Harnessing our Gut Reactions
By Patrick Magahis
All of the microorganisms in the human gut, including bacteria, fungi, parasites, and other microscopic agents such as viruses, are collectively known as gut microbiota. By producing and releasing metabolites and bioactive components, these microbe populations influence essential bodily processes such as host metabolism, immunity to diseases, and overall health.1 Exactly how these microbiota products are structured and how their unique mechanisms serve different physiological roles is an emerging field of study for many researchers. Scientists believe that gaining a deeper understanding of how each individual’s microbial metabolism of nutrients and xenobiotics—biological agents that are foreign to the human body—enables the release of bioactive compounds, as well as their subsequent ability to act on host cells, will be a key step towards successfully harnessing the therapeutic potential of the gut microbiome.2
Such potential advances towards optimizing the efficacy of microbiota-interacting drugs in humans come at a crucial time in medicine. The rapid emergence of resistant bacteria - dubbed “The Antibiotic Crisis” - is occurring worldwide, endangering the efficacy of antibiotics, which have transformed medicine and saved millions of lives.3 The Centers for Disease Control and Prevention (CDC) has classified a number of bacteria as presenting urgent, serious, and concerning threats, many of which are already responsible for placing a substantial clinical and financial burden on the U.S. healthcare system, patients, and their families. “Superstrain” bacteria that can target humans as well as their livestock and crops threaten entire populations, and industries. As a result, doctors forced to rely on very powerful and possibly harmful drugs to try to treat patients This crisis has been attributed to the overprescription, overuse, and misuse of these medications, as well as a lack of new drug development by the pharmaceutical industry due to reduced economic incentives and challenging regulatory requirements. Evidently, coordinated efforts are desperately needed to implement new policies, renew research efforts, and pursue steps to manage the crisis. As such, by unraveling the nature and physiological role of previously unknown bacterial metabolites involved in the fine regulation of host metabolism, host proteases, and drug response by gut bacteria, there exists hope for a reliable and effective alternative to antibiotics.4
Four studies published are 2017 currently form the foundation of research in the field and have paved the way for revealing the potential of this new treatment. Cohen et al. observed that the bacterial gut microbiota can produce small lipid metabolites that possess the specific ability to modulate the activity of several G-protein coupled receptors (GPCRs).5 Utilizing sequences obtained from the Human Microbiome Project, they were able to identify several singular GPCRs that were especially receptive to these bioactive metabolites such as GPR119, which plays a major role in controlling glucose homeostasis (therefore making it an attractive therapeutic target for diabetes and obesity). Similarly, Guo et al. focused on bacterial dipeptide aldehydes produced by bacterial strains from the class Clostridia. They showed that these dipeptide aldehydes are able to specifically inhibit human cathepsins, and such a mediated interaction could enable gut microbiota to stably modulate the human intestinal human system by occupying phagocytes in gut epithelial and immune cells.6
While these first two studies primarily focus on utilizing the products produced spontaneously from gut bacteria, other research has elucidated how bacterial byproducts can also be released after a microbial interaction with xenobiotics (such as drugs and environmental toxicants). Scott et al. and Garcia-Gonzalez et al. conducted studies that used a model organism, the nematode Caenorhabditis elegans, and a single bacterial strain.7 Their results demonstrate that bacteria can metabolically complement C. elegans to modulate the effects of a chemotherapeutic agent, 5-fluorouracil.8 Using large collections of bacterial mutants, the teams revealed that this 5-fluorouracil agent can be consistently transformed into 5-fluorouridine monophosphate, which can impair specific host RNA synthesis processes. Such findings can prove incredibly versatile and useful in determining how better to treat human RNA diseases.
Innovative approaches to studying the evolving interactions between gut microbiota and host metabolic and immunity processes are at the forefront of biomedical research. With the increasing burden of antibiotic resistance on hospital systems and the pharmaceutical industry worldwide, the management of drug efficacy and the modulation of existing treatments with gut microbiota directs us to pay attention to the microbiomes populating our body.
Notes
All of the microorganisms in the human gut, including bacteria, fungi, parasites, and other microscopic agents such as viruses, are collectively known as gut microbiota. By producing and releasing metabolites and bioactive components, these microbe populations influence essential bodily processes such as host metabolism, immunity to diseases, and overall health.1 Exactly how these microbiota products are structured and how their unique mechanisms serve different physiological roles is an emerging field of study for many researchers. Scientists believe that gaining a deeper understanding of how each individual’s microbial metabolism of nutrients and xenobiotics—biological agents that are foreign to the human body—enables the release of bioactive compounds, as well as their subsequent ability to act on host cells, will be a key step towards successfully harnessing the therapeutic potential of the gut microbiome.2
Such potential advances towards optimizing the efficacy of microbiota-interacting drugs in humans come at a crucial time in medicine. The rapid emergence of resistant bacteria - dubbed “The Antibiotic Crisis” - is occurring worldwide, endangering the efficacy of antibiotics, which have transformed medicine and saved millions of lives.3 The Centers for Disease Control and Prevention (CDC) has classified a number of bacteria as presenting urgent, serious, and concerning threats, many of which are already responsible for placing a substantial clinical and financial burden on the U.S. healthcare system, patients, and their families. “Superstrain” bacteria that can target humans as well as their livestock and crops threaten entire populations, and industries. As a result, doctors forced to rely on very powerful and possibly harmful drugs to try to treat patients This crisis has been attributed to the overprescription, overuse, and misuse of these medications, as well as a lack of new drug development by the pharmaceutical industry due to reduced economic incentives and challenging regulatory requirements. Evidently, coordinated efforts are desperately needed to implement new policies, renew research efforts, and pursue steps to manage the crisis. As such, by unraveling the nature and physiological role of previously unknown bacterial metabolites involved in the fine regulation of host metabolism, host proteases, and drug response by gut bacteria, there exists hope for a reliable and effective alternative to antibiotics.4
Four studies published are 2017 currently form the foundation of research in the field and have paved the way for revealing the potential of this new treatment. Cohen et al. observed that the bacterial gut microbiota can produce small lipid metabolites that possess the specific ability to modulate the activity of several G-protein coupled receptors (GPCRs).5 Utilizing sequences obtained from the Human Microbiome Project, they were able to identify several singular GPCRs that were especially receptive to these bioactive metabolites such as GPR119, which plays a major role in controlling glucose homeostasis (therefore making it an attractive therapeutic target for diabetes and obesity). Similarly, Guo et al. focused on bacterial dipeptide aldehydes produced by bacterial strains from the class Clostridia. They showed that these dipeptide aldehydes are able to specifically inhibit human cathepsins, and such a mediated interaction could enable gut microbiota to stably modulate the human intestinal human system by occupying phagocytes in gut epithelial and immune cells.6
While these first two studies primarily focus on utilizing the products produced spontaneously from gut bacteria, other research has elucidated how bacterial byproducts can also be released after a microbial interaction with xenobiotics (such as drugs and environmental toxicants). Scott et al. and Garcia-Gonzalez et al. conducted studies that used a model organism, the nematode Caenorhabditis elegans, and a single bacterial strain.7 Their results demonstrate that bacteria can metabolically complement C. elegans to modulate the effects of a chemotherapeutic agent, 5-fluorouracil.8 Using large collections of bacterial mutants, the teams revealed that this 5-fluorouracil agent can be consistently transformed into 5-fluorouridine monophosphate, which can impair specific host RNA synthesis processes. Such findings can prove incredibly versatile and useful in determining how better to treat human RNA diseases.
Innovative approaches to studying the evolving interactions between gut microbiota and host metabolic and immunity processes are at the forefront of biomedical research. With the increasing burden of antibiotic resistance on hospital systems and the pharmaceutical industry worldwide, the management of drug efficacy and the modulation of existing treatments with gut microbiota directs us to pay attention to the microbiomes populating our body.
Notes
- http://s3-service-broker-live-19ea8b98-4d41-4cb4-be4c-d68f4963b7dd.s3.amazonaws.com/uploads/ckeditor/attachments/8816/KAiM-jan18.pdf
- Ibid
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378521/
- Nature - efficacy of gut microbiota
- Cohen, L. J. et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature 549, 48–53 (2017).
- Guo, C. J. et al. Discovery of reactive microbiotaderived metabolites that inhibit host proteases. Cell 168, 517–526.e18 (2017).
- Scott, T. A. et al. Host–microbe co-metabolism dictates cancer drug efficacy in C. elegans. Cell 169, 442–456.e18 (2017).
- Garcia-Gonzalez, A. P. et al. Bacterial metabolism affects the C. elegans response to cancer
