A recent study reveals that probiotics are not equally effective in preventing Clostridioides difficile (C. diff.) colonization. The research highlights a specific group of enzymes called bile salt hydrolases (BSHs), which can restrict C. diff. colonization by modifying existing bile acids and generating a new type of bile acids in the gut’s microbial environment.
They have found that certain enzymes within a group known as bile salt hydrolases (BSHs) can alter existing bile acids and create a new class of bile acids in the gut’s microbial environment, thereby restricting the growth of C. diff.
This discovery could pave the way for “designer” probiotics that are tailor-made to protect against disease by introducing specific BSHs to the gut after antibiotic treatment.
However, the study found that interactions between BSHs and bile acids depend on the type of bacteria the BSHs come from, making it crucial to select the right suite of BSH-producing bacteria.
Bile salt hydrolase (BSH) enzymes play a crucial role in chemically modifying bile acids, which are produced in the liver and are essential in regulating fat absorption, modulating cholesterol levels, shaping the immune system, and influencing the type of bacteria that can thrive in the gut.
Despite the long-standing suspicion that BSHs from beneficial bacteria have a crucial role to play in the bile acid pool, gut microbial composition, and host health, little was known about their functioning and potential impacts on host health. However, the latest research has begun to unravel the mystery of BSHs and how they can be harnessed to improve health outcomes.
“The old dogma – that BSHs are needed for gut colonization because they render toxic bile acids non-toxic – oversimplified what’s actually happening,” explains corresponding author Casey Theriot.
“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.”
Microbiologists, chemists, biochemists, and physicians from NC State, UNC Chapel Hill, and UC San Diego worked under Theriot’s direction on the new study to delve further into BSHs.
They specifically examined a large number of BSHs from various Lactobacillaceae bacteria, which is the family that includes the majority of probiotic strains, and then incorporated BSHs from the gut microbiota (nearly 1,000 unique BSHs in total).
In UNC-Chapel Hill’s College of Arts and Sciences, Matthew Redinbo holds the position of Kenan Distinguished Professor of Chemistry. He and his colleagues in the department, with Morgan Walker leading the way as a graduate student at the time, played a crucial role in discovering the structure of BSHs and understanding how they selectively interact with bile acids through the addition or removal of specific amino acids.
“We found the tiny molecular fingerprint that defined whether a BSH would ‘turn left’ or ‘turn right’ in terms of what they processed,” adds Redinbo. “Knowing that allowed Casey’s team to steer the bile acid pool in whatever direction they wanted.”
The researchers used a mix of Lactobacillus BSHs to see if they could change the bile acid pool enough to change C. diff colonization in both human stool samples from people who were likely to get C. diff infection (CDI) and in a mouse model of CDI. BSH cocktail pre-treatment affected C. diff colonization in mice and human stool samples. It’s interesting to observe that the mice treated with BSH had higher amounts of MCBAs in their gut microbiome.
To establish if the MCBAs also inhibited the germination and development of C. diff, they tested the MCBAs in vitro against C. diff. In the majority of instances, the presence of MCBAs blocked several C. diff life cycle phases.
“This is more evidence that BSHs are driving changes in the bile acid pool – including making MCBAs – that could serve to inhibit C. diff,” adds Theriot. “We’ve uncovered a new function for BSH enzymes.”
“This work highlights the importance of BSHs as key intestinal enzymes and promising new therapeutics,” remarks co-author Matt Foley. “Using BSHs in combination with other strategies may offer a new approach to treat C. diff.”
The finding is the first step, according to the researchers, toward developing probiotics that may be specifically designed to protect against a range of bacterial infections and intestinal illnesses. Nevertheless, additional investigation is required to learn how and why the BSHs choose particular MCBAs to create and/or target.
“This is an important illustration of how deciphering the biochemical and genetic basis for probiotic functionality both leads to a better understanding of how we can combat gut disease with novel modalities, and also practically design and formulate next-generation commercial probiotics,” adds c-corresponding author Rodolphe Barrangou.
Source: 10.1038/s41564-023-01337-7
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