A new probiotic candidate to treat C. diff

Molecular structure of the antibiotic enroflaxcin.

A brief letter was recently published in Nature that identifies a bacteria that may confer resistance to C. difficile.  In addition, they discovered how three commonly prescribed antibiotics alter a patient's risk for C. diff.  

The researchers treated mice with 3 different antibiotics, enrofloxacin, ampicillin, and clindamycin. While the overall microbiome bacterial density was unchanged for each antibiotic, each one altered C. diff susceptibility differently: enrofloxacin did not increase likelihood of getting infected, ampicillin induced transient susceptibility, and clindamycin greatly increased long-term chances of getting infected.

The researchers then identified 11 bacteria that were associated with C. diff resistance.  They  tested one of these bacteria, Clostridium scindens, on humans taking antibiotics that either already had C. diff infections or were susceptible for infection.  They discovered that the probiotic conferred substantial resistance to infection.  Interestingly, this probiotic also led to weight loss.

The researchers then studied how this bacteria could be preventing C. diff infection.  They discovered that this particular bacteria had a rare ability to break down bile into secondary structures, called secondary bile acids.  They tested these secondary bile acids against C. diff and they inhibited C. diff growth.

These results, taken collectively, may be immensely important in treating d. Diff.  Specific types of antibiotics that are known to not increase infection risk, along with probiotics like C. scindens could be combined into new therapies.  This could be important in treating this disease without more rudimentary approaches like fecal microbiota transfers (FMTs).

Human genetics, the microbiome, and obesity

Editors note: Happy birthday to our intern, Becky Siegert.  She has been helping to bring you the blogs for the past 3 weeks, and we at the AMI deeply appreciate her help with them.  Enjoy the day, Becky!

An article was published last week in Cell out of Ruth Ley's lab at Cornell University that discovered a connection between host genetics and the microbiome.  In doing so, the researchers discovered which aspects of the microbiome were heritable, and how some heritable bacteria in the microbiome are related to obesity.

The researchers obtained stool samples from almost a thousand humans that were twins.  They discovered that twins had more similar microbiomes than non related individuals, and that identical twins had even more similar microbiomes than fraternal twins.  Then, by meticulously analyzing their data sets along with other published twins data they discovered which specific types of bacteria were the most heritable.  They discovered that the bacteria from the family Christensenellaceae were the most heritable.  Interestingly, this family seems to exert great influence over the existence or non existence of other important bacteria in the gut, and it often occurs with methane producing archaea.  Additionally, this family of bacteria appeared to be associated with a low body mass index (BMI), or leanness.  To test the effect of this family of bacteria on obesity the researchers performed a series of microbiome transplants from humans to germ free mice.  In one test, an obese microbiome that was amended with a Christensenellaceae bacteria prior to transplantation resulted in weight loss for the mouse.  In other tests the amount of weight gain in mice mirrored the amount of Christensenellaceae.

This study is important in many ways.  First, it unambiguously connects host genetics to the microbiome.  Second, it connects a specific family of bacteria, Christensenellaceae, to BMI.  This family is heritable and seems to play a large role in shaping the rest of the microbiome.  Altogether this paper adds a new dimension to the microbiome and nutrition.  Many studies associate certain genes with obesity, but perhaps the microbiome is actually responsible.

Humans lack gut bacterial diversity compared to their ape ancestors

The diversity of microbes in the human body has important consequences on disease and nutrition, with less diversity often linked to autoimmune diseases, obesity, and gastrointestinal disorders. In a study published this week in the journal Proceedings of the National Academy of Sciences, researchers studied the evolution of the human microbiome by comparing the microbial communities in the gut of human’s closest relatives, the African apes, to human’s. They found that the human microbiome had much less diversity than that of African apes, and even less diversity was observed in American’s guts compared to humans in non-industrialized nations.

The scientists collected hundreds of fecal samples from wild chimpanzees from Tanzania, wild bonobos from the Democratic Republic of the Congo, and wild gorillas from Cameroon, as well as from humans living urban lifestyles in the U.S. and Europe, rural lifestyles in Malawi, preindustrial lifestyles in southern Amazon rainforests of Venezuela, and hunter-gatherer lifestyles in Tanzania.

Results of the identification of microbes found in each fecal sample showed that the human gut microbiome is significantly less diverse than that of apes, even though there are also substantial differences among the multiple ape species. These findings confirm that microbial diversity has decreased significantly during human evolution and has changed even more rapidly in humans than among ape populations.

People living in urban cities in the United States had the least microbiome diversity, which could be a result of cultural differences, differences in diet, increase in c-section prevalence, increased use of antibacterial cleaning products, and antibiotics. As we have seen in previous studies, lower levels of microbiome diversity in humans has been linked to both immune system and gastrointestinal diseases. At this point we don’t fully understand the implications that these changes in human gut diversity over time are having but it is important to better understand this as we develop new therapeutics by manipulating the microbial communities in our gut.  

Insects may be contributing to antibiotic resistance

A review in Applied and Environmental Microbiology from earlier this year provided evidence for an elusive link in antibiotic resistance.  Livestock that are used for food are fed antibiotics to increase their body mass.  This creates a selective pressure for antibiotic resistance in their gut, and it is well known that many antibiotic resistant strains originate in these animals.  There is now mounting evidence that the antibiotic resistant strains of bacteria seen in humans are actually those same strains that originated from livestock.  How, though, is this antibiotic resistance being transferred from animals to humans?  According to this review: insects!

The authors detail studies showing that the feces of livestock animals contain many antibiotic resistant bacteria.  Other studies have shown that many insects found in farms can acquire these antibiotic resistant strains in their own guts by feeding off the feces of the animals.  The connection to humans is demonstrated in studies showing that when insects land on human food to eat, they can transfer their gut microbiome to these surfaces.  Thus the vector of antibiotic resistance between animals and humans is the guts of insects.  Furthermore, the authors show the same horizontal gene transfer that spreads antibiotic resistance in the guts of animals and humans also occurs in insects.

The authors of this article conclude that there should be an increase in pest control in farms, restaurants, and kitchens.  Antibiotic resistance is a growing problem, and small measures like keeping flies away from our food are certainly worthwhile.  Still, the most obvious solution is to outlaw antibiotic use in livestock all together, something that Europe has done since 2006.

The oral microbiome of the medieval man

Plaque that forms on teeth, also called calculus, can be preserved for a very long time, and traps all types of biomolecules and bacteria that are found in our mouths. An article published by Nature Genetics explores a study conducted to observe the oral microbiome on calculi of ancient human teeth and its differences from the oral microbiome that exists today. In this study, the ancient calculi showed the historical importance of gene transfer in the microbiome, which has been, and still is a rich consortium of bacteria that readily and rapidly exchange gene. 

The researchers studied the teeth of four adult human skeletons from the medieval city of Dalheim, Germany, who showed signs of mild to severe periodontal disease, as well as the current teeth of nine people. Interestingly, the same bacteria, proteins, and pathogens were identified in both the ancient and modern calculus, despite the differences in oral hygiene and diet between each time period. Researchers also found evidence of antibiotic resistance genes, like efflux pumps, in many members of the ancient plaque.  This means that horizontal gene transfer was clearly occurring between members of the oral microbiome, and the genes for some forms of antibiotic resistance have ancient roots.  However, other genetic adaptations for antibiotic resistance against modern drugs were not identified, even those that are ubiquitous in the oral microbiome today.  This should be no surprise, as modern antibiotics were not in use in the Middle Ages.

Medieval dental calculi, and fecal samples for that matter, give us a peak at what the ancient microbiome looked like.  By studying it, we can learn how the human oral microbiome has adapted over time in response to changes in human behavior, diets, hygiene, and antibiotic use.  

What happens to our microbiome when we get sick?

Editors Note:  Yesterday a piece about the AMI was published by the website Gut Microbiota for Health.  Read about it here.

When people get sick, what happens to their gut bacteria? Does their microbiome become weaker like the rest of their body? A recent study led by a group at the University of Chicago and published in Nature found that in mice, the intestines begin producing a specific type of sugar, fucose, to keep the bacteria in their guts healthy when the rest of their body becomes ill. 

To observe this occurrence, the team of scientists exposed different sets of mice to a molecule that causes them to get sick, simulating infection. When the first set of mice was given this molecule, fucose was quickly and abundantly produced in their intestine. When the second set of mice, mice that were bred to lack a specific gene (Fut2) that allows them to produce fucose, was made to become sick, the mice recovered from the illness much slower than the mice able to produce fucose.

This study showed that these sugars keep the microbiome healthy when its host gets sicks and help the host recover faster. What does this mean for humans?  Do we too produce this sugar when we become sick?

Unfortunately, approximately 20% of humans lack this important gene for producing fucose and these same people have been associated with a higher incidence of Chrohn’s disease.  In this study, the gut microbes of the mice engineered to lack the gene for creating fucose had greater harmful bacteria in their gut than normal mice. It is likely that the production of fucose in our bodies not only helps feeds our healthy bacteria, but it also helps stave off potentially pathogenic bacteria from proliferating.

This important interaction may lead to new therapeutics that directly influence the microbiome.  So remember, always 'feed' your cold.