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In an effort to combat childhood malnutrition, which affects around 200 million children worldwide, researchers at Washington University School of Medicine in St. Louis have developed a specialized therapeutic food aimed at enhancing the growth and overall health of children by fostering beneficial gut microbes. Under the leadership of physician-scientist Jeffrey I. Gordon, MD, the research team focused on understanding the responses of children’s gut microbiomes to this innovative food therapy.
Recent findings from their study highlight the significant effects of a particular gut bacterium associated with improved growth in Bangladeshi children consuming a microbiota-directed therapeutic food known as MDCF-2. This food has been engineered to support the growth of healthy microbes in the gut. Remarkably, the researchers identified a strain of bacteria that contained a previously uncharacterized gene enabling it to produce and metabolize essential molecules that regulate a myriad of physiological functions, including appetite regulation, immune response, neuron function, and the pathogenic potential of harmful bacteria.
The research outcomes were detailed in the journal Science on October 25.
“By employing new treatments for childhood malnutrition that focus on restoring gut microbiomes, we can gain deeper insights into the role our microbial allies play in health,” stated Gordon, who serves as the Dr. Robert J. Glaser Distinguished University Professor and directs the Edison Family Center for Genome Sciences & Systems Biology at WashU Medicine. “Our research is uncovering how gut microbes influence different physiological processes, revealing their remarkable biochemical capabilities that were previously underestimated.”
A clearer understanding of how gut microbes influence human health may pave the way for innovative strategies aimed at improving health outcomes and inform the development of new treatments for a variety of conditions beyond just malnutrition.
During two randomized controlled trials involving malnourished Bangladeshi children, the researchers identified specific microbial communities whose composition and activity were linked to improvements in growth among participants. A notable microbe identified in this context was Faecalibacterium prausnitzii.
The study’s co-first authors, Jiye Cheng, PhD, and Sid Venkatesh, PhD, undertook experiments with mice raised in sterile environments, which were then introduced to defined microbial communities derived from the gut microbiomes of Bangladeshi children. They observed that levels of two important lipid signaling molecules known as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were significantly lower in the mice colonized by a specific strain of F. prausnitzii, compared to those without this strain. This finding is particularly significant as OEA and PEA are known to play vital roles in managing inflammation, metabolism, and appetite regulation.
Using various bioinformatics and biochemical techniques, Gordon’s team identified the enzyme fatty acid amide hydrolase (FAAH), produced by the bacterial strain, which is responsible for the breakdown of OEA and PEA. The human variant of FAAH is recognized for its involvement in degrading certain neurotransmitters, regulating a variety of physiological functions throughout the body. This distinction is crucial as FAAH is also a target for several experimental drugs aimed at addressing issues like chronic pain, mood disorders, and anxiety.
Cheng and Venkatesh emphasized that the revelation of the FAAH enzyme in F. prausnitzii marks the first discovery of a microbial enzyme of its kind, shedding light on the role of gut bacteria in managing levels of N-acylethanolamides, including OEA and PEA, in the gastrointestinal tract.
Further analysis of fecal samples from malnourished children participating in the therapy trials indicated that the treatment successfully reduced levels of OEA while promoting the proliferation of F. prausnitzii and the activity of its enzyme. These results suggest that the bacterial enzyme may lower intestinal OEA, an appetite-suppressing molecule, which is particularly beneficial for children facing malnutrition challenges.
The findings not only reveal new understanding regarding the advantages of the therapeutic food but also illustrate how the bacterial enzyme exhibits capabilities far exceeding those of its human counterpart. It has the unique ability to synthesize lipid-modified amino acids and various novel compounds that act as modulators of human cell receptors and regulators of immune responses in the gut.
The distinct structural differences between the human and bacterial FAAH enzymes imply that investigational drugs targeting the human variant are unlikely to affect the bacterial one. This insight opens avenues for developing targeted therapies aimed at influencing the bacterial enzyme’s activity and product formation, emphasizing the unique functions that microbes perform that are not encoded in the human genome yet play essential roles in human health. Gordon articulated this potential, noting, “We now recognize that we possess two variations of this enzyme existing in distinct locations—our human cells and our gut microbiome.”
Gordon and his colleague Michael Barratt, PhD, also co-authored the paper, underscoring that the discovery of the gut bacterial enzyme creates new possibilities for exploring the therapeutic effects of the food treatment. Barratt pointed out that microbial enzymes like this one might elucidate individual variations in responses to orally administered medications, alongside their dietary processing abilities.
“The capabilities of the microbial version of this enzyme are truly remarkable,” Gordon remarked. “Moving forward, we are keen to investigate whether similar enzymes present in other bacterial genomes could complement or perform entirely different roles than FAAH. These microorganisms are exceptional chemists, and we are only beginning to understand their full potential.”
Cheng, Venkatesh, Barratt, and Gordon have filed a patent application through Washington University in St. Louis, which encompasses therapeutic applications of F. prausnitzii FAAH.
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