hunger for a much longer period of time.

"Together, these two sets of neurons create a feed-forward, feed-back loop," said Knight. "One is using taste to slow things down and anticipate what's coming. The other is using a gut signal to say, 'This is how much I really ate. Ok, I'm full now!'"

The CGC brain cells' response to stretch signals from the gut is to release GLP-1, the hormone mimicked by Ozempic, Wegovy and other new weight-loss drugs.

These drugs act on the same region of the brainstem that Ly's technology has finally allowed researchers to study. "Now we have a way of teasing apart what's happening in the brain that makes these drugs work," he said.

A deeper understanding of how signals from different parts of the body control appetite would open doors to designing weight-loss regimens designed for the individual ways people eat by optimizing how the signals from the two sets of brain cells interact, the researchers said.

Read more at Science Daily

New drug-like molecule extends lifespan, ameliorates pathology in worms and boosts function in mammalian muscle cells

Having healthy mitochondria, the organelles that produce energy in all our cells, usually portends a long healthy life whether in humans or in C. elegans, a tiny, short-lived nematode worm often used to study the aging process. Researchers at the Buck Institute have identified a new drug-like molecule that keeps mitochondria healthy via mitophagy, a process that removes and recycles damaged mitochondria in multicellular organisms. The compound, dubbed MIC, is a natural compound that extended lifespan in C. elegans, ameliorated pathology in neurodegenerative disease models of C. elegans, and improved mitochondrial function in mouse muscle cells. Results are published in the November 13, 2023, edition of Nature Aging.

The impact of mitochondrial dysfunction in age-related disease

Defective mitophagy is implicated in many age-related diseases. It's tied to neurodegenerative disorders such as Parkinson's and Alzheimer's; it plays a role in cardiovascular diseases including heart failure; it influences metabolic disorders including obesity and type 2 diabetes; it is implicated in muscle wasting and sarcopenia and has a complex relationship with cancer progression. Even though interventions that restore mitophagy and facilitate the elimination of damaged mitochondria hold great promise for addressing these conditions, not one treatment has been approved for human use despite advances in the field.

What's MIC?

MIC (Mitophagy-Inducing Compound) is a coumarin, which are naturally bioactive compounds that have anticoagulant, antibacterial, antifungal, antiviral, anticancer, and antihyperglycemic properties (among others) as well as being an antioxidant with neuroprotective effects. Coumarin is found in many plants and is found in high concentrations in certain types of cinnamon, which is one of the most frequent sources for human exposure to the substance.

A new mechanism of action in mitophagy

The project started in a mouse model of Parkinson's disease where researchers in the laboratory of Julie Andersen, PhD, a senior author of the paper, were looking at known enhancers of mitophagy, including rapamycin. "Co-author Shankar Chinta, PhD, started screening natural compounds in neuronal cells and MIC came up as a major hit," she said. "Rather than taking MIC immediately into a mouse model we wanted to understand its impact on overall aging and identify its mechanism of action, so we took the work into the worm where we found that MIC is in a different class of molecules that enhance the expression of a key protein, TFEB."

In an effort spearheaded by Andersen and research scientist Manish Chamoli, PhD, lead author of the study, researchers found that MIC enhanced the activity of transcription factor TFEB, which is a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is the intracellular recycling process whereby cells clean up damaged proteins; it derives its abilities from the lysosome. Researchers found that MIC robustly increased the lifespan of C. elegans while also preventing mitochondrial dysfunction in mammalian cells.

"This paper helps support the overall notion of TFEB being a key autophagy regulator that extends lifespan, "said Buck professor and Chief Scientific Officer Malene Hansen, PhD, who collaborated on the paper. She added, "Mitophagy is a selective and very significant form of autophagy. The field has recognized TFEB as a player when it comes to quality control in mitochondria. This study provides a possible translational route to induce mitophagy in a TFEB-dependent fashion."

A link to the brain/gut connection

Mechanistically MIC works upstream of TFEB by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12 (in worms)/FXR (in humans), which in turn induces mitophagy and extends lifespan. FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, where it acts to regulate levels of TFEB as part of a feed-fast cycle, but recently TFEB was shown to also be present in brain neurons. This provided Andersen with the clue needed to piece together MIC's potential mechanism of action in the latter. "This study provides another piece of the puzzle when it comes to understanding the brain/gut connection in terms of health and disease," said Andersen.

FXR is regulated by bile salts which are formed in the gut microbiome. "The gut microbiome impacts the body's use of bile acids. Aging impacts our microbiome," said Chamoli. "If levels of bile acids aren't correct it hinders mitophagy. That's how FXR can impact neuronal health. Neurons have a lot of mitochondria which makes mitophagy important in terms of neurodegeneration," he said, noting that experiments are underway to explore neuronal FXR as a therapeutic target for Alzheimer's disease as part of a jointly funded grant shared by the Andersen and Lithgow labs.

MIC as a general geroprotective therapeutic

"There's a bottleneck in efforts to develop potential therapeutics in the field of geroscience, and the bottleneck is that we don't have enough molecules in the pipeline," said Gordon Lithgow, PhD, Buck Professor and Vice President of Academic Affairs and senior co-author. "MIC is a great candidate to bring forward given its therapeutic effect across multiple models and the fact that it is a naturally occurring molecule."

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Common origin behind major childhood allergies

Several major childhood allergies may all stem from the community of bacteria living in our gut, according to a new study led by researchers at the University of British Columbia and BC Children's Hospital.

The research, published in Nature Communications, identifies gut microbiome features and early life influences that are associated with children developing any of four common allergies -- eczema, asthma, food allergy and/or hay fever. The findings could lead to methods of predicting whether a child will develop allergies, and ways to prevent them from developing at all.

"We're seeing more and more children and families seeking help at the emergency department due to allergies," said Dr. Stuart Turvey, professor in the department of pediatrics at UBC and an investigator at BC Children's Hospital Research Institute, and co-senior author on the study. "Hundreds of millions of children worldwide suffer from allergies, including one in three children in Canada, and it's important to understand why this is happening and how it can be prevented."

The study is one of the first to examine four distinct school-aged pediatric allergies at once. While these allergic diseases each have unique symptoms, the Turvey lab was curious whether they might have a common origin linked to the infant gut microbiota composition.

"These are technically different diagnoses, each with their own list of symptoms, so most researchers tend to study them individually," says Dr. Charisse Petersen, co-senior author on the paper and postdoctoral fellow in the Turvey lab. "But when you look at what is going wrong at a cellular level, they actually have a lot in common."

For the study, researchers examined clinical assessments from 1,115 children who were tracked from birth to age five. Roughly half of the children (523) had no evidence of allergies at any time, while more than half (592) were diagnosed with one or more allergic disorders by an expert physician. The researchers evaluated the children's microbiomes from stool samples collected at clinical visits at three months and one year of age.

The stool samples revealed a bacterial signature that was associated with the children developing any of the four allergies by five years of age. The bacterial signature is a hallmark of dysbiosis, or an imbalanced gut microbiota, that likely resulted in a compromised intestinal lining and an elevated inflammatory response within the gut.

"Typically, our bodies tolerate the millions of bacteria living in our guts because they do so many good things for our health. Some of the ways we tolerate them are by keeping a strong barrier between them and our immune cells and by limiting inflammatory signals that would call those immune cells into action," says Courtney Hoskinson, a PhD candidate at UBC and first author on the paper. "We found a common breakdown in these mechanisms in babies prior to the development of allergies."

Many factors can shape the infant gut microbiota, including diet, how we are born, where we live, and our exposure to antibiotics. For example, antibiotics may wipe out sensitive bacteria, while breastfeeding tends to replenish and provide necessary food for bacteria in the infant gut. The researchers examined how these types of influences affected the balance of gut microbiota and the development of allergies.

"There are a lot of potential insights from this robust analysis," says Dr. Turvey. "From these data we can see that factors such as antibiotic usage in the first year of life are more likely to result in later allergic disorders, while breastfeeding for the first six months is protective. This was universal to all the allergic disorders we studied."

Now the researchers hope to leverage the findings to inform treatments that correct an imbalanced gut microbiota and could potentially prevent allergies from developing.

"Developing therapies that change these interactions during infancy may therefore prevent the development of all sorts of allergic diseases in childhood, which often last a lifetime," says Dr. Turvey.

The research is part of the Canadian Healthy Infant Longitudinal Development (CHILD) Cohort Study that recruited families through BC Children's Hospital and BC Women's Hospital + Health Centre and other pediatric hospitals across Canada. Since launching in 2008, the team of Canadian researchers has tracked the health, growth and environments of kids from birth and made important discoveries about how asthma and allergies develop.

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Scientists investigate the evolution of animal developmental mechanisms, show how some of Earth's earliest animals evolved

Lacking bones, brains, and even a complete gut, the body plans of simple animals like sea anemones appear to have little in common with humans and their vertebrate kin. Nevertheless, new research from Investigator Matt Gibson, Ph.D., at the Stowers Institute for Medical Research shows that appearances can be deceiving, and that a common genetic toolkit can be deployed in different ways to drive embryological development to produce very different adult body plans.

It is well established that sea anemones, corals, and their jellyfish relatives shared a common ancestor with humans that plied the Earth's ancient oceans over 600 million years ago. A new study from the Gibson Lab, published in Current Biology on June 13, 2023, illuminates the genetic basis for body plan development in the starlet sea anemone, Nematostella vectensis. This new knowledge paints a vivid picture of how some of the earliest animals on earth progressed from egg to embryo to adult.

"Studying the developmental genetics of Nematostella is sort of like taking a time machine into the very distant past," said Gibson. "Our work allows us to ask what life looked like long ago -- hundreds of millions of years before the dinosaurs. How did ancient animals develop from egg to adult, and to what extent have the genetic mechanisms that guide embryonic development endured across millennia?"

Most contemporary animals, from insects to vertebrates, develop by forming a head-to-tail series of segments that assume distinct identities depending on their position. Within a given segment, there is a further axis of polarity that informs cells whether they are at the front or back of the segment. Collectively, this is referred to as segment polarization.

Shuonan He, Ph.D., a former predoctoral researcher from the Gibson Lab, uncovered genes involved during development of the sea anemone, Nematostella vectensis, that guide the formation of segments and others that direct segment polarity programs strikingly similar to organisms higher up the evolutionary tree of life, including humans.

"The significance is that the genetic instructions underlying the construction of extremely different animal body plans, for example, a sea anemone and a human, are incredibly similar," said Gibson. "The genetic logic is largely the same."

This new study builds upon a 2018 study published in Science from the Gibson Lab that showed that sea anemones have an internal bilateral symmetry early in development with eight radial segments. The study demonstrated that Hox genes -- master development genes that are crucial for human development -- act to delineate boundaries between segments and likely had an ancient role in segment construction.

The team's latest finding explores how segments form and what accounts for differences in their identities. Using spatial transcriptomics, or the differences in gene expression between segments, the team discovered hundreds of new segment-specific genes. These include two crucial genes that encode transcription factors that govern segment polarization under the control of Hox genes and are required for the proper placement of sea anemone muscles.

The astonishing diversity of organisms on Earth can be compared to the assembly of Legos. "Whether you construct a dinosaur, a sea anemone, or a human, many of the core genetic building blocks are largely the same despite drastically different animal forms," said Gibson.

This is the first time that scientists have evidence of a molecular basis for segment polarization in a pre-bilaterian animal. While extensively studied in bilateral species like fruit flies and humans, the idea that cnidarian animals possess segmentation was unexpected. Now, the team has evidence that these segments are also polarized.

"This provides further evidence that investigating a broad diversity of animals can have direct implications for understanding general principles, including those which apply to human biology," said Gibson. "Going one step further, by understanding the logic of sea anemone development and comparing it to what we see in vertebrates, we can also extrapolate back in time to understand how animals likely developed hundreds of millions of years ago."

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Your baby's gut is crawling with unknown viruses

Babies tumble about with more than 200 previously unknown viral families within their intestines. This large number comes as a surprise to researchers from the University of Copenhagen and COPSAC, who closely studied the diapers of 647 Danish babies and made the first mapping of its kind. These viruses most likely play an important role in protecting children from chronic diseases.

Viruses are usually associated with illness. But our bodies are full of both bacteria and viruses that constantly proliferate and interact with each other in our gastrointestinal tract. While we have known for decades that gut bacteria in young children are vital to protect them from chronic diseases later on in life, our knowledge about the many viruses found there is minimal.

A few years back, this gave University of Copenhagen professor Dennis Sandris Nielsen the idea to delve more deeply into this question. As a result, a team of researchers from COPSAC (Copenhagen Prospective Studies on Asthma in Childhood) and the Department of Food Science at UCPH, among others, spent five years studying and mapping the diaper contents of 647 healthy Danish one-year-olds.

"We found an exceptional number of unknown viruses in the faeces of these babies. Not just thousands of new virus species -- but to our surprise, the viruses represented more than 200 families of yet to be described viruses. This means that, from early on in life, healthy children are tumbling about with an extreme diversity of gut viruses, which probably have a major impact on whether they develop various diseases later on in life," says Professor Dennis Sandris Nielsen of the Department of Food Science, senior author of the research paper about the study, now published in Nature Microbiology.

The researchers found and mapped a total of 10,000 viral species in the children's faeces -- a number ten times larger than the number of bacterial species in the same children. These viral species are distributed across 248 different viral families, of which only 16 were previously known. The researchers named the remaining 232 unknown viral families after the children whose diapers made the study possible. As a result, new viral families include names like Sylvesterviridae, Rigmorviridae and Tristanviridae.

Bacterial viruses are our allies

"This is the first time that such a systematic an overview of gut viral diversity has been compiled. It provides an entirely new basis for discovering the importance of viruses for our microbiome and immune system development. Our hypothesis is that, because the immune system has not yet learned to separate the wheat from the chaff at the age of one, an extraordinarily high species richness of gut viruses emerges, and is likely needed to protect against chronic diseases like asthma and diabetes later on in life," states Shiraz Shah, first author and a senior researcher at COPSAC.

Ninety percent of the viruses found by the researchers are bacterial viruses -- known as bacteriophages. These viruses have bacteria as their hosts and do not attack the children's own cells, meaning that they do not cause disease. The hypothesis is that bacteriophages primarily serve as allies:

"We work from the assumption that bacteriophages are largely responsible for shaping bacterial communities and their function in our intestinal system. Some bacteriophages can provide their host bacterium with properties that make it more competitive by integrating its own genome into the genome of the bacterium. When this occurs, a bacteriophage can then increase a bacterium's ability to absorb e.g. various carbohydrates, thereby allowing the bacterium to metabolise more things," explains Dennis Sandris Nielsen, who continues:

"It also seems like bacteriophages help keep the gut microbiome balanced by keeping individual bacterial populations in check, which ensures that there are not too many of a single bacterial species in the ecosystem. It's a bit like lion and gazelle populations on the savannah."

Shiraz Shah adds:

"Previously, the research community mostly focused on the role of bacteria in relation to health and disease. But viruses are the third leg of the stool and we need to learn more about them. Viruses, bacteria and the immune system most likely interact and affect each other in some type of balance. Any imbalance in this relationship most likely increases the risk of chronic disease."

The remaining ten percent of viruses found in the children are eukaryotic -- that is, they use human cells as hosts. These can be both friends and foes for us:

"It is thought-provoking that all children run around with 10-20 of these virus types that infect human cells. So, there is a constant viral infection taking place, which apparently doesn't make them sick. We just know very little about what's really at play. My guess is that they're important for training our immune system to recognise infections later. But it may also be that they are a risk factor for diseases that we have yet to discover," says Dennis Sandris Nielsen.

Could play an important role in inflammatory diseases

The researchers have yet to discover where the many viruses in the one-year-olds come from. Their best answer thus far is the environment:

"Our gut is sterile until we are born. During birth, we are exposed to bacteria from the mother and environment. It is likely that some of the first viruses come along with these initial bacteria, while many others are introduced later via dirty fingers, pets, dirt that kids put in their mouths and other things in the environment," says Dennis Sandris Nielsen.

As Shiraz Shah points out, the entire field of research speaks to a huge global health problem:

"A lot of research suggests that the majority of chronic diseases that we're familiar with -- from arthritis to depression -- have an inflammatory component. That is, the immune system is not working as it ought to -- which might be because it wasn't trained properly. So, if we learn more about the role that bacteria and viruses play in a well-trained immune system, it can hopefully lead us to being able to avoid many of the chronic diseases that afflict so many people today."

The research groups have begun investigating the role of gut viruses in relation to a number of different diseases that occur in childhood, such as asthma and ADHD.

Read more at Science Daily

New evidence: Immune system cells in the gut linked to stress-induced depression

In experiments with mice and humans, a team led by Johns Hopkins Medicine researchers says it has identified a particular intestinal immune cell that impacts the gut microbiome, which in turn may affect brain functions linked to stress-induced disorders such as depression. Targeting changes mediated by these immune cells in the gut, with drugs or other therapies, could potentially bring about new ways to treat depression.

The findings of the study were published March 20, 2023 in the journal Nature Immunology.

"The results of our study highlight the previously unrecognized role of intestinal gamma delta T cells (γδ T cells) in modifying psychological stress responses, and the importance of a protein receptor known as dectin-1, found on the surface of immune cells, as a potential therapeutic target for the treatment of stress-induced behaviors," says Atsushi Kamiya, M.D., Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study's senior author.

Dectin-1 binds to certain antigens, or proteins, to signal immune cells to activate in specific ways. This receptor, the researchers say, may be involved in the microbiome alteration and immune-inflammatory responses in the colon of mice, which suggests that it may be involved in stress responses via γδ T cells in the intestinal immune system.

On the basis of previous studies suggesting that immune inflammatory responses in the gut are related to depression, Kamiya and his team designed experiments to focus on understanding stress-induced behaviors produced by an imbalance in the gut microbiota -- types of microorganisms found in a specific environment, such as bacteria, fungi and viruses.

To this end, the team examined the effects of chronic social defeat stress (CSDS) on the gut microbiota in mice. CSDS is a standard rodent test to study stress-induced disorders such as depression. In a series of experiments, the researchers simulated potential stress inducing environments that could mimic similar responses in human environments. After each exposure, the mice were assessed and classified as stress-resilient (stress did not diminish social interactions) or stress-susceptible (stress increased social avoidance).

Fecal samples were then collected and put through genetic analysis to identify the diversity of bacteria in the gut microbiota of the mice. The analysis showed that the intestinal organisms were less diverse in stress-susceptible mice than in stress-resilient mice. It specifically revealed that there were less Lactobacillus johnsonii (L. johnsonii) -- a type of probiotic, or "good" bacteria -- in stress-susceptible mice compared to stress-resilient mice.

"We found that stress increased the γδ T cells, which in turn increased social avoidance," says Xiaolei Zhu, M.D., Ph.D., assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and the study's lead author. "However, when the stressed mice were given L. johnsonii, social avoidance decreased and the γδ T cells went to normal levels, suggesting that CSDS-induced social avoidance behavior may be the result of lower levels of the bacteria and γδ T cell changes."

Looking for potential natural approaches for prevention of depression rooted somehow in the gut, the researchers explored how changes in dectin-1 on CSDS-induced elevation of γδ T cells responded to pachyman. A compound extracted from wild mushrooms, pachyman is used as a natural anti-inflammatory agent and for treating depression in Eastern medicine. For this experiment, mice were fed a dose of pachyman, which was shown in previous research to affect immune function. Data from flow cytometry analysis -- a technology used to measure the physical and chemical characteristics of a population of cells -- provided evidence that dectin-1 binds to pachyman, inhibiting CSDS-induced γδ17 T cell activity and easing social avoidance behavior.

To gain insight into how the alterations in the gut microbiota could impact the human brain, the researchers investigated the makeup of gut organisms in people with major depressive disorder (MDD) compared to people without MDD. From June 2017 to September 2020, 66 participants, ages 20 or older, were recruited at Showa University Karasuyama Hospital, Keio University Hospital and Komagino Hospital in Tokyo, Japan. Of the study participants, 32 had MDD (17 women and 15 men). The other 34 participants (18 women and 16 men) who did not have MDD formed the control group.

Stool samples were collected from all study participants, who had comprehensive evaluations including psychiatric history and standard screening assessments for depression and anxiety. In these assessments, higher scores indicate greater depressive symptoms. Genetic analysis of the stool samples showed no difference in the diversity of intestinal bacteria between the subjects with MDD and the control group. However, the relative abundance of Lactobacillus was inversely related to higher depression and anxiety scores in the MDD group, meaning that the more Lactobacillusfound in the gut, the lower the potential for depression and anxiety, the researchers say.

"Despite the differences of intestinal microbiota between mice and humans, the results of our study indicate that the amount of Lactobacillus in the gut may potentially influence stress responses and the onset of depression and anxiety," says Kamiya.

The investigators say more research is needed to further understand how γδ T cells in the intestinal immune system may impact the neurological functions in the brain and the role of dectin-1 in other cell types along the gut-brain connection under stress conditions.

"These early-stage findings show that, in addition to probiotic supplements, targeting drugs to such types of receptors in the gut immune system may potentially yield novel approaches to prevent and treat stress-induced psychiatric symptoms such as depression," says Kamiya.

Read more at Science Daily

Robotic drug capsule can deliver drugs to gut

One reason that it's so difficult to deliver large protein drugs orally is that these drugs can't pass through the mucus barrier that lines the digestive tract. This means that insulin and most other "biologic drugs" -- drugs consisting of proteins or nucleic acids -- have to be injected or administered in a hospital.

A new drug capsule developed at MIT may one day be able to replace those injections. The capsule has a robotic cap that spins and tunnels through the mucus barrier when it reaches the small intestine, allowing drugs carried by the capsule to pass into cells lining the intestine.

"By displacing the mucus, we can maximize the dispersion of the drug within a local area and enhance the absorption of both small molecules and macromolecules," says Giovanni Traverso, the Karl van Tassel Career Development Assistant Professor of Mechanical Engineering at MIT and a gastroenterologist at Brigham and Women's Hospital.

In a study appearing today in Science Robotics, the researchers demonstrated that they could use this approach to deliver insulin as well as vancomycin, an antibiotic peptide that currently has to be injected.

Shriya Srinivasan, a research affiliate at MIT's Koch Institute for Integrative Cancer Research and a junior fellow at the Society of Fellows at Harvard University, is the lead author of the study.

Tunneling through

For several years, Traverso's lab has been developing strategies to deliver protein drugs such as insulin orally. This is a difficult task because protein drugs tend to be broken down in acidic environment of the digestive tract, and they also have difficulty penetrating the mucus barrier that lines the tract.

To overcome those obstacles, Srinivasan came up with the idea of creating a protective capsule that includes a mechanism that can tunnel through mucus, just as tunnel boring machines drill into soil and rock.

"I thought that if we could tunnel through the mucus, then we could deposit the drug directly on the epithelium," she says. "The idea is that you would ingest this capsule and the outer layer would dissolve in the digestive tract, exposing all these features that start to churn through the mucus and clear it."

The "RoboCap" capsule, which is about the size of a multivitamin, carries its drug payload in a small reservoir at one end and carries the tunnelling features in its main body and surface. The capsule is coated with gelatin that can be tuned to dissolve at a specific pH.

When the coating dissolves, the change in pH triggers a tiny motor inside the RoboCap capsule to start spinning. This motion helps the capsule to tunnel into the mucus and displace it. The capsule is also coated with small studs that brush mucus away, similar to the action of a toothbrush.

The spinning motion also helps to erode the compartment that carries the drug, which is gradually released into the digestive tract.

"What the RoboCap does is transiently displace the initial mucus barrier and then enhance absorption by maximizing the dispersion of the drug locally," Traverso says. "By combining all of these elements, we're really maximizing our capacity to provide the optimal situation for the drug to be absorbed."

Enhanced delivery

In tests in animals, the researchers used this capsule to deliver either insulin or vancomycin, a large peptide antibiotic that is used to treat a broad range of infections, including skin infections as well as infections affecting orthopedic implants. With the capsule, the researchers found that they could deliver 20 to 40 times more drug than a similar capsule without the tunneling mechanism.

Once the drug is released from the capsule, the capsule itself passes through the digestive tract on its own. The researchers found no sign of inflammation or irritation in the digestive tract after the capsule passed through, and they also observed that the mucus layer reforms within a few hours after being displaced by the capsule.

Another approach that some researchers have used to enhance oral delivery of drugs is to give them along with additional drugs that help them cross through the intestinal tissue. However, these enhancers often only work with certain drugs. Because the MIT team's new approach relies solely on mechanical disruptions to the mucus barrier, it could potentially be applied to a broader set of drugs, Traverso says.

"Some of the chemical enhancers preferentially work with certain drug molecules," he says. "Using mechanical methods of administration can potentially enable more drugs to have enhanced absorption."

While the capsule used in this study released its payload in the small intestine, it could also be used to target the stomach or colon by changing the pH at which the gelatin coating dissolves. The researchers also plan to explore the possibility of delivering other protein drugs such as GLP1 receptor agonist, which is sometimes used to treat type 2 diabetes. The capsules could also be used to deliver topical drugs to treat ulcerative colitis and other inflammatory conditions by maximizing the local concentration of the drugs in the tissue to help treat the inflammation.

Read more at Science Daily

Cravings for fatty foods traced to gut-brain connection

A dieter wrestling with cravings for fatty foods might be tempted to blame their tongue: the delicious taste of butter or ice cream is hard to resist. But new research investigating the source of our appetites has uncovered an entirely new connection between the gut and the brain that drives our desire for fat.

At Columbia's Zuckerman Institute, scientists studying mice found that fat entering the intestines triggers a signal. Conducted along nerves to the brain, this signal drives a desire for fatty foods. Published September 7, 2022, in Nature, the new study raises the possibility of interfering with this gut-brain connection to help prevent unhealthy choices and address the growing global health crisis caused by overeating.

"We live in unprecedented times, in which the overconsumption of fats and sugars is causing an epidemic of obesity and metabolic disorders," said first author Mengtong Li, PhD, a postdoctoral researcher in the lab of the Zuckerman Institute's Charles Zuker, PhD, supported by the Howard Hughes Medical Institute. "If we want to control our insatiable desire for fat, science is showing us that the key conduit driving these cravings is a connection between the gut and the brain."

This new view of dietary choices and health started with previous work from the Zuker lab on sugar. Researchers found that glucose activates a specific gut-brain circuit that communicates to the brain in the presence of intestinal sugar. Calorie-free artificial sweeteners, in contrast, do not have this effect, likely explaining why diet sodas can leave us feeling unsatisfied.

"Our research is showing that the tongue tells our brain what we like, such as things that taste sweet, salty or fatty," said Dr. Zuker, who is also a professor of biochemistry and molecular biophysics and of neuroscience at Columbia's Vagelos College of Physicians and Surgeons. "The gut, however, tells our brain what we want, what we need."

Dr. Li wanted to explore how mice respond to dietary fats: the lipids and fatty acids that every animal must consume to provide the building blocks of life. She offered mice bottles of water with dissolved fats, including a component of soybean oil, and bottles of water containing sweet substances known to not affect the gut but that are initially attractive. The rodents developed a strong preference, over a couple of days, for the fatty water. They formed this preference even when the scientists genetically modified the mice to remove the animals' ability to taste fat using their tongues.

"Even though the animals could not taste fat, they were nevertheless driven to consume it," said Dr. Zuker.

The researchers reasoned that fat must be activating specific brain circuits driving the animals' behavioral response to fat. To search for that circuit, Dr. Li measured brain activity in mice while giving the animals fat. Neurons in one particular region of the brainstem, the caudal nucleus of the solitary tract (cNST), perked up. This was intriguing because the cNST was also implicated in the lab's previous discovery of the neural basis of sugar preference.

Dr. Li then found the communications lines that carried the message to the cNST. Neurons in the vagus nerve, which links the gut to the brain, also twittered with activity when mice had fat in their intestines.

Having identified the biological machinery underlying a mouse's preference for fat, Dr. Li next took a close look at the gut itself: specifically the endothelial cells lining the intestines. She found two groups of cells that sent signals to the vagal neurons in response to fat.

"One group of cells functions as a general sensor of essential nutrients, responding not only to fat, but also to sugars and amino acids," said Dr. Li. "The other group responds to only fat, potentially helping the brain distinguish fats from other substances in the gut."

Dr. Li then went one important step further by blocking the activity of these cells using a drug. Shutting down signaling from either cell group prevented vagal neurons from responding to fat in the intestines. She then used genetic techniques to deactivate either the vagal neurons themselves or the neurons in the cNST. In both cases, a mouse lost its appetite for fat.

"These interventions verified that each of these biological steps from the gut to the brain is critical for an animal's response to fat," said Dr. Li. "These experiments also provide novel strategies for changing the brain's response to fat and possibly behavior toward food."

The stakes are high. Obesity rates have nearly doubled worldwide since 1980. Today, nearly half a billion people suffer from diabetes.

"The overconsumption of cheap, highly processed foods rich in sugar and fat is having a devastating impact on human health, especially among people of low income and in communities of color," said Dr. Zuker. "The better we understand how these foods hijack the biological machinery underlying taste and the gut-brain axis, the more opportunity we will have to intervene."

Scott Sternson, PhD, a professor of neuroscience at University of California, San Diego, who was not involved in the new research highlighted its potential for improving human health.

"This exciting study offers insight about the molecules and cells that compel animals to desire fat," said Dr. Sternson, whose work focuses on how the brain controls appetite. "The capability of researchers to control this desire may eventually lead to treatments that may help combat obesity by reducing consumption of high-calorie fatty foods."

Read more at Science Daily

DNA in Viking feces sheds new light on 55,000-year-old relationship between gut companions

Using stool samples from Viking latrines, researchers at the University of Copenhagen have genetically mapped one of the oldest human parasites -- the whipworm. The mapping reflects the parasite's global spread and its interaction with human beings, a delicate relationship that can make us healthier and ill.

Using fossilized eggs in up to 2500-year-old feces from Viking settlements in Denmark and other countries, researchers at the University of Copenhagen's Department of Plant and Environmental Sciences and the Wellcome Sanger Institute (UK) have made the largest and most in-depth genetic analysis of one of the oldest parasites found in humans -- the whipworm.

The study, published in Nature Communications, presents completely new knowledge about the parasite's development and prehistoric dispersal. This knowledge can be applied in efforts to prevent the parasite's drug resistance and its future spread.

The study suggests that human and parasite have developed a delicate interaction over thousands of years, whereby the parasite tries to stay "under the radar" not to be repelled, which allows it more time to infect new people. From other studies, it is known that the whipworm stimulates the human immune system and the gut microbiome, to the mutual benefit of both host and parasite.

While whipworm (Trichuris trichiura) is now rare in industrialized countries, and most often only causes minor problems among healthy individuals, the parasite is estimated to affect 500 million people in developing countries.

"In people who are malnourished or have impaired immune systems, whipworm can lead to serious illness. Our mapping of the whipworm and its genetic development makes it easier to design more effective anti-worm drugs that can be used to prevent the spread of this parasite in the world's poorest regions," says Professor Christian Kapel of UCPH's Department of Plant and Environmental Sciences.

Fossilized latrine poop from Copenhagen and Viborg

Eggs, not worms, made it possible for researchers to examine the genetic material of thousands-of-years-old whipworms. Due to extremely durable chitin in egg capsules, their internal DNA has been well preserved while the eggs have been buried in moist soil.

By examining fossilized stool samples which were previously discovered in the latrines of Viking settlements in Viborg and Copenhagen, the researchers isolated the eggs under a microscope, sieved them from the stool and subjected them to refined genetic analyses that the researchers have been perfecting for years in previous studies.

"We have known for a long time that we could detect parasite eggs up to 9000 years old under a microscope. Lucky for us, the eggs are designed to survive in soil for long periods of time. Under optimal conditions, even the parasite's genetic material can be preserved extremely well. And some of the oldest eggs that we've extracted some DNA from are 5000 years old. It has been quite surprising to fully map the genome of 1000-year-old well-preserved whipworm eggs in this new study," explains Christian Kapel.

The researchers examined archaeological stool samples from several locations. These ancient genetic samples are compared with contemporary samples obtained from people with whipworms from around the world. Doing so has provided researchers with an overview of the worm's genome and its evolution over ten-thousands of years.

"Unsurprisingly, we can see that the whipworm appears to have spread from Africa to the rest of the world along with humans about 55,000 years ago, following the so-called 'out of Africa' hypothesis on human migration," explains Christian Kapel.

Can live unnoticed in the intestine for months

A whipworm can grow five to seven centimeters in length and live unnoticed in the intestine of a healthy individual for several months. During this time, it lays eggs continuously, which are expelled through feces. In people with weakened immune systems, whipworm can cause a wide range of gastrointestinal diseases, malnutrition and even delay childhood development.

Worms are transmitted via the fecal-oral route, meaning that microscopic parasite eggs in soil can spread to drinking water or food, after which they are ingested through the mouth of a new host.

"The eggs lie in the ground and develop for roughly three months. Once matured, eggs can survive in the wild for even longer, as they wait to be consumed by a new host in whose digestive tract they will then hatch. Their entire life cycle is adapted to survive in soil for as long as possible," explains Christian Kapel.

As such, the golden years for these worms in our part of the world were when our toilet and kitchen conditions, as well as personal hygiene, were significantly different than today.

Read more at Science Daily

How the gut may help to drive COVID-19

New findings from Flinders University have demonstrated a molecular link between COVID-19 and serotonin cells in the gut.

The research could help provide further clues to what could be driving COVID-19 infection and disease severity and supports previous evidence that antidepressants, known as selective serotonin reuptake inhibitors (SSRIs), could reduce the severity of COVID symptoms.

COVID-19 displays an array of symptoms, which can regularly include gastrointestinal issues such as diarrhoea. Recent research has indicated that these gut symptoms in COVID-19 patients worsen with the severity of the disease, and this is linked to heightened gut-derived serotonin, released to cause gut dysfunction, increasing the body's immune response and potentially worsening patient outcomes.

Published in the world's leading gastrointestinal research journal Gut, this new collaborative study involved three Flinders research teams, including teams led by ARC DECRA Fellow Dr Alyce Martin and FAME Director of Bioinformatics and Human-Microbe Interactions, Professor Robert Edwards.

"Our study endeavoured to understand whether the gut could be a site of disease transmission and what genes might be associated with the virus entering the cells lining the gut wall," says study senior author Professor Damien Keating, Deputy Director of the Flinders Health and Medical Research Institute and Head of the Gut Sensory Systems research group.

The researchers looked at gene expression amongst the different cell types that line the gut wall, analysing whole genome sequences from thousands of individual cells from within the intestine.

They found specialised cells within the gut that synthesised and released serotonin had a highly enriched expression of a particular SARS-CoV-2 receptor and were the only type of cell that expressed all the genes associated with COVID-19.

"Many genes linked to COVID-19 were found expressed in the different cell types lining the gut wall but only serotonin cells expressed all three receptors for the virus," says Professor Keating.

"Expression of all three SARS-CoV-2 receptors triples the rate of cell infectivity, compared to expression of only two receptors."

With the exact sites of infection and the primary drivers of COVID-19 disease severity not yet fully understood, the authors say this study provides important information on the gut's role in the virus.

"Our study adds further evidence that COVID-19 is far more likely to infect cells in the gut and increase serotonin levels through direct effects on specific gut cells, potentially worsening disease outcomes," says Professor Keating.

"It also provides further support to emerging clinical evidence that antidepressant drugs, which block serotonin transport around the body, may serve as a beneficial treatment.

"As COVID-19 continues to circulate, further research will be required to advance our understanding of the gut's role in this virus and continue to find treatment options to work alongside vaccinations."

Read more at Science Daily

Why breast-fed premature infants have a healthier gut than formula-fed ones

Human breastmilk has long been considered "liquid gold" among clinicians treating premature infants in a newborn intensive care unit (NICU). Breastmilk-fed "preemies" are healthier, on average, than those fed formula. Why is that true, however, has remained a mystery.

New research from the University of Maryland School of Medicine's (UMSOM) Institute for Genome Sciences (IGS), published online in the journal mBio in June found it is not just the content of breastmilk that makes the difference. It is also the way the babies digest it.

The research, led by Bing Ma, PhD, Assistant Professor of Microbiology and Immunology at UMSOM and a researcher at IGS, discovered a strain of the Bifidobacterium breve bacteria or B. breve in the gut of breastfed babies who received higher volumes of breastmilk than their counterparts. Those preemies had better nutrient absorption because they developed an intact intestinal wall, one week after birth. B. breve was much less prevalent in both formula-fed babies and breastfed babies with "leaky gut." Babies with leaky gut do not develop a barrier to protect against bacteria and digested food from getting into the bloodstream. For the first time, the team also found that the way B. breve metabolizes breastmilk keeps breastfed babies healthier and allows them to gain weight by strengthening their underdeveloped intestinal barrier.

An immature or "leaky" gut can lead to necrotizing enterocolitis (NEC), which is the third leading cause of newborn death in United States and worldwide. In fact, NEC impacts up to 10 percent of premature babies with a devasting mortality rate as high as 50 percent.

"Our discovery could lead to promising and practical clinical interventions to strengthen the babies' gut and, therefore, increase survival rates of the most vulnerable preemies," said Dr. Ma.

Bifidobacterium in the gut or microbiome has long been known to have health benefits. It includes a diverse set of strains that have very different properties. Some strains are only found in adults; some are mostly in adolescence. One strain, Bifidobacterium infantis, has been seen predominantly in full-term infants.

The researchers followed 113 premature babies who were born between 24 and 32 weeks' gestation. This study found Bifidobacterium breve (B. breve) only in preemies who had improved gut barrier function within one week after birth. Dr. Ma and her colleagues discovered that Bifidobacterium breve is genetically equipped to digest nutrients within the cell membrane rather than the more typical external digestion process in which bacteria secrete digestive enzymes onto nutrients to break them down.

At the most basic level, the gut microbiome in these breastfed preemies with more B. breve metabolizes carbohydrates differently than it does formula. The researchers say they hypothesize that this process of metabolism then strengthens and matures the intestinal barrier faster, protecting fragile newborns from disease.

"We now know that it is not the breastmilk alone that helps preemies develop their intestinal barrier faster," Dr. Ma said. "We will need to find the best way to prophylactically administer B. breve early in life, rather than rely on transmission from breastmilk or even the mother's gut or vaginal microbiota during the birthing process. This is especially critical in formula-fed preemies."

Dr. Ma said that more studies are needed to determine if the B. breve originated in the breastmilk, gut, mother's vagina, or even environment.

Read more at Science Daily

Diet type can increase potentially harmful gas in the gut

Published in Clinical Nutrition, researchers from the University of Minnesota Medical School looked at colonic hydrogen sulfide -- a toxic gas in the body that smells like rotten eggs -- production in people in response to animal- and plant-based diet interventions.

"Although the role of hydrogen sulfide has long been a subject of great interest in the pathogenesis of multiple important diseases -- such as ulcerative colitis, colon cancer, and obesity -- past investigations have not been able to link dietary data, microbiome characterization and actual hydrogen sulfide production," said Alexander Khoruts, MD, a gastroenterologist in the U of M Medical School and M Health Fairview. "This is what we have done here."

From a human cohort, the study supports the general hypothesis that hydrogen sulfide produced by the gut microbiota increases with an animal-based diet. However, the results also suggested the existence of gut microbiome enterotypes that respond differentially and even paradoxically to different dietary input.

The study found that:
 

• In the majority of participants, a plant-based diet resulted in a lower hydrogen sulfide production compared to an animal-based (i.e., western) diet.
• As expected, a plant-based diet contained more fiber, while an animal-based diet contained more protein.
• In some individuals, plant-based diets did not lower hydrogen sulfide production and even led to some increases in it.
• Preliminary results suggested the existence of different compositions of gut microbiota (enterotypes) that correlate with differential responsiveness to diet in terms of hydrogen sulfide production.

"The study was consistent with the general understanding that regular intake of fiber-containing foods is beneficial to gut health," said Dr. Levi Teigen, a nutrition researcher in the Division of Gastroenterology in the U of M Medical School. "Future analyses of the gut microbiome may help to individualize nutrition interventions."

Read more at Science Daily

Got food cravings? What's living in your gut may be responsible

Eggs or yogurt, veggies or potato chips? We make decisions about what to eat every day, but those choices may not be fully our own. New University of Pittsburgh research on mice shows for the first time that the microbes in animals' guts influence what they choose to eat, making substances that prompt cravings for different kinds of foods.

"We all have those urges -- like if you ever you just feel like you need to eat a salad or you really need to eat meat," said Kevin Kohl, an assistant professor in the Department of Biology in the Kenneth P. Dietrich School of Arts and Sciences. "Our work shows that animals with different compositions of gut microbes choose different kinds of diets."

Despite decades of speculation by scientists about whether microbes could influence our preferred diets, the idea has never been directly tested in animals bigger than a fruit fly. To explore the question, Kohl and his postdoc Brian Trevelline (A&S '08), now at Cornell University, gave 30 mice that lacked gut microbes a cocktail of microorganisms from three species of wild rodents with very different natural diets.

The duo found that mice in each group chose food rich in different nutrients, showing that their microbiome changed their preferred diet. The researchers published their work today in the Proceedings of the National Academy of Sciences.

While the idea of the microbiome affecting your behavior may sound far-fetched, it's no surprise for scientists. Your gut and your brain are in constant conversation, with certain kinds of molecules acting as go-betweens. These byproducts of digestion signal that you've eaten enough food or maybe that you need certain kinds of nutrients. But microbes in the gut can produce some of those same molecules, potentially hijacking that line of communication and changing the meaning of the message to benefit themselves.

One such messenger will be familiar to anyone who's had to take a nap after a turkey dinner: tryptophan.

"Tryptophan is an essential amino acid that's common in turkey but is also produced by gut microbes. When it makes its way to the brain, it's transformed into serotonin, which is a signal that's important for feeling satiated after a meal," Trevelline said. "Eventually that gets converted into melatonin, and then you feel sleepy."

In their study, Trevelline and Kohl also showed that mice with different microbiomes had different levels of tryptophan in their blood, even before they were given the option to choose different diets -- and those with more of the molecule in their blood also had more bacteria that can produce it in their gut.

It's a convincing smoking gun, but tryptophan is just one thread of a complicated web of chemical communication, according to Trevelline. "There are likely dozens of signals that are influencing feeding behavior on a day-to-day basis. Tryptophan produced by microbes could just be one aspect of that," he said. It does, however, establish a plausible way that microscopic organisms could alter what we want to eat -- it's one of just a few rigorous experiments to show such a link between the gut and the brain despite years of theorizing by scientists.

There's still more science to do before you should start distrusting your food cravings, though. Along with not having a way to test the idea in humans, the team didn't measure the importance of microbes in determining diet compared to anything else.

"It could be that what you've eaten the day before is more important than just the microbes you have," Kohl said. "Humans have way more going on that we ignore in our experiment. But it's an interesting idea to think about."

Read more at Science Daily

Decoding a direct dialog between the gut microbiota and the brain

Gut microbiota by-products circulate in the bloodstream, regulating host physiological processes including immunity, metabolism and brain functions. Scientists from the Institut Pasteur (a partner research organization of Université Paris Cité), Inserm and the CNRS have discovered that hypothalamic neurons in an animal model directly detect variations in bacterial activity and adapt appetite and body temperature accordingly. These findings demonstrate that a direct dialog occurs between the gut microbiota and the brain, a discovery that could lead to new therapeutic approaches for tackling metabolic disorders such as diabetes and obesity. The findings are due to be published in Science on April 15, 2022.

The gut is the body's largest reservoir of bacteria. A growing body of evidence reveals the degree of interdependence between hosts and their gut microbiota, and emphasizes the importance of the gut-brain axis. At the Institut Pasteur, neurobiologists from the Perception and Memory Unit (Institut Pasteur/CNRS), immunobiologists from the Microenvironment and Immunity Unit (Institut Pasteur/Inserm), and microbiologists from the Biology and Genetics of the Bacterial Cell Wall Unit (Institut Pasteur/CNRS/Inserm) have shared their expertise to investigate how bacteria in the gut directly control the activity of particular neurons in the brain.

The scientists focused on the NOD2 (nucleotide oligomerization domain) receptor which is found inside of mostly immune cells. This receptor detects the presence of muropeptides, which are the building blocks of the bacterial cell wall. Moreover, it has previously been established that variants of the gene coding for the NOD2 receptor are associated with digestive disorders, including Crohn's disease, as well as neurological diseases and mood disorders. However, these data were insufficient to demonstrate a direct relationship between neuronal activity in the brain and bacterial activity in the gut. This was revealed by the consortium of scientists in the new study.

Using brain imaging techniques, the scientists initially observed that the NOD2 receptor in mice is expressed by neurons in different regions of the brain, and in particular, in a region known as the hypothalamus. They subsequently discovered that these neurons' electrical activity is suppressed when they come into contact with bacterial muropeptides from the gut. "Muropeptides in the gut, blood and brain are considered to be markers of bacterial proliferation," explains Ivo G. Boneca, Head of the Biology and Genetics of the Bacterial Cell Wall Unit at the Institut Pasteur (CNRS/Inserm). Conversely, if the NOD2 receptor is absent, these neurons are no longer suppressed by muropeptides. Consequently, the brain loses control of food intake and body temperature. The mice gain weight and are more susceptible to developing type 2 diabetes, particularly in older females.

In this study, the scientists have demonstrated the astonishing fact that neurons perceive bacterial muropeptides directly, while this task was thought to be primarily assigned to immune cells. "It is extraordinary to discover that bacterial fragments act directly on a brain center as strategic as the hypothalamus, which is known to manage vital functions such as body temperature, reproduction, hunger and thirst," comments Pierre-Marie Lledo, CNRS scientist and Head of the Institut Pasteur's Perception and Memory Unit.

The neurons thus appear to detect bacterial activity (proliferation and death) as a direct gauge of the impact of food intake on the intestinal ecosystem. "Excessive intake of a specific food may stimulate the disproportionate growth of certain bacteria or pathogens, thus jeopardizing intestinal balance," says Gérard Eberl, Head of the Microenvironment and Immunity Unit at the Institut Pasteur (Inserm).

Read more at Science Daily

Scientists map entire human gut at single cell resolution

If you get nervous, you might feel it in your gut. If you eat chili, your gut might revolt, but your friend can eat anything and feel great. You can pop ibuprofen like candy with no ill effects, but your friend's belly might bleed and might get no pain relief. Why is this? The quick answer is because we're all different. The next questions are how different exactly, and what do these differences mean for health and disease? Answering these is much more difficult, but the UNC School of Medicine lab of Scott Magness, PhD, is revealing some interesting scientific answers.

For the first time, the Magness lab used entire human GI tracts from three organ donors to show how cell types differ across all regions of the intestines, to shed light on cellular functions, and to show gene expression differences between these cells and between individuals.

This work, published in Cellular and Molecular Gastroenterology and Hepatology, opens the door to exploring the many facets of gut health in a much more precise manner at greater resolution than ever before.

"Our lab showed it's possible to learn about each cell type's function in important processes, such as nutrient absorption, protection from parasites, and the production of mucus and hormones that regulate eating behavior and gut motility," said Magness, associate professor in the Joint UNC-NC State Department of Biomedical Engineering and senior author of the paper. "We also learned how the gut lining might interact with the environment through receptors and sensors, and how drugs could interact with different cell types."

The Sensitive Gut

Think of a typical pharmaceutical commercial voiceover when the voice actor pleasantly recites possible side effects, such as diarrhea, vomiting, intestinal bleeding, and other unpleasant collateral damage. Well, the Magness lab is attempting to understand why those side effects happen, down to the level of individual cells, their functions, their locations, and their genes.

For this research, the Magness lab focused on the epithelium: the single-cell thick layer separating the inside of the intestines and colon from everything else. Like other cell populations and the microbiota, the epithelium is incredibly important to human health, and for years scientists have been exploring it. But until now, researchers could only take tiny biopsies the size of grains of rice from a few parts of the digestive tract, usually from the colon or limited regions of the small intestine.

"Such exploration would be like looking at the United States from space but only investigating what's going on in Massachusetts, Oklahoma, and California," Magness said. "To really learn about the country, we'd want to see everything."

Magness leaned on co-first authors, postdoctoral fellow Joseph Burclaff, PhD, and graduate student, Jarrett Bliton, both trainees in the Magness lab.

"Not only do we want to identify where the cells are located, but we want to know exactly which cell types do what, and why," Burclaff said. "So, staying with the map analogy, we don't want to just say, 'oh, there's North Carolina'. We want to know where to get the best barbecue. We want a ground level view to know as much as possible."

In the past, researchers would mash up those rice-sized biopsies to identify all epithelial cell types and learn some general features of these cells. Magness's approach was to sample thousands of individual cells from every part of the lower digestive tract (small intestine and colon) to create an atlas and then study the potential roles of these cells through the genes that each cell expresses. Knowing all of this would deepen scientific knowledge about the gut epithelium and hopefully encourage other scientists to explore each cell's function in biology, in disease, and in the unfortunate scenario of pharmaceutical side effects.

To do such a deep individual cell dive, Magness needed two things: better technology and the entire digestive tracts of humans.

The Biology of Data

UNC-Chapel Hill acquired state-of-the-art RNA sequencing technology several years ago for the creation of the Advanced Analytics Core Facility through the UNC Center for Gastrointestinal Disease and Biology, which developed the scientific and intellectual heft -- research faculty, staff, postdocs, and students -- to use state-of-the-art equipment.

The Magness Group acquired human digestive tracts through a research agreement with organ donor services at HonorBridge. When intestines are harvested for transplant and if they are not claimed by higher-priority groups, HonorBridge staff coordinates with the Magness Group to donate the transplant-grade organs for research.

Six to eight hours after harvest, the Magness lab receives intact intestinal tracts, each about 15 to 30 feet long. They remove the epithelial layer, which is one long connected piece of tissue despite being only one cell thick. Then the researchers use enzymes to break down the epithelium into individual cells. For this study, they repeated this for organs from three separate donors.

Using sequencing technology to characterize gene expression, the Magness group first extracts RNA from each cell while keeping each cell separate, and then they run single-cell sequencing, which takes a snapshot of which genes each intestinal cell is expressing and how much.

"The picture we get from each cell is a mosaic of all the different types of genes the cells make and this complement of genes creates a 'signature' to tell us what kind of cell it is and potentially what it is doing," Magness said. "Is it a stem cell or a mucous cell or a hormone-producing cell or an immune-signaling cell?

Burclaff added, "We were able to see the differences in cell types throughout the entire digestive tracts, and we can see different gene expression levels in the same cell types from three different people. We can see the different sets of genes turned on or off in individual cells. This is how, for instance, we might begin to understand why some people form toxicity to certain foods or drugs and some people don't."

A major problem with this kind of research is the sheer amount of data produced. The single cell sequencing picks up about 11,000 'reads', or individual samples of gene products in just one cell, and in many thousands of individual cells, each with different combinations of the 20,000-plus human genes that are turned on or off. This creates almost 140,000,000 data points for all the 12,590 cells in the study that have to be put into a visualizable format so that scientists can make sense of the vast amount of information.

"The human brain can only comprehend two dimensions, three is challenging," Magness said. "Add time, and it's even trickier to comprehend what a single cell is up to. The amount of data our experiments produced was basically millions of dimensions all at once."

Bliton devised computational techniques to filter the data to produce a manageable data set that included cell populations from all portions of the GI tract. Then, based on what Magness and other researchers had already learned of each cell type, Bliton could computationally identify each cell type from each region. He then plotted these data in a manner that humans can understand and interpret.

Reining in the immense data allowed the scientists to learn a lot about each cell type. Consider the tuft cell, discovered 40 years ago and so named because they look as if they have tufts of hair on their surface. Turns out these tuft cells express similar genes as those on taste buds on the tongue. Other researchers discovered that these tuft cells sensed worm infections and sent signals to the immune system to begin waging war. The Magness lab showed that tuft cells exhibit a set of genes thought to be important for sensing and "tasting" other kinds of intestinal content so it can signal the immune system if need be. This would represent a much broader function than sensing if there's a parasite in your gut or not.

"Not only did we describe every single cell type and every single gene they express individually, but we also looked at potential functions," Burclaff said. "If you look at intestinal mucus, which is a complex mixture that protects the cells, we show which cells express various mucin proteins, how much, and in which regions of the digestive tract. We looked at where specific enzymes that digest food are expressed. We looked at cells with anti-inflammatory gene expression and synapse genes where the gut is probably connected to nerves so it can talk to the rest of the body. We looked at aquaporins, proteins involved in transferring water through the intestinal membrane."

What the Magness group found was a whole new level of variation in potential functions that had not previously been appreciated through mashing up biopsy samples.

The researchers explored all epithelial receptors -- the cell surface proteins used to communicate with other cells and molecules and with the environment of the gut. Magness and colleagues could see which receptors were expressed the most and in which cell types, painting a new picture of how cells might interact with gut contents such as nutrients, microbes, toxins, and drugs.

"As far as we know, we're the first to do this kind of analysis across the length of the human gut from three full donors," Bliton said. "We can look at each cell type and predict which pharmaceuticals might affect which cell type individually."

For instance, there's a class of drugs to treat inflammatory bowel disease; they're designed to hit specific targets, certain immune cells that trigger inflammation. But the Magness lab learned that some epithelial cells express the same genes as those in the immune cells that are intended to be the target. This finding indicates there could be "off-target" effects in epithelial cells that are not intended and could lead to side-effects.

"This was not known," Burclaff said. "Lots of drugs have bad GI side effects. And it could be because the drugs are affecting individual cells along the entire length of the GI tract. We show where these receptors are most expressed and in which cell types."

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