Remodeling gut microbiomes to fight disease

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You are what you eat — right down to the microbiome living in your gut. Diet can affect which microbes are in the intestinal tract, and research has shown that harmful gut microbiome changes can lead to illnesses such as heart disease, obesity and cancer. Today, scientists will report the development of molecules that can change, or remodel, unhealthful gut microbiomes in mice into more healthful ones.

The research could also someday be applied to other conditions related to diet.

The researchers will present their results at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition. ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,500 presentations on a wide range of science topics.

“The gut microbiome contains hundreds of different species of bacteria and is where the largest concentration of bacteria living in us resides,” says M. Reza Ghadiri, Ph.D., leader of the study. “If we all ate a healthy diet, exercised and didn’t age, we wouldn’t have problems with our gut microbiome and many diseases. But, that’s not how all people live. Current methods aimed at improving the makeup of gut microbiomes have involved prebiotics, probiotics or drug therapies. Our goal was to take a totally new approach — to remodel the microbiome.”

The key to the research is a class of molecules called self-assembling cyclic D, L-?-peptides. They were created in Ghadiri’s laboratory originally to kill pathogenic bacteria. Peptides are short chains of amino acids linked together; they are the building blocks of proteins. Ghadiri’s peptides are not found in nature and have a highly specific mode of activity and selectivity against different bacterial species.

“Our hypothesis was that instead of killing bacteria, if we could selectively modulate the growth of certain bacteria species in the gut microbiome using our peptides, more beneficial bacteria would grow to fill the niche, and the gut would be ‘remodeled’ into a healthful gut,” Ghadiri explains. “Our theory was that process would prevent the onset or progression of certain chronic diseases.”

To test this hypothesis, Ghadiri chose cardiovascular disease and used a strain of mice known as LDL receptor knockout mice. “These mice have been bred to thrive on low-fat diets, but when they are fed a diet high in saturated fat — a so-called Western diet — they develop high plasma cholesterol, especially the LDL or ‘bad’ type,” Ghadiri explains. “Within 10 to 12 weeks, they develop plaques in their arteries such as you would find in atherosclerosis patients.” LDL receptor knockout mice are the “gold standard” to test the effectiveness of statins, which are widely used to reduce cholesterol levels.

To find the best peptides to test on the mouse model, the team developed a mass screening assay. The scientists grew a representative mouse microbiome in the lab and then tested various peptides with it. Ghadiri then selected two peptides that appeared to be the most effective for remodeling the mouse gut microbiome into a state resembling the gut microbiome of the mice on a low-fat diet.

The subsequent study included three groups of mice. One group was fed a low-fat diet, another group was fed a Western diet, and a third group was fed a Western diet plus oral doses of one or the other of the two peptides. From fecal samples, the researchers sequenced the gut microbiome from all three groups before and after dosing. They also measured the levels of molecules that affect the immune system, inflammation and metabolism, and examined the animals’ arteries for plaques.

“Mice fed the Western diet with our peptides had a 50% reduction in total plasma cholesterol, and there was no significant plaque in the arteries, compared to the mice fed a Western diet and no peptides,” Ghadiri says. “We also saw suppressed levels of molecules that increase inflammation and rebalanced levels of disease-relevant metabolites. These mice resembled those on a low-fat diet.”

The mechanisms by which this takes place most likely involve genes that affect bile acids, which in turn affect the metabolism of cholesterol, as well as other genes that affect inflammatory processes such as atherosclerosis Ghadiri says.

“This is the first time anyone has shown that there are molecules to purposefully remodel the gut microbiome and turn an unhealthful gut into a more healthful one,” he says. “This opens up clear therapeutic possibilities. We can sequence the guts of individuals and eventually develop therapies.”

Learn more: Remodeling unhealthful gut microbiomes to fight disease

 

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3D printed pill can sample the gut microbiome for diagnosis and treatment

Microbiome sampling pill in the small intestine. Source: Nano Lab, Tufts University

The pill is the first known working device capable of non-invasively and accurately assessing the profile of bacterial species inhabiting any stage of the gastrointestinal tract.

A research team led by Tufts University engineers has developed a 3D printed ingestible pill that samples bacteria found in the gut — known as the microbiome — as it passes through the gastrointestinal tract (GI). The ability to profile bacterial species inhabiting the gut could have important implications for the understanding of conditions that affect and are affected by the intestinal microbiome, according to the researchers.

The 3D printed pill described in the journal Advanced Intelligent Systems represents the first non-invasive diagnostic tool capable of providing a profile of microbiome populations throughout the entire GI tract, according to the researchers. Current methods of sampling the microbiome involve primarily the analysis of fecal DNA and metabolites, but that approach provides little information of the environment upstream of the distal colon, where bacterial species can vary significantly.

The pill has been studied extensively in vitro and in vivo and found to provide accurate identification of bacterial populations and their relative abundance, the paper says. It has been tested in pigs and primates, yet clinical trials will be needed to determine if the pill can be used routinely in humans for clinical care.

More than 1,000 species of bacteria inhabit the healthy gut. The vast majority of these bacteria have a beneficial, supportive role in digestion and protection against disease. When the natural balance of the microbiome is disturbed, a condition called “dysbiosis” occurs, which can be associated with inflammation, susceptibility to infections, and even the exacerbation of other diseases such as cancer. Research is increasingly unveiling specific microbiome metabolites that have beneficial or protective effects against disease.

“We are learning quite a lot about the role of gut microbiome in health and disease. However, we know very little about its biogeography,” said Sameer Sonkusale, professor of electrical and computer engineering at Tufts University’s School of Engineering and corresponding author of the study. “The pill will improve our understanding of the role of spatial distribution in the microbiome profile to advance novel treatments and therapies for a number of diseases and conditions.”

The pill is more sophisticated than just a sponge. It is manufactured in a 3D printer with microfluidic channels that can sample different stages of the GI tract. The surface of the pill is covered with a pH sensitive coating, so that it does not absorb any samples until it enters the small intestine (bypassing the stomach) where the coating dissolves. A semi-permeable membrane separates two chambers in the pill – one containing helical channels that take up the bacteria and the other containing a calcium salt-filled chamber. The salt chamber helps create an osmotic flow across the membrane which pulls the bacteria into the helical channels. A small magnet in the pill enables one to hold it at certain locations in the gut for more spatially targeted sampling using a magnet outside the body. A fluorescent dye in the salt chamber helps locate the pill after it exits the GI tract.

“The design of this device makes it incredibly easy to use, posing little risk to the subject, yet providing so much information,” said Giovanni Widmer, professor of infectious disease and global health at Cummings School of Veterinary Medicine at Tufts University, and co-author of the study responsible for testing the pill’s effectiveness in animals and for high throughput sequencing the microbiome samples.

The researchers see this technology as bridging an important gap in understanding the complexity of the ecosystem of the gut. “We have advanced technologies to analyze bacterial populations using DNA sequencing, but until now have not had a way to sample bacteria throughout the GI tract in a way that is not invasive,” said Hojatollah Rezaei Nejad, a post-doctoral fellow studying novel applications of 3D printing in Sonkusale’s laboratory at Tufts and lead author of the study. “By sampling non-invasively, this pill could help us better identify and understand the role of different intestinal bacterial species in health and disease.”

Learn more: 3D printed pill samples gut microbiome to aid diagnosis and treatment

 

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A non-invasive test for bowel diseases and perhaps more

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Gut diseases such as inflammatory bowel disease (IBD) are increasingly prevalent worldwide, especially in industrialised countries. In 2015 alone, 250,000 people in the UK were diagnosed with IBD, and 3 million in the United States (1, 2). Symptoms can include pain and swelling of the stomach, bloody diarrhoea, weight loss and extreme tiredness.

A new study in Experimental Physiology proposes a novel, non-invasive test for assessing gut function that may help screen and monitor treatment of gut diseases using only a small sample (1 mL) of blood and stool.  How well your gut functions is determined by the gut-blood barrier , a complex multi-layer system. This can be compared to a fine-tuned filter that precisely controls the passage of nutrients and prevents bacteria passing from inside the bowel into the bloodstream.

In those with IBD, and other intestinal diseases, the gut-blood barrier is impaired.  Here the intestinal wall is more like a ripped sieve, allowing more bacterial products to pass from the gut into the blood. This is commonly referred to as a leaky gut.

This test measures the concentration of gut bacterial products (produced by bacteria during metabolism) in the patient’s blood and stool.  The authors believe that with further research this assessment of gut leakage will be very important in the diagnosis and treatment of IBD and other intestinal diseases.

The usual strategy for diagnosing and monitoring IBD is based on a colonoscopy, which is invasive, often requires anaesthesia, and assesses structural lesions, rather than gut malfunction. Gut disorders can happen before there are visible structural changes, so diagnosing based on functional tests evaluating gut leakage could allow clinicians to detect the disease earlier.  While there is no cure for IBD, it is controllable. Early diagnosis would enable patients to control symptoms before they became severe, improving their quality of life.

This new research provides a non-invasive, simple test that could not only be useful for diagnosing IBD, but also other gut disorders, such as celiac disease and food allergies. It’s also helpful for detecting  diseases that result in a leaky gut, such as heart failure, high blood pressure and liver ailments.

Marcin Ufnal, senior author on the study said:

“This may be a very important tool for diagnosis and treatment of gut and other diseases, using the leaky gut as a marker for disease, as well as a potential target for treatment. “

Learn more: New, non-invasive test for bowel diseases

 

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Can gut bacteria prevent and even reverse food allergies?

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Study finds altered gut microbiota in infants with food allergy; oral therapy to replenish bacteria prevented food allergy and suppressed established disease in mice.

Every three minutes, a food-related allergic reaction sends someone to the emergency room in the U.S. Currently, the only way to prevent a reaction is for people with food allergies to completely avoid the food to which they are allergic. Researchers are actively seeking new treatments to prevent or reverse food allergies in patients. Recent insights about the microbiome — the complex ecosystem of microorganisms that live in the gut and other body sites — have suggested that an altered gut microbiome may play a pivotal role in the development of food allergies. A new study, led by investigators from Brigham and Women’s Hospital and Boston Children’s Hospital, identifies the species of bacteria in the human infant gut that protect against food allergies, finding changes associated with the development of food allergies and an altered immune response. In preclinical studies in a mouse model of food allergy, the team found that giving an enriched oral formulation of five or six species of bacteria found in the human gut protected against food allergies and reversed established disease by reinforcing tolerance of food allergens. The team’s results are published in Nature Medicine.

“This represents a sea change in our approach to therapeutics for food allergies,” said co-senior author Lynn Bry, MD, PhD, director of the Massachusetts Host-Microbiome Center at the Brigham. “We’ve identified the microbes that are associated with protection and ones that are associated with food allergies in patients. If we administer defined consortia representing the protective microbes as a therapeutic, not only can we prevent food allergies from happening, but we can reverse existing food allergies in preclinical models. With these microbes, we are resetting the immune system.”

The research team conducted studies in both humans and preclinical models to understand the key bacterial species involved in food allergies. The team repeatedly collected fecal samples every four to six months from 56 infants who developed food allergies, finding many differences when comparing their microbiota to 98 infants who did not develop food allergies. Fecal microbiota samples from infants with or without food allergies were transplanted into mice who were sensitized to eggs. Mice who received microbiota from healthy controls were more protected against egg allergy than those who received microbiota from the infants with food allergies.

Using computational approaches, researchers analyzed differences in the microbes of children with food allergies compared to those without in order to identify microbes associated with protection or food allergies in patients. The team tested to see if orally administering protective microbes to mice could prevent the development of food allergies. They developed two consortia of bacteria that were protective. Two separate consortia of five or six species of bacteria derived from the human gut that belong to species within the Clostridiales or the Bacteroidetes could suppress food allergies in the mouse model, fully protecting the mice and keeping them resistant to egg allergy. Giving other species of bacteria did not provide protection.

“It’s very complicated to look at all of the microbes in the gut and make sense of what they may be doing in food allergy, but by using computational approaches, we were able to narrow in on a specific group of microbes that are associated with a protective effect,” said co-first author Georg Gerber, MD, PhD, MPH, co-director of the Massachusetts Host-Microbiome Center and chief of the Division of Computational Pathology in the Department of Pathology at the Brigham. “Being able to drill down from hundreds of microbial species to just five or six or so has implications for therapeutics and, from a basic science perspective, means that we can start to figure out how these specific bacteria are conferring protection.”

To understand how the bacteria species might be influencing food allergy susceptibility, the team also looked at immunological changes, both in the human infants and in mice. They found that the Clostridiales and Bacteroidetes consortia targeted two important immunological pathways and stimulated specific regulatory T cells, a class of cells that modulate the immune system, changing their profile to promote tolerant responses instead of allergic responses. These effects were found both in the pre-clinical models and also found to occur in human infants.

The new approach represents a marked contrast to oral immunotherapy, a strategy that aims to increase the threshold for triggering an allergic reaction by giving an individual small but increasing amounts of a food allergen. Unlike this approach, the bacteriotherapy changes the immune system’s wiring in an allergen-independent fashion, with potential to broadly treat food allergies rather than desensitizing an individual to a specific allergen.

“When you can get down to a mechanistic understanding of what microbes, microbial products, and targets on the patient side are involved, not only are you doing great science, but it also opens up the opportunity for finding a better therapeutic and a better diagnostic approach to disease. With food allergies, this has given us a credible therapeutic that we can now take forward for patient care,” said Bry.

Learn more: New Therapy Targets Gut Bacteria to Prevent and Reverse Food Allergies

 

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Fecal transplants from young to aged mice can stimulate the gut microbiome and revive the gut immune system

The image shows a confocal microscope image of immune cells in the epithelial lining of the intestine of a young mouse. The cells are localised within specialised lymphoid tissue in the epithelial lining of the intestine called a Peyer’s patch. Here, B and T cells interact to mediate an effective antibody response against the gut microbiota. Naïve B cells are shown in orange, while proliferating cells – including germinal centre B cells – are blue. All T cells are stained green and regulatory Foxp3+ T cells can be recognised by their purple centre. Image credit: Marisa Stebegg, Babraham Institute.

  • Faecal transplants from young mice replenishes the gut microbiome and boosts the gut immune system in older mice.
  • The study demonstrates that the decline in the gut immune response due to age is not irreversible and that it can be boosted in older individuals.
  • The gut microbiome could be a target for the treatment of a range of age-associated symptoms to facilitate healthy ageing.

Faecal transplants from young to aged mice can stimulate the gut microbiome and revive the gut immune system, a study by immunologists at the Institute has shown. The research is published in the journal Nature Communications today.

The gut is one of the organs that is most severely affected by ageing and age-dependent changes to the human gut microbiome have been linked to increased frailty, inflammation and increased susceptibility to intestinal disorders. These age-dependent changes to the gut microbiome happen in parallel with a decrease in function of the gut immune system but, until now, it was unknown whether the two changes were linked.

“Our gut microbiomes are made up of hundreds of different types of bacteria and these are essential to our health, playing a role in our metabolism, brain function and immune response,” explains lead researcher Dr Marisa Stebegg. “Our immune system is constantly interacting with the bacteria in the gastrointestinal tract. As immunologists who study why our immune system doesn’t work as well as we age, we were interested to explore whether the make-up of the gut microbiome might influence the strength of the gut immune response.”

Co-housing young and aged mice (mice naturally like to sample the faecal pellets of other mice!) or more directly performing faecal transfer from young to aged mice boosted the gut immune system in the aged mice, partly correcting the age-related decline.

“To our surprise, co-housing rescued the reduced gut immune response in aged mice. Looking at the numbers of the immune cells involved, the aged mice possessed gut immune responses that were almost indistinguishable from those of the younger mice.” commented Dr Michelle Linterman, group leader in the Immunology programme at the Babraham Institute.

The results show that the poor gut immune response is not irreversible and that the response can be strengthened by challenging with appropriate stimuli, essentially turning back the clock on the gut immune system to more closely resemble the situation in a young mouse.

The results of the study have relevance for treating age-related symptoms, confirming a link between the effects of the ageing immune system and age-associated changes in the gut microbiome. By demonstrating the effectiveness of interventions that have a positive impact on the composition of the gut microbiome, this research suggests that faecal transplants, probiotics, co-habitation and diet might all prove to be ways to facilitate healthy ageing.

Learn more: Could boosting the gut microbiome be the secret to healthier older age?

 

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