Research opens possibility of reducing risk of gut bacterial infections with next-generation probiotic

A team of researchers is exploring the possibility that next-generation probiotics – live bacteria that are good for your health – would reduce the risk of infection with the bacterium Clostridium difficile. In laboratory-grown bacterial communities, the researchers determined that, when supplied with glycerol, the probiotic Lactobacillus reuteri produced reuterin, an antibacterial compound that selectively killed C. difficile. The study appears in Infection and Immunity.

C. difficile causes thousands of deaths and billions of dollars in healthcare expenses in the U.S. each year. Although most patients respond to antibiotic treatment, up to 35 percent will relapse and require extended antibiotic treatments,” said first and corresponding author Dr. Jennifer K. Spinler, instructor of pathology & immunology at Baylor College of Medicine, who oversees microbial genetics and genomics efforts at the Texas Children’s Microbiome Center at Texas Children’s Hospital.

C. difficile infections are the most common cause of diarrhea associated with the use of antibiotics. If these bacteria attempt to invade the human gut, the ‘good bacteria,’ which outnumber C. difficile, usually prevent them from growing. However, when a person takes antibiotics, for example to treat pneumonia, the antibiotic also can kill the good bacteria in the gut, opening an opportunity for C. difficile to thrive into a potentially life-threatening infection.

“When repeated antibiotic treatments fail to eliminate C. difficile infections, some patients are resorting to fecal microbiome transplant – the transfer of fecal matter from a healthy donor – which treats the disease but also could have negative side effects,” Spinler said. “We wanted to find an alternative treatment, a prophylactic strategy based on probiotics that could help prevent C. difficile from thriving in the first place.”

“Probiotics are commonly used to treat a range of human diseases, yet clinical studies are generally fraught by variable clinical outcomes and protective mechanisms are poorly understood in patients. This study provides important clues on why clinical efficacy may be seen in some patients treated with one probiotic bacterium but not with others,” said senior author Dr. Tor Savidge, associate professor of pathology & immunology and of pediatrics at Baylor and the Texas Children’s Microbiome Center.

Working in the Texas Children’s Microbiome Center, Spinler and her colleagues tested the possibility that probiotic L. reuteri, which is known to produce antibacterial compounds, could help prevent C. difficile from establishing a microbial community in lab cultures.

An unexpected result with major implications for a preventative strategy

Spinler and Savidge established a collaboration with co-author Dr. Robert A. Britton, professor of molecular virology and microbiology at Baylor and member of the Dan L Duncan Comprehensive Cancer Center.

The Britton lab uses mini-bioreactor arrays – multiple small culture chambers – that provide a platform in which researchers could recreate the invasion of an antibiotic-treated human intestinal community by C. difficile.

“Using the mini-bioreactors model we showed that L. reuteri reduced the burden of C. difficile infection in a complex gut community,” Britton said. “To achieve its beneficial effect, L. reuteri requires glycerol and converts it into the antimicrobial reuterin.”

The literature reports reuterin as a broad-spectrum antibiotic; it affects the growth of a wide variety of bacteria when they are tested individually in the lab. What was intriguing in this study is that reuterin didn’t have a broad-spectrum effect in the mini-bioreactor bacterial community setting.

“I expected reuterin to have an antibacterial effect on several different types of bacteria in the community, but it only affected C. difficile and not the good bacteria, which was exciting because it has major implications for a preventative strategy,” Spinler said.

“Although these results are too preliminary to be translated directly into human therapy, they provide a foundation upon which to further develop treatments based on co-administration of L. reuteri and glycerol to prevent C. difficile infection,” said co-author Dr. Jennifer Auchtung, director of the Cultivation Core at Baylor’s Alkek Center for Metagenomics and Microbiome Research and assistant professor of molecular virology and microbiology at Baylor.

In the future, this potential treatment could be administered prophylactically to patients before they take antibiotics known to disrupt normal gut microbes. The L. reuteri/glycerol formulation would help maintain the healthy gut microbial community and also help prevent the growth of C. difficile, which would result in decreased hospital stay and costs and reduced long-term health consequences of C. difficile recurrent infections.

Gut bacteria could protect cancer patients and pregnant women from Listeria, study suggests

Researchers at Memorial Sloan Kettering Cancer Center in New York have discovered that bacteria living in the gut provide a first line of defense against severe Listeria infections. The study, which will be published June 6 in The Journal of Experimental Medicine, suggests that providing these bacteria in the form of probiotics could protect individuals who are particularly susceptible to Listeria, including pregnant women and cancer patients undergoing chemotherapy.

Listeria monocytogenes is a major pathogen acquired by eating contaminated food, but healthy adults can generally fend off an infection after suffering, at worst, a few days of gastroenteritis. However, some individuals, including infants, pregnant women, and immunocompromised cancer patients, are susceptible to more severe forms of listeriosis, in which the bacterium escapes the gastrointestinal tract and disseminates throughout the body, causing septicemia, meningitis, and, in many cases, death.

Patients with some forms of cancer are as much as 1,000 times more likely to develop listeriosis, possibly because chemotherapy drugs can suppress a patient’s immune system. But a team of researchers led by Simone Becattini and Eric G. Pamer wondered whether the gut microbiome–the community of bacteria that naturally lives in the gastrointestinal tract–might also play a role in limiting L. monocytogenes infection. Chemotherapy disrupts the microbiome, and gut bacteria are known to prevent other food-borne pathogens from colonizing the gastrointestinal tract by, for example, secreting antibacterial toxins.

The researchers found that disrupting the microbiome with antibiotics made laboratory mice more susceptible to L. monocytogenes infection, increasing the pathogen’s ability to colonize the gastrointestinal tract and spread into the circulatory system to cause the animals’ death. The effect of antibiotics was even more noticeable in immunocompromised mice lacking key immune cells; these animals succumbed to even small doses of L. monocytogenes if their microbiomes were disrupted by antibiotic treatment.

Mice treated with the common chemotherapy drugs doxorubicin and cyclophosphamide were vulnerable to Listeria infection, and they became even more susceptible when they were also treated with antibiotics.

The researchers identified four species of gut bacteria–all members of the Clostridiales order–that together were able to limit L. monocytogenes growth in laboratory cultures. Transferring these probiotic bacteria into germ-free mice protected the rodents from Listeria infection by limiting the pathogen’s ability to colonize the gastrointestinal tract and disseminate into other tissues. “Thus, augmenting colonization resistance functions in immunocompromised patients by introducing these protective bacterial species might represent a novel clinical approach to prevent L. monocytogenes infection,” says Becattini.

“Our results also raise the possibility that in other at-risk categories for listeriosis, such as infants or pregnant women, disruptions to the gut microbiome could be a contributing factor to susceptibility,” Becattini continues. “Pregnant women in their third trimester, the phase in which susceptibility to Listeria is known to be highest, show an altered microbiome, with a marked reduction in Clostridiales species.”

Microbes In Your Gut Influence Major Eye Disease

Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the industrialized world, affecting over 10 million individuals in North America. A study lead by Dr. Przemyslaw (Mike) Sapieha, researcher at Hôpital Maisonneuve-Rosemont (CIUSSS de l’Est-de-l’Île-de-Montréal) and professor at the University of Montreal, published in EMBO Molecular Medicine, uncovered that bacteria in your intestines may play an important role in determining if you will develop blinding wet AMD.

AMD is characterized by a heightened immune response, sizeable deposits of fat debris at the back of the eye called soft drusen (early AMD), destruction of nerve cells, and growth of new diseased blood vessels (wet AMD, late form). While only accounting for roughly 10% of cases of AMD, wet AMD is the primary form leading to blindness. Current treatments becomes less effective with time. It is therefore important to find new ways to prevent the onset of this debilitating disease.

While many studies on the genetics of AMD have identified several genes that predispose to AMD, no single gene can account for development of the disease. Epidemiological data suggests that in men, overall abdominal obesity is the second most important environmental risk factor, after smoking, for progression to late-stage blinding AMD. Until now, the mechanisms that underscore this observation remained ill defined. Elisabeth Andriessen, a PhD student in the lab of Professor Sapieha found that changes in the bacterial communities of your gut, such as those brought on by a diet rich in fat, can cause long-term low-grade inflammation in your whole body and eventually promote diseases such as wet AMD. Among the series of experiments conducted as part of this study, the group performed fecal transfers from mice receiving regular fat diets, compared to those receiving a high fat diet, and found a significant amelioration of wet AMD.

“Our study suggests that diets rich in fat alter the gut microbiome in a way that aggravates wet AMD, a vascular disease of the aging eye. Influencing the types of microbes that reside in your gut either through diet or by other means may thus affect the chances of developing AMD and progression of this blinding disease”, says Dr Sapieha. Professor Sapieha holds the Wolfe Professorship in Translational Vision Research and a Canada Research Chair in retinal cell biology.