The Importance of the Human Microbiome in Drug Discovery

Trillions of microorganisms live symbiotically on, and within, human beings and have vital implications in health and disease.

Human Microbiome

Human Microbiome. Image Credit: Kateryna Kon/Shutterstock.com

The human microbiome is involved in several biological processes, including modulating metabolism, regulating epithelial development, and influencing the innate immune response. Recent advances in ‘omics’ technologies, such as metagenomics and metabolomics, have unraveled the crucial role of the microbiome in chronic diseases such as obesity, inflammatory bowel disease (IBD), atherosclerosis, diabetes, liver disease, neurological disorders, and even cancers.

What is the role of the human microbiome?

The composition and function of the human microbiome is determined by the location, age, sex, race, as well as the diet of the host. The human microbiome helps in metabolizing indigestible compounds and maintaining energy homeostasis, supplying essential nutrients, and defending against pathogens.

Digestion

The human microbiome aids in the digestion of certain foods that otherwise cannot be digested by the stomach and the small intestine. Bacteroides help in the digestion of dietary fibers such as xyloglucans (found in vegetables) and bacteria such as Lactobacillus and Bifidobacterium help in the digestion of other non-digestible fibers (fructo-oligosaccharides and oligosaccharides).

Lipid and protein homeostasis

Short-chain fatty acids (SCFAs) regulate gut motility, inflammation, and glucose, and energy metabolism. The human microbiome produces SCFAs, such as acetic, propionic, and butyric acids, which are quickly absorbed by the colon and serve as an energy source to the host intestinal epithelium. The gut microbiome produces several essential vitamins, including B3, B5, B6, B12, K, biotin, and tetrahydrofolate, and aid in the absorption of iron from the intestinal lumen.

Stimulates the immune response

The human microbiome stimulates the humoral and cellular mucosal immune systems, which prevent exogenous pathogen intrusion. Signals and metabolites generated by the microbiome are sensed by the hematopoietic and non-hematopoietic cells of the innate immune system and translated into physiological responses. They also generate a tolerogenic response that acts on gut dendritic cells and inhibits the type 17 T-helper cell (Th17) anti-inflammatory pathway.

The gut bacteria indirectly modulate immune function through interactions with invading pathogens. Broad-spectrum antibiotics which lead to ablation of the gut microbiome predisposes individuals to opportunistic pathogens like Clostridium difficile. Bacteria also possess molecular weapons such as bacteriocins, microcins, and Type VI secretion systems that help keep pathogens at bay.

Affects neuroendocrine function and behavior

The microbiome produces butyrate which modulates levels of neuropeptides such as leptin and peptide YY which govern satiety. They also influence circulating levels of neurotransmitters, such as serotonin, and bacterial enzymes can synthesize the neurotransmitter tryptamine.

Further, germ-free mice display higher levels of behavioral anxiety, attributed to higher levels of circulating ACTH and corticosterone. In mouse models of autism spectrum disorders, administration of B. fragilis leads to a reversal in behavioral abnormalities by correcting dysbiotic microbiota.

Microbiome in drug metabolism

The gut bacteria play an important role in reductions of chemical bonds in certain drugs, as well as other transformations including hydrolysis, dehydroxylation, acetylation, deacetylation, and deconjugation of glucuronides and sulfates.

The human microbiome affects the metabolism of various drugs from anti-epileptic zonisamide to insulin and the hormone calcitonin used to treat high calcium levels in the blood and some diseases of the bone. Patients’ responsiveness to a cholesterol-lowering drug correlates with blood levels of three bile acids produced by gut bacteria.

Drug reactions with microbiomes can have potentially toxic and often lethal effects. One anticancer drug causes intense, delayed diarrhea as a result of bacterial activity. However, a molecule called SBX-1 inhibited microbial enzymes and thus could block these toxic effects.

The gut bacteria produce tyrosine decarboxylase that converts the Parkinson’s drug levodopa(L-dopa) into dopamine as the drug passes through the small intestine before it reaches the brain. There is a strong correlation between the abundance of the bacterial gene for tyrosine decarboxylase with a need for a higher dose of L-dopa to control Parkinson's symptoms.

Gut bacteria aids in the synthesis of trimethylamine N-oxide (TMAO) produced from fatty foods such as egg yolks, meat, and dairy. TMAO accelerates plaque development in the arteries and can lead to cardiovascular disease. Therefore, blocking microbial TMAO synthesis could reduce fatty deposits and serves as a route to treating cardiac disease.

Microbiome therapeutics

There is a lot of clinical focus to harness the yet untapped power of the microbiome to treat or ward off a variety of diseases. Altering the microbial composition of the gut through exogenous administration of live microbes is called probiotic treatment. Prebiotics are compounds other than live microbes that are consumed to favorably impact the microbiome composition or function.

Fecal Microbiota Transplantation (FMT) involves the transfer of an entire microbial community from a healthy individual to a diseased recipient to replace the disease-associated microbiome. FMT is quite efficient in the treatment of Clostridium difficile infection. However, there are caveats to consider with FMTs including inadvertent transplantation of pathobionts and negative interactions with the recipient’s existing microbial community.

Postbiotics affect the microbiome’s downstream signaling pathways. They mitigate the negative effects of an excess, scarcity, or dysregulation of metabolites involved in these pathways. Therefore, one effective way to counteract and rectify dysbiosis is via exogenous administration or inhibition of these metabolites.  Examples are SCFA’s which are altered in IBD and have an anti-inflammatory effect, flavonoids that have been implicated in therapies for metabolic diseases, and the organic acid taurine, which ameliorates intestinal inflammation.

Finally, we are at the doorstep of a new era of personalized medicine driven by the human microbiome, in which customized treatments would be employed given that each individual’s human microbiome reacts uniquely to treatments. The future of human microbiome-based drug discovery would depend not only on the complete microbiome composition but also the individual genetic makeup, environmental factors, and dietary elements to create personalized treatment plans.

Sources:

  • MARKEY, K. A., VAN DEN BRINK, M. R. M. & PELED, J. U. 2020. Therapeutics Targeting the Gut Microbiome: Rigorous Pipelines for Drug Development. Cell Host Microbe, 27, 169-172.
  • WALLACE, B. D. & REDINBO, M. R. 2013. The human microbiome is a source of therapeutic drug targets. Curr Opin Chem Biol, 17, 379-84.
  • WEERSMA, R. K., ZHERNAKOVA, A. & FU, J. 2020. Interaction between drugs and the gut microbiome. Gut, 69, 1510-1519.

Further Reading

Last Updated: Aug 24, 2021

Dr. Poornima Balaji

Written by

Dr. Poornima Balaji

Poonam is passionate about all things science and medicine. She has over 20 years of experience in research in cardiovascular physiology, biochemistry, and molecular biology. Poonam has worked as an independent scientist both in the United States and in Australia and has several publications in high-impact journals. (11 publications with ~700 citations; h index of 11).

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