Dec. 17, 2019

Are we born with our diseases? How our microbiomes influence lifelong health

Research shows the way we're born and the microbes we're exposed to early in life set the course for our health over the entire span of our lives

We have trillions of microbes all over our bodies — they live in our mouths, our guts and all over our skin. These bacteria, viruses and fungi form a protective layer between us and our environment. They also perform a fundamental role in our health by constantly interacting with the brain, immune system and every other part of the body.

The largest community of microbes (also called microbiota) live in our gut. There, tens of trillions of microorganisms influence how we digest food, absorb nutrients and, we’re learning, communicate with the brain. So far, the gut microbiome has attracted the most attention from scholars. And these researchers are beginning to better understand how the composition of our gut microbiome is associated with disease. We’re finding that an unbalanced microbiome — too much of one type of microorganism or not enough of another — can change how our immune systems function and affect many other aspects of our physiology.

“Every week new studies are published linking the microbiome to exciting discoveries in the health sector,” says Dr. Marie-Claire Arrieta, PhD, an assistant professor in the Departments of Paediatrics and Physiology & Pharmacology and member of the Snyder Institute for Chronic Diseases and the Alberta Children’s Hospital Research Institute in the Cumming School of Medicine, and co-author of Let Them Eat Dirt: Saving Your Child from an Oversanitized World. “The potential in microbiome science is endless.”

Researchers explore questions such as how an altered microbiota affects our health, how the presence — or absence — of specific microbes may increase our chances of developing a particular disease, and how the microbes in the gut influence disease elsewhere in the body.

And this incredibly complex system may start to affect our health before we’re even born.

The journey begins

Research has shown the placenta — the organ that feeds the fetus in utero — doesn’t have a microbiome. But some researchers have found a link between maternal microbiota and a later link to childhood diseases. “It’s believed that this is caused by metabolites produced by microbes in the maternal gut which are able to permeate the sterile placenta and reach the baby,” says Erik van Tilburg Bernardes, a PhD student in Arrieta’s lab who studies early-life microbial alterations.

Researchers including Dr. Kathy McCoy, PhD, director of the International Microbiome Centre at UCalgary, did a study where they exposed pregnant mice to a transient microbe — that is, mutated bacteria unable to live inside the mouse’s gut — and found a change in the offspring’s immune and intestinal development. “This brief presence of foreign bacteria in the maternal gut impacted the pup’s physiology after it was born,” says van Tilburg Bernardes. “The researchers have noted that pups born from these groups of mothers had different numbers of important immune system cells, among other changes.”

When a woman gives birth, as soon as baby begins to move down the birth canal they’re exposed to — and colonized by — their mother’s microbes. “Babies born via natural birth have an initial colonizing community dominated by maternal vaginal and fecal microbes, whereas babies born via caesarean section are primarily colonized by skin microbes,” says Arrieta. “A growing practice during C-sections is seeding the babies with the vaginal microbes, aiming to foster a more complex and beneficial microbiota minutes after birth.” However, this is still experimental. We don’t know yet whether it’s effective and some medical practitioners worry about the safety of this practice.

We are born sterile, and once out of the mother’s womb, we are rapidly colonized by microbes.

Those first few minutes of an infant’s life are crucial. How a baby is born and what microbes they receive sets up their microbiome for life — protecting them against disease or making them more susceptible.

“We are born sterile, and once out of the mother’s womb, we are rapidly colonized by microbes that set the path for other colonizers that come later,” says van Tilburg Bernardes. “This is why the mode of birth and the microbes we initially encounter have such strong influences on our lifelong health. These pioneer microbes arrive in the immature neonatal gut and promote changes that allow for better establishment of subsequent microorganisms.”

One of these important changes performed by microbiota is reducing the amount of oxygen in our intestines. Many of the microbes in our microbiota can’t thrive in the presence of oxygen. So while our bodies need oxygen to survive, a healthy gut needs to be essentially oxygen-free.

The first 100 days

The microbiome changes a lot in the first few months after birth. The first hundred days of baby’s life are “a critical window of opportunity,” says Arrieta. Their microbiota develops rapidly and is highly susceptible to any disturbances. In fact, those first hundred days have huge implications for subsequent childhood diseases.

“Work by our group has shown that microbial dysbiosis, or imbalance, that happens within the first three months of life increases the chances of a child being diagnosed with asthma by school age,” says Arrieta. “Also, work with mice supports the theory that microbial colonization early in life is fundamental in reducing the severity of both inflammatory bowel disease and allergic asthma.” Introducing these microbes into the gut later on is too late — it doesn't have the same effect.

Milk and microbes

What babies ingest in the first few months of their lives — breast milk or formula — can determine what specific microbial groups thrive in their guts. Breast milk not only contains carbohydrates, proteins, fats and vitamins that help a baby grow, it’s also rich in immune system molecules that protect against pathogens and promote healthy development of the infant’s immune system.

“Maternal milk is the sole source of very important molecules, including specific sugars, that are the main food source for a group of microbes called Bifidobacteria and Proteobacteria in the gut,” says Emily Mercer, a master's student in Arrieta’s lab who studies the microbiome and its connection with our brains. “Although formula milk has several nutritious molecules, it's unable to completely mimic maternal milk, making the microbiota of formula-fed babies different than breast-fed babies.”

The World Health Organization recommends breast-feeding exclusively for up to six months of life but there are a number of medical, cultural and other reasons that may prevent a woman from nursing her baby. More and more, though, formula-fed babies are given probiotics to increase the growth of important microbes in their guts during their first few months of life.

Furthermore, researchers and the formula industry are constantly trying to improve formula to better mimic breast milk. “But they're not quite there yet,” says Mercer. “Formula-fed infants are at a higher risk of developing chronic conditions such as asthma and obesity, and are more prone to infections. It appears the associations between formula milk and disease development may come from the gut microbiome.”

From milk to solids

At about six months old, babies are ready to expand their diet and begin trying solid foods like cereal. While the recommendations about how and when to start giving babies solid food are always shifting, most experts agree that it’s important to introduce new foods one at a time to see how the baby, and its digestive tract, adjust.

Eventually a healthy baby will eat a diverse diet with fruits, vegetables, grains, nuts, legumes and meat or meat alternatives. (Because babies lack sufficient iron and iron is important for healthy brain development, supplementing their diet with iron-enriched cereals, meat or meat alternatives is important). As soon as baby takes their first few bites of solid foods, their gut microbiota starts to change and move away from milk-loving microbes to become more diverse and include more microbes that specialize in digesting solid foods. “We completely change which microbes preferentially grow, increasing the diversity and complexity of the microorganisms in our guts,” says Mercer. “This makes our microbiota shift toward microorganisms called Bacteroides and Firmicutes, which are carried for the rest of our lives.”

A nutritious diet will produce a much more health-promoting microbiome.

In those first few months, the baby’s microbiome essentially programs the immune system and tells it to watch for certain pathogens. A healthy microbiome also forms a protective layer in our guts and other parts of the body to prevent infections. The microbiome blocks potentially harmful microorganisms from establishing themselves by competing for the nutrients they need to thrive, producing specific protective molecules, and directly fighting the invading microbes.

By age two or three, a child has a fairly stable, adult-like microbiome and it remains more or less the same for the rest of their lives. “This highlights the importance of being mindful of what we feed our microbes and how we direct their ecosystem succession during the early developmental period,” says Arrieta. “A nutritious diet will produce a much more health-promoting microbiome than if we feed our children highly processed foods rich in sugars and food additives.”

This core group of microbes in a three-year-old’s gut is pretty much set, although environmental factors can alter the composition of organisms and change how they influence us. “Everything surrounding us has its own microbiome, such as soil, plants, and rivers, and numerous studies are working towards connecting microbes to different environmental features,” Arrieta says. Before a child starts pre-school, their microbiota has a similar composition to an adult’s. It undergoes minor changes until they reach adolescence. After that, in adulthood, it generally experiences only very small changes.

“But sustained poor eating habits or other uncontrolled conditions, such as the need for long-term antibiotics, malnutrition or moving to a new area, can promote microbial changes and impact normal microbiota functions. These changes can influence how our microbes produce vitamins, digest fibers, support our metabolism and maintain intestinal barriers,” says Arrieta.

Keeping us healthy

Throughout the course of our lives, our microbiomes feed us important metabolites and vitamins that our immune systems need to stay healthy. These include short-chain fatty acids (SCFA). Microbes produce SCFA by processing complex carbohydrates, or fibre molecules. SFCA have been shown to influence the development, function and survival of our immune cells, including the ones in our brains.

SCFA are also known to prevent the growth of certain types of cancers, while inducing growth of normal cells in our bodies. “They are essential for the maintenance of intestinal wall integrity, as they provide a source of energy for the cells that line our intestine,” says van Tilburg Bernardes. “Furthermore, studies in populations diagnosed with inflammatory and metabolic diseases, such as irritable bowel syndrome (IBS), diabetes and obesity, have shown very different levels of SCFA produced by their microbiomes, which have been linked to disease in these individuals.”

The microbes in our gut also directly interact with immune system cells in the intestine, increasing the number of specific cells that regulate how we respond to inflammation.

Intestinal immune cells are able to take signals from bacteria in the gut and send them to other places in the body, such as the lungs or skin, to activate cells there that create an immune response. “This immune modulation allows for better control and secretion of substances involved in inflammatory responses, called cytokines and chemokines,” says van Tilburg Bernardes. Keeping our cytokines and chemokines in check prevents our body from overreacting to harmless agents and reduces the allergic reactions or excessive inflammation that cause dermatitis or eczema (which is inflammation in the skin), asthma (inflammation in the lungs) and IBS or inflammatory bowel disease (IBD), which are both inflammation in the intestines.

Using the microbiome to treat disease

Cancer cells have their own microbiome.  And researchers are studying how microbes in cancer cells may influence cancer outcomes. Several types of cancers contain microbes and recent research has found the microbiome of pancreatic cancers look quite different in long- and short-term survivors. The study suggests the more diverse the microbiome, the better the prognosis.

“Cancer cells from long-term survivors have a more diverse microbiome, with an increased number of B and T immune cells, which drive a more effective anti-tumour immune response and increase patient survival rates,” says Mercer. “This study also showed the gut microbiome influences the type of organisms found inside the tumours, and showed that what we have in our guts can increase the rate of tumour growth in a mouse model.”

Researchers also find that the microbiome can influence how well people react to different cancer treatments. In one study, a group of oncologists examined the microbiome of several melanoma patients before the patients received immunotherapy — a treatment that aims to boost a person’s immune system to help fight against malignant cells. The researchers found the people who responded to immunotherapy had different microbes in their guts than people who did not respond to the treatment.

Since then, other researchers have shown that the gut microbiome can influence therapies for cancer, as well Parkinson’s disease, high cholesterol, diabetes, pain, epilepsy and degenerative bone problems. Restoring certain microbes in the gut has been shown to help prevent and treat some of these conditions.

Fecal microbial transplantation is a promising new treatment for the gastrointestinal infection caused by Clostridium difficile (C. diff.). Stool microbes from a healthy donor are transplanted into the infected person (after dangerous microbes are removed) and help clear out the infection. Researchers find mixed results in using this process to treat people with IBD, IBS, autism, antibiotic-induced acquired infections, obesity and other disorders. And pharmaceutical companies are testing mixtures of microbes meant to restore balance in the microbiome. “The next decade will hopefully see new products in the market,” says Mercer.

The senior microbiome

When we reach old age, several changes in our bodies impact our microbiota and it begins to lose its diversity and therefore its resilience. Older people may have difficulty eating, which changes what nutrients are available for the microbiota to thrive. Losing important microorganisms, in turn, makes the microbiome less resistant to environmental disturbances. On top of this, the immune system weakens with age, making people more vulnerable to infections that require antibiotics. But as we know, as well as taking out the dangerous pathogen, antibiotics also harm the entire gut microbiome.

While most of these physiological changes are inevitable with age, they can be delayed considerably with a healthy lifestyle. “Our understandings of the microbiome changes that occur in old age are still being established," says Arrieta. "But we do see a decrease in health-promoting microbial composition which reduces the level of metabolites and nutrient absorption. While older people still require a balanced diet, efforts to maintain a healthy microbiome may require greater consideration, as a number of different health effects are at play in old age.” Eventually, researchers may uncover specialized nutritional strategies that will help keep the aging microbiome robust and resilient.

As the fascinating work studying the microbiome continues in labs around the world, Arrieta, her students and colleagues are “driven by the huge array of possibilities it offers and discoveries yet to be made.” In Arrieta’s lab, scholars with a diverse range of expertise — medicine, microbiology, immunology, biochemistry and pharmacy — are working together to understand how the trillions of microbes in our guts shape our health and our lives.

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Dr. Marie-Claire Arrieta, PhD, is an assistant professor in the departments of Paediatrics and Physiology & Pharmacology and a member of the Snyder Institute for Chronic Diseases and the Alberta Children’s Hospital Research Institute in the Cumming School of Medicine. Her research interests lie in the role of the intestinal microbiota in human health and disease. Read more about Marie-Claire

Erik van Tilburg Bernardes is a PhD student in the Arrieta lab who studies early-life microbial alterations. Read more about Erik

Emily Mercer is a master's student in the Arrieta lab who studies the microbiome and its connection with our brains. Read more about Emily

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