ILLUSTRATION: © Ian Phillips/www.i2iart.com

Like most people, Carrie, a former border customs officer in Vancouver, never thought much about the trillions of microscopic creatures inhabiting her body—until internal germ warfare first threatened—then saved—her life.

A broad-spectrum antibiotic prescribed prior to dental surgery set the stage for an infection of Clostridium difficile, antibiotic-resistant bacteria whose toxins attack the intestines. C. difficile is one of the most common infections in hospitals and long-term care facilities; it spreads easily and is difficult to control. Nearly one in 10 hospitalized adults contract C. difficile—and up to 17.9 per cent of them die within 30 days.

Even though Carrie, then 25, was healthy, she developed severe persistent diarrhea. “I felt like I was trying to digest shards of glass,” she recalls. She was in and out of hospital for two years as specialists treated her with antibiotics known to fight C. difficile. But the bloody diarrhea and pain “always returned with a vengeance.” She used up her sick leave and had to quit her job to accommodate never-ending trips to the toilet and more and more frequent trips to clinics and the hospital. A trim 120 to start, her weight eventually dropped to 95 pounds.

When she checked into hospital for the last time in 2001, “I thought I was going to die.” Instead, she met Dr. Ted Steiner, an infectious diseases expert at the University of British Columbia. “She had failed every other standard treatment,” said Steiner, who suggested something novel—transplanting healthy bacterial colonies from someone else’s stool. Given the procedure’s near perfect success rates and no reports of complications, Carrie decided to go ahead. Within a week she was back to normal, soon rebuilt her life and started a thriving business. The ‘ick factor’ is pretty high around this topic, and fearing loss of clients, Carrie chose a pseudonym for this story.

If you’re surprised one dose of gut microbes can cure an infection that had defeated some of the most potent antibiotics, hold onto your hat, there’s more to come. Gut flora—and bacteria particularly—have recently been shown to play a role in a surprising range of diseases and conditions, including allergies and asthma, obesity, skin diseases, gastrointestinal illnesses—even mental health and some cancers. Since microbe colonies in people with diseases differ from those of healthy people, could something as simple as adding or subtracting specific bacteria prevent, treat or cure certain diseases?

It’s such a tantalizing idea that scores of researchers around the world are collaborating on the International Human Microbiome Consortium (IHMC), a five-year, $250 million collaboration to determine whether humans share a core set of microbes, to develop technology to study them and to study their role in human health and disease. The results are likely to revolutionize prevention and treatment of disease.

Beneficial bacteria have already been used to reduce anxiety, increase immunity of elderly people and those with disease and reduce risk of post-antibiotic diarrhea or vaginal infection, says Dr. Gregor Reid, director of the Canadian Research and Development Centre for Probiotics at the Lawson Health Research Institute at the University of Western Ontario in London. In Africa, a UWO project trains ‘yogurt mamas’ to make probiotic yogurt that boosts immunity of HIV/AIDS patients. Prolonging adults’ lives a few years reduces the number of children going into orphanages, reports Ombeni Sefue, Tanzania’s high commissioner.

Research has so far just scratched the surface of possibilities.

“In the human body there are at least 100 times more bugs than your own cells (but) we have no clue what 90 per cent of them do,” says Dr. Bhagirath Singh, Canada’s IHMC representative and scientific director of the Institute of Infection and Immunity of the Canadian Institutes of Health Research, a major funder of a dozen Canadian Microbiome Initiative (CMI) projects now sequencing genes, categorizing microflora and examining associations between microflora and health and disease.

ILLUSTRATION: © Ian Phillips/www.i2iart.com

Much of the Canadian research is focused on the human gut. It is home to trillions of microscopic organisms—bacteria, viruses and fungi among them—collectively called gut flora or microbiota. A healthy adult gut has about two kilograms of these organisms—500 or more different species, mostly bacteria. Most are benign or beneficial. A few like C. difficile can be deadly.

For about a century bad actors have hogged the limelight as health professionals embraced the germ theory of disease—that some or all disease is caused by pathogenic organisms. Some of the greatest advances in public health are rooted in this theory. Death rates plummeted from better handling of human waste and by curtailing the spread of disease through the power of simple handwashing.

Identification of disease-causing organisms has resulted in the development of life-saving drugs and vaccines. The smallpox virus killed more than 300 million in the 20th century alone prior to development of a vaccine that prevented and eventually eradicated it. Vaccines for prevention and antibiotics for treatment have virtually eliminated diphtheria in Canada. Before 1920 there were 12,000 annual cases—and 1,000 deaths—from this bacterial infection. It produces a deadly toxin that damages the heart, nervous system and kidneys. Sometimes throat tissue becomes so swollen, people die of suffocation.

It seems there’s always some microscopic creature in a black hat gunning for humans. The idea the only good bacteria are dead bacteria is cemented by sensationalistic media reports like those about necrotizing fasciitis (better known as flesh-eating disease, although the bacteria don’t actually eat flesh, but release toxins that destroy skin and muscle). But if our gut bacteria really wore hats, we’d see that many of them are white. Bacteria have enzymes we lack that help us digest food; they synthesize vitamin K and certain B vitamins; they produce hormones that direct fat storage; they are important to our inflammatory response; and bacteria help ‘train’ our immune systems by spurring growth of some immune cells and helping the body recognize pathogens.

Beneficial gut bacteria like lactobacilli and bifidobacteria (the main yogurt bacteria) cover the surface of the digestive tract. They provide a natural barrier to hostile invaders and keep the population of resident bad actors under control, mostly by starving them out. But they’ve been collateral damage in our battles against pathogens. When broad spectrum antibiotics kill the good bacteria along with the bad, there’s a population explosion among opportunistic antibiotic-resistant pathogens that can cause serious infections. Frequent exposure to antibiotics makes these pathogens even more virulent.

The lifestyle in developed nations further affects the mix of gut bacteria, beginning at a very early age. In the first year of life, specific types of beneficial bacteria trigger development of key immune cells and stimulate growth of cells lining the gut. Breast-fed babies have a different mix of microflora than formula-fed babies. Antibiotics prescribed for things like ear infections kill beneficial gut bacteria. By age two, children are introduced to the low-fibre, high-fat, salty, over-sweetened Western diet that starves some beneficial bacteria. And now research is linking lack of beneficial bacteria to dramatic increases in diseases like allergies and asthma and health conditions like obesity and related skyrocketing rates of adult-onset diabetes and heart disease.

Have we taken clean living too far? Some experts in childhood allergies and immune disorders think lack of exposure to infectious agents in childhood has affected immune system development, raising susceptibility to allergic diseases, a theory called the hygiene hypothesis. About 12 per cent of Canadian children and eight per cent of adults have asthma and about 40 per cent of the population suffers from hay fever.

In the last 30 years, childhood asthma and allergy has doubled, but “in developing countries infants have more of the good bacteria and allergies and asthma are less common,” says Anita Dr. Kozyrskyj, pediatrics research chair on the University of Alberta’s medical faculty.

Her CMI project is correlating antibiotic use with changes in microbiota in stool samples taken at three months and one year of age. Her earlier research showed between half and two-thirds of Canadian children are given antibiotics by the age of one, and that those children are more likely to develop asthma by seven.

Research results may change how antibiotics are prescribed to infants or they may lead to development of narrow-spectrum drugs that spare beneficial bacteria. As well, promising European research shows probiotics offer some protection against atopic dermatitis, “one of the first signs of the allergic march,” says Kozyrskyj. “A newborn or child develops atopic dermatitis, then hay fever and then asthma.” A Dutch study found babies given probiotics developed eczema half as often, and an Australian study showed probiotics relieved symptoms in nearly all babies tested. It’s thought an imbalance in microflora leads to degradation of the gut lining, allowing food molecules to pass through to the bloodstream, leading to allergic responses like eczema, hay fever, asthma and inflammatory diseases. Probiotics may help by improving the gut lining so allergens can’t get through, and by reducing inflammation.

Lack of protective gut flora could also help explain why Canada has among the highest incidences of inflammatory bowel disease (IBD) in the world, with an estimated total annual economic impact of $1.8 billion. More than 200,000 Canadians live with Crohn’s Disease or ulcerative colitis, and rates are climbing—particularly among children, and especially among children of immigrants.

Dr. Alain Stintzi of the University of Ottawa’s Institute of Systems Biology, is comparing the microbiota—bacteria, fungi, viruses, etc.—of children with IBD to those without.

No two people—not even twins—have the exact same combination of microbes. “It’s kind of like a fingerprint, some people call it a pooprint, unique to you,” says Dr. George Tolomiczenko, executive director of research for the Crohn’s and Colitis Foundation of Canada. The colonies of microflora may differ from person to person, but everyone seems to have a combination capable of certain core functions, adds Stintzi.

Although still analyzing data, Stintzi has noticed that children with IBS have a greater diversity of bacteria. “Now the question is which bacteria might be implicated” in IBS and do they cause the disease, maintain it, or keep inflammation going? Or are they involved in switching on genes that increase susceptibility?

Dr. Brett Finlay, a specialist in host-pathogen interactions at the University of British Columbia, has seen change in gut bacteria alter the effects of a disease. Salmonella normally causes a lethal typhoid-like infection in mice, but if treated with antibiotics before infection, “they get diarrhea, which is what people get. We haven’t changed the mice, haven’t changed the salmonella, we’ve changed the flora and get a completely different disease.”

Such research is raising interesting questions (and has spurred large-scale Canadian research projects) about the interplay of genes, microbiota and environment, says Tolomiczenko. For instance, although there is a genetic component to IBD, not everyone with the genes develops the disease.

CMI researchers in Alberta are characterizing the microbial community in the IBD gut and “linking it with environmental things like air pollution,” says Dr. Karen Madsen of the University of Alberta’s faculty of medicine. “If you look at postal codes, you can pick up hotbeds of activity. There’s disease on that side of the freeway, but not on this side, so what’s the difference?”

Intrigued by reports of IBD relapses following stressful experiences, Dr. Emma Allen-Vercoe at the University of Guelph is examining the relationship between human stress hormones and gut flora. She has one of the few labs where anaerobic bacteria, which cannot survive in the presence of oxygen, can be cultivated. She’s developed a containment system dubbed Robogut that mimics the human gut, providing a safe home for culturing anaerobic bacteria for analysis by fellow researchers.

In Robogut, reaction from a human host can’t skew results, which set the stage for some startling findings right at the beginning of her study. Her plan is to culture gut microbes from healthy people, then people with IBD, expose the microbes to human stress hormones and compare results. She expected the microbe colony from a healthy person would react, then recover quickly. Instead, “we’re not seeing recovery to normal; once the change has been made, it’s there for good in the vessel.” Yet, in humans, the colony returns to normal. Could the human host somehow direct that process or could bacteria and the host interact to bring that about? “Now we’re in completely uncharted territory. It’s one thing to think bacteria can even react with human hormones, but to think bacteria can send signals back the other way.…”

Amee Manges at McGill University in Montreal is asking why some people who’ve taken antibiotics and have been exposed to C. difficile are never colonized, while others are exposed and colonized but never develop disease and still others become ill. Could antibiotics interact with gut flora to make some people more susceptible? “That would tell us something very new about the disease model,” she said.

Or are some people missing key members of the gut microbiome? If so, it will take more research to show if it’d be safe and effective to introduce those bacteria. “If you’re going to develop a cocktail of micro-organisms, a sort of superprobiotic cocktail, you’d have to know exactly what the composition would be,” said Manges. “And you have to be very concerned about providing infectious organisms, even if you’re pretty sure they’re benign.”

But that day will come, predict Madsen and Steiner, who anticipate research will result in treatments aimed at modifying gut microbes and also alter drug treatment practices. Certain cancer drugs don’t work on people with certain genes, so a genetic test is needed to decide what to prescribe to whom. Also, certain bacteria are needed to release the active component in some drugs, and others destroy certain medications. “I think we’re going to get to the point where we’ll have to see which bugs are in the gut in order to see which treatments will work,” says Madsen. “I think you’ll do a genetic profile and a microbial profile” before prescribing.

A new way of looking at disease has already emerged, says Tolomiczenko. “Immunology, microbiology and genetics have to be juggled at the same time to get the full picture.” This “systems biology way of thinking…makes you more cautious in saying ‘this is the cure for everything.’” In future, doctors are likely to prescribe drugs and bugs to cure what ails you.

ILLUSTRATION: © Ian Phillips/www.i2iart.com

Your Daily Belly Boost

A balance of gut microbes contributes to good health, but aging and disease—along with taking antibiotics, drinking alcohol and diets high in sugar—all weaken the armies of little allies that aid our immune and digestive systems.

We can help maintain that diverse population of microflora by ingesting live bacteria in probiotics or by causing a population explosion among resident bacteria by taking prebiotics, fibre we can’t digest, but which is favourite chow for some beneficial bugs.

“It’s so beneficial for (treating and preventing) so many different disease conditions I think everybody would benefit from probiotics,” says naturopath Dr. Jean-Jacques Dugoua of the Liberty Clinic and Liberty Research Group in Toronto. Risks are rare and side effects few (mostly short-term gas and bloating).

As we age, we produce less stomach acid and digestive enzymes and our gut flora population changes. These are key players in digestion and immunity. “We know bifidobacteria decline as we age,” says Dr. Gregor Reid, director of the Canadian Research and Development Centre for Probiotics at the Lawson Institute in London, Ont. “We think replenishing them might help improve immunity and regularity.” Research points to improvements in a host of other conditions, including allergies, insulin resistance and cholesterol control.

As we age, “things become unbalanced, more to the side of the ‘bad’ guys,” explains Dugoua. When digestion weakens “you are more susceptible to invaders” like those that arrive on groceries, including produce from distant countries that carry micro-organisms foreign to us.

We can increase helpful bacteria by eating cultured and fermented foods, including yogurt, aged cheese, fermented (not pickled) sauerkraut, kefir and tempeh as well as ethnic specialties like lassi, kim-chi and miso. Yogurt is probably the most familiar, but all yogurts are not created equal, warns Reid. Any yogurt has some bacteria, but those labelled probiotic have populations large enough for proven health effects. Look for labels with ‘live’ or ‘active’ bacterial cultures; some brands name the type of bacteria. The ‘best before’ date is important because cultures die off over time.

Yogurt is also easy to make at home, with the bonus of being cheaper and less tart than grocery brands. Buy yogurt starter at a health food or grocery store and follow directions.

Dugoua warns against products containing sugars, the favoured food of harmful bacteria, as well as sugar and alcohol in the diet. And be wary of food products with added probiotics, including chocolates, flavoured drinks and ice cream, advises Reid. “In Canada there are a lot of products called probiotic but they’re not really probiotics.” True probiotic food products have been proven in human trials to have health benefits, he says, but it’s difficult for consumers to know which products have been tested since it’s not on labels.

Choosing a good probiotic supplement is somewhat easier. They carry a Health Canada natural product number. Look for high counts (millions to billions) and a variety of bacteria, including lactobacilli and bifidobacteria, the most populous in the gut. Variety is desirable because different species populate different areas of the gastrointestinal (GI) tract, says Dugoua. You want high counts because many don’t survive the digestive system’s harsh environment. Take supplements after meals—acidity is lower when the stomach’s full, and more bacteria will survive.

Supplements are particularly important when taking antibiotics. “People believe if you take an antibiotic, it goes specifically to your ears, or sinuses or whatever,” says Dugoua, “but actually it kills everything,” allowing for overgrowth of harmful microbes that cause post-antibiotic infections. Dugoua suggests taking probiotics about six hours after each dose of antibiotics and keeping up with high doses of probiotics for several weeks after finishing the antibiotics.

If you want a population boom among resident helpful bacteria, boost intake of prebiotics. The two most common are fructooligosaccharides (FOS) and inulin. FOS is found in a variety of fruits, vegetables and grains. Inulin is found in onions, leeks, artichokes, chicory, asparagus and Jerusalem artichokes. Both are available as supplements. On the horizon are supplements that contain both prebiotics and probiotics.

“Probiotics need to be part of your diet,” says Dugoua. “It should be something you take daily.”

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