Researchers found that certain enzymes within a class known as bile salt hydrolases (BSHs) can restrict Clostridioides difficile (C. diff.) colonization by both altering existing bile acids and by creating a new class of bile acids within the gut’s microbial environment. The work could lead to ‘designer’ probiotics that protect against disease by introducing specific BSHs to the gut after antibiotic treatment, according to the researchers.
Selecting the right suite of BSH-producing bacteria is critical, because the study found that interactions between BSHs and bile acids differ depending upon the type of bacteria the BSHs come from. Certain bacteria within the gut microbiota contain BSH enzymes, which chemically modify bile acids. Bile acids are made in the liver and play an important role in modulating cholesterol levels, regulating fat absorption, shaping the immune system, and affecting which bacteria can colonize the gut.
Although researchers had long suspected a connection between BSHs from beneficial bacteria, the bile acid pool, gut microbial composition and host health, until now relatively little was known about how BSHs function and their potential impacts on host health.
“The old dogma—that BSHs are needed for gut colonization because they render toxic bile acids non-toxic—oversimplified what’s actually happening,” says Casey Theriot, co-corresponding author of the study. “The reality is that BSHs’ interactions are context-dependent, meaning they’re affected by the type of bacteria they come from. And they don’t just interact with bile acids produced by the host. BSHs in the microbiota can create and interact with a new class of bile acids called microbial conjugated bile acids (MCBAs)—bile acids that we didn’t even know existed until recently.”
In the new study, Theriot and his team looked at hundreds of BSHs from different Lactobacillaceae bacteria, which houses most probiotic strains, and then included BSHs from the gut microbiota (nearly 1,000 unique BSHs in total).
The researchers used a cocktail of Lactobacillus BSHs to figure out if they could change the bile acid pool enough to alter C. diff colonization in both human stool samples collected from patients susceptible to C. diff infection (CDI) and in a mouse model of CDI.
In both human stool samples and mice, the researchers saw that pre-treatment with BSH cocktails impacted C. diff colonization.
The researchers noted elevated levels of MCBAs in the gut microbiota of the BSH-treated mice.
To determine whether the MCBAs were also involved in inhibiting C. diff germination and growth, they tested the MCBAs against C. diff in vitro. In most cases, the presence of MCBAs inhibited multiple steps of the C. diff life cycle.
“This is more evidence that BSHs are driving changes in the bile acid pool, including making MCBAs, that could serve to inhibit C. diff,” Theriot said. “We’ve uncovered a new function for BSH enzymes.”
Reference:
Foley, et al. Bile salt hydrolases shape the bile acid landscape and restrict Clostridioides difficile growth in the murine gut. Nat Microbiol, 20
