AgBioResearch

Much of the Western world appears on a mission to keep bacteria at bay. The increased use of antibacterial soaps and cleaning solutions has resulted in a billion-dollar industry that encourages consumers to destroy the microscopic foes inhabiting homes and workspaces to prevent the spread of illness and disease. What often goes unmentioned is the fact that the human body is home to roughly 100 trillion microbes living on the skin and in the mouth, nose and intestines — and not all of them are bad.

For decades, scientists have been well aware of these microbial communities, which assist in many vital physiological processes rangind from digesting to synthesizing vitamins. Collectively termed the "microbiota," these communities include all of the microorganisms - bacteria, fungi and viruses - that reside in or on the human body.

Over the past 10 years, several labs have discovered evidence that suggests that longterm changes in the microbiota can increase susceptibility to infections and chronic disease. Some believe antibiotics are a key source of this change because they do not discriminate between beneficial bacteria and the disease-causing bacteria they’re meant to target. Scientists across the United States are exploring the microbiota and the millions of genes associated with them (referred to as the “microbiome”). Some are specifically focused on understanding the consequences of disrupting or depleting these microbial communities.

To assist the National Institutes of Health (NIH) with insights about the microbiome, Linda Mansfield, Michigan State University (MSU) AgBioResearch microbiologist and veterinarian, is exploring the role of antibiotics in making humans more susceptible to infections caused by Campylobacter jejuni, a serious bacterial threat. She believes there is a link between antibiotic use, microbiota modification and the onset of an autoimmune disease triggered by the bacterium.

A double-edged sword

During the 20th century, antibiotics completely changed how infectious diseases were treated and helped raise life expectancy in the industrialized world by more than 55 percent. When used properly, they are generally safe and effective, and can be lifesaving. The Centers for Disease Control and Prevention and Prevention (CDC) reports, however, that frequently these drugs are prescribed incorrectly—and to the detriment of people around the globe.

According to the CDC, studies show that up to 50 percent of all the antibiotics prescribed for people are unnecessary or are not optimally effective as prescribed. They report that 30 percent of antibiotics received by hospitalized adult patients are unnecessary, and 58 percent of all antibiotics prescribed in 2007 were for children with acute viral respiratory infections — illnesses antibiotics cannot cure.

Mansfield said that these practices and the misuse of antibiotics in other industries, such as to promote the growth of food animals (see related story on page 8), have resulted in the evolution of infectious bacteria that demonstrate resistance to every antibiotic currently on the market. Additionally, each time an individual takes an antibiotic, he or she is exposed to the drug side effects. The most common are allergic reactions, adverse drug reactions and potentially deadly bouts of diarrhea caused by the bacterium Clostridium difficile (C. difficile).

“Antibiotic treatments can predispose people to being susceptible to certain pathogens; C. difficile is one of them,” Mansfield explained. “There are functions of the microbiota that help ward off pathogens and prevent infections. Certain antibiotics can deplete microbial communities and, we hypothesize, remove some of the healthy, defensive bacteria.”

When antibiotics kill beneficial bacteria, disease-causing bacteria such as C.difficile can go unchecked. It colonizes the gastrointestinal tract and releases toxins that cause inflammation in the large intestine, resulting in diarrhea, fever, abdominal cramps and, in some cases, death.

C. difficile is the most common cause of antibiotic-associated diarrhea; it is also the most common cause of hospital-acquired infections. Once infected, a number of patients experience recurring C. difficile infections, enduring as many as 25 bouts in a year. The most effective therapy for breaking the cycle of these recurring infections is a fecal transplant, which involves transferring stool from a healthy, usually related, donor into the infected individual’s gastrointestinal tract.

“You are basically resistant to C. difficile until you receive antibiotics,” she said. “My colleague, Robert Britton, has been researching this pathogen as part of our work with the MSU Enterics Research Investigational Network [ERIN] and is working to [develop a platform for the delivery of biotherapeutics].”

Mansfield, a professor in the MSU College of Veterinary Medicine with a joint appointment in the Department of Microbiology and Molecular Genetics, is the principal investigator in ERIN. She collaborates with two co-principal investigators: Britton, MSU AgBioResearch microbiologist, and Shannon Manning, MSU AgBioResearch molecular epidemiologist. Together, the three study the gastrointestinal microbiome and how food-borne pathogens affect it. NIH funds this multidisciplinary research in support of its Human Microbiome Project.

Just as evidence points to a relationship between antibiotic exposure and C. difficile susceptibility, there is a link between antibiotic exposure and the development of Guillain-Barré Syndrome (GBS), an autoimmune disease that attacks nerve cells.

“We’re working on another pathogen that has the same kind of presentation as C.difficile: Campylobacter jejuni,” she said. “This is a very common pathogen that is usually derived from chicken meat. We have evidence that susceptibility is influenced by antibiotic treatment.”

Past antibiotic drug treatments are not the only trigger of the disease, but they have become the most common.

Campylobacter jejuni (C. jejuni) is part of a family of drug-resistant bacteria characterized by the CDC as a serious threat to global health. There are approximately 1.3 million Campylobacter infections in the United States each year, resulting in 13,000 hospitalizations and 120 deaths. Understanding the disease mechanisms and their relation to the human microbiome has become increasingly important as the number of infections has risen and the link to GBS has become clear.

Mansfield is determined to further that understanding.

A matter of life and limb

As part of their work with ERIN, Mansfield and Manning set out to identify the root of the high incidence of diarrheal infections in Michigan. Manning hypothesized that the food-borne pathogen Enterohaemorrhagic Escherichia coli (EHEC) was to blame, but together they found that C. jejuni was the primary culprit.

C. jejuni infections are the most common cause of bacterial gastroenteritis in Michigan and are most often acquired when people consume raw or undercooked poultry, unpasteurized milk or contaminated water. Like C. difficile, C. jejuni colonizes the gastrointestinal tract and causes intestinal inflammation resulting in vomiting and diarrhea, and, for some, the long-term complications associated with GBS.

“People start out with a C. jejuni infection and recover from the gastrointestinal disease; some then begin to feel a progressive tingling in their hands and feet — this is the GBS,” she said. “It tends to ascend, starting in the nerves in the legs and then moving upward toward the chest, eventually leading to paralysis in some.”

She explained that a percentage of patients experience paralysis only in their limbs; in others, the paralysis advances until they can no longer breathe on their own, forcing reliance on an iron lung or respirator for support.

“It’s a very frightening disease for people because they never know if they’re going to get better,” she explained. “The good news is that many people do get better, but others are left with permanent disabilities.”

C. jejuni initiates the disease because some components of its surface coat look like human nerves. When this happens, the immune system is tricked into producing antibodies that attack and damage the peripheral nervous system.

Mansfield and her research team were the first to use a mouse model to show that C.jejuni employs this molecular mimicry. Their goal was to learn more about the factors that facilitate the intestinal inflammation and destructive autoimmune response caused by the bacterium.

“In our mouse models, we found that significant changes occurred in the genes that were controlling C. jejuni’s surface coat during infection,” she said. “When genes are replicated, they can slip a little bit, so the matching isn’t always perfect. When this occurs, it changes the reading frame of the gene, affecting which genes are expressed and which ones aren’t. We think that’s one of the mechanisms involved in altering C.jejuni’s surface coat so that it can make the molecular mimicry [that leads to] GBS.”

She also uncovered a second important insight about C. jejuni: the bacterium can evolve inside its host in real time.

It’s widely understood that pathogens adapt to their environment by changing the genes they express through the evolutionary processes of mutation and selection, which preserve favorable genetic changes that help organisms survive. However, very little is known about how bacteria adapt during infection.

She and her lab made progress in exploring this area of microbiology by demonstrating that C. jejuni rapidly changes from one heritable genetic state to another in its host.

“The results of the study tell us that it will be difficult to develop a vaccine to protect against a bug like Campylobacter jejuni, so traditional vaccine strategies are probably not useful,” she explained. “This could explain why so many vaccines that have been developed for this bacterium in humans and animals have not worked.”

Additionally, this finding warns researchers and healthcare professionals that each time someone is infected, C. jejuni changes, increasing the odds that it might change in such a way as to stimulate an autoimmune response.

“We want to prevent people from becoming infected because there will always be some who will have adverse immune reactions,” she concluded. “Currently, the only form of treatment is plasmapheresis, which involves ‘cleaning’ the blood — but it works for only a small number of patients. Because there’s no other cure, in aggressive cases of GBS, treatment becomes a matter of giving patients the breathing support they need until they recover or pass away. There is a desperate need for a cure.”

A part to play

Scientists believe that humans are born essentially bacteria-free and spend the first three years of life acquiring the vast communities of microbes that will be their constant companions, changing and growing along with their host. Research suggests that these commensal communities have evolved with humans over thousands of years and are essential to survival.

In light of this understanding and all of the new findings produced through research efforts across the nation, people are urged to be mindful of their tiny allies. Despite the persuasive messaging heard in the media, some bacteria are good for humans, and taking small precautions such as employing basic hand hygiene and good food safety practices, and exercising antibiotic safety (see opposite page) will go a long way toward protection.

Mansfield points out that, though there is still much to be done in the agricultural and medical industries, consumers have more control over their exposure to potentially harmful bacteria — and ultimately the direction of their long-term health — than they might realize. Many health-threatening diarrheal infections are the result of food-borne pathogens. As a veterinarian, Mansfield is as equally invested in reducing the risk of food-sourced pathogen exposure as she is in understanding their pathological mechanisms.

“It’s so important to know where your food comes from and to take simple steps —such as keeping meat separate from greens, cooking food thoroughly and washing produce before it’s eaten — that provide another level of important protection fully within our control,” she concluded. “It’s enlightening to know how much risk you can eliminate by performing these simple practices.”

There is much to be learned about the microbial communities residing in and on the human body, but one thing is clear: in the face of the daunting issue of antibiotic resistance and all of the complications surrounding it, even the small steps — and life forms — have a significant impact.

Antibiotic Resistance brochure