The noble laureate in Physiology or medicine 1958, Joshua Lederberg had coined the term "microbiome" in the year 2001 to describe the biological community of pathogenic, commensal, and symbiotic microorganisms that live inside living organism. About 10-100 trillion symbiotic microbial cells are carried by each individual, mostly in the gut, that are known as the human microbiota. While the term "human microbiome" refers to the genetic material of microorganisms (microbiota) that live at a specific location within the human body. Numerous anatomical body locations, including the skin, mucosa, gastrointestinal system, respiratory tract, urogenital tract, and mammary gland, are colonized by microorganisms. The human microbiome plays a critical role in immunity, metabolism, and nutritional extraction. It is also essential for the creation of bioactive compounds including lipids, vitamins, and amino acids.[1] 

Why human micro biome holds importance in research?  

Recent research have highlighted the function of gut microbiota and its metabolites in modifying therapy results in human diseases. The drug-microbiota interaction is known to cause individual variability in drug response (IVDR) or adverse drug reactions (ADR).  Numerous sub-disciplines have emerged from this topic, such as pharmacomicrobiomics, pharmacometabonomics, and pharmacometagenomics.These subfields seek to investigate how microbiota variation impacts IVDR in human disorders as well as the impact of microbiome on PK and PD. The National Institutes of Health (NIH) launched the Human Microbiome Project (HMP) in 2007 as a cooperative initiative to thoroughly investigate the diversity and functions of the human microbiota. The project intends to examine the role of microbiota in IVDR, characterize microbiota from diverse body regions in humans using highthroughput sequencing techniques, and provide new research tools and resources for the scientific community. The term "pharmacomicrobiomics" was coined in 2010 to characterize the impact of changes in the composition and function of the microbiota on IVDR and host genetics. Microbiome differences have implications for both pharmacomicrobiomics, which studies how different microbiomes affect medication action, toxicity, and disposition, and personalized medicine.[2] 

Microbiome factor in drug discovery & development  

There are three domains in which the microbiome directly influences drug development:  

(1) microbial impacts on drug safety and efficacy,  

(2) drug effects on collateral microbiome community restructuring, and  

(3) possible adverse effects of novel therapies targeting the microbiome. 

Drugs can be significantly changed clinically by the microbiome without the patient knowing, and in the most extreme situations, this can result in deadly drug interactions. The 'canonical' pharmacokinetics of pharmaceuticals can be changed by activating, deactivating, toxifying, or releasing metabolites. For instance, Bacteroides species toxify brivudine using a conserved purine nucleoside phosphorylase, Eggerthella lenta's cgr operon inactivates digoxin, Helicobacter pylori absorbs and inactivates L-dopa, and microbiome β-glucuronidases deconjugate the irinotecan metabolite SN-38G, regenerating the drug's cytotoxic form.[3] 

Medication is starting to show up as a significant factor affecting the composition of the human gut microbiome. Although the importance of non-antibiotic medications was not well understood until recently, antibiotics with broad-spectrum effects are also recognized to have a direct effect on our gut microbiota. They therefore result in a variety of gastrointestinal adverse consequences, including infections with Clostridium difficile. The adverse effects of antibiotics on the gut microbiome have drawn increased attention lately. For instance, β-lactams are known to kill bacteria and have strainspecific action, we reasoned that they might produce long-lasting effects on community composition by irreversibly depleting certain members of the microbiota. [4] 

Therapeutics of which there are presently nine varieties: dietary modifications, prebiotics, probiotics, synbiotics, antibiotics, faecal microbiota transplantation (FMT), phage therapy, live biotherapeutics, and microbiome mimetics, are examples of microbiome-based medicines. By transferring a faecalassociated microbiota from a healthy individual, FMT, as opposed to antibiotics and phage treatments, can restore bacterial diversity and health-associated functions like colonization resistance. FMTs are not always successful, and there is even anecdotal evidence of unintentional changes occurring, like an abrupt increase in weight after an FMT.[5] 

Micro-biome based therapeutics  

Many microbiome-based medications may already have human use approval from the FDA or other strict regulatory bodies, negating the need for preclinical safety studies. Typical meals that might contain probiotics, postbiotics, or prebiotics are among them, as are other medications that have been repurposed as microbiome mimics. Following the completion of the ECOSPOR clinical studies, the FDA approved Seres and Nestle's VOWSTTM (also known as SER-109) to treat rCDI on April 26, 2023. Bacterial spores that have been purified from healthy human donor feces and pre-screened for pathogens are found in the VOWSTTM capsules. UTIs may join the list of infections if evidence on other microbiome medication leads, such as SER-109 and SER-155, continue to demonstrate effectiveness in modifying the gut flora. Similarly based on clinical program outcomes, such as the Phase 3 PUNCHTM CD3 trial, which was randomized, double-blind, placebo-controlled, and showed that a single dose of REBYOTA was more effective than a placebo in reducing CDI recurrence following standard-of-care antibiotic treatment, the FDA approved REBYOTA. The area of microbiome-based treatments known as "live biotherapeutics" deals with the application of live organisms—such as bacteria—for the purpose of illness prevention, treatment, or cure. Phase III clinical studies are now investigating advanced live biotherapeutics that aim to treat illnesses like hyperoxaluria (OxThera) and chronic renal failure (Kibow Pharmaceuticals).[5] 

Micro-biome therapeutics stand in drug market 

The commercial market for medicines based on microbiomes is still in its infancy, and opinions on the worldwide worth of these treatments differ greatly. The prescription-based market was only estimated to be worth $115 million in 2021, but according to Strategic Market Research, it is expected to grow to $1.3 billion by 2030. The global microbiome market has been expected to grow from $390 million in 2022 to $570 million in 2023, according to a different Research and Markets analysis. In contrast to other significant pharmaceutical markets like oncology, the market size projections for microbiome-based therapies are generally modest, notwithstanding these variances. Nevertheless, these approximations typically fail to account for the possibility that treatments based on the microbiome could displace traditional treatments in the medical field. Given the range of possible applications, this is a plausible scenario. By 2030, we anticipate that the global market for prescription drugs based on microbiomes would be worth many billions of dollars.[6] 

In conclusion, the growing significance of the human microbiome in comprehending and regulating human health, especially in relation to medication therapy and customized treatment. Microbiomebased therapies and interventions will probably become more and more important in healthcare as research advances.The composition and function of the human microbiome influence pharmacological efficaciousness, adverse effects, and the possibility of customized therapy, among other aspects of human health and medicine. 

References: 

1. Ursell LK, Metcalf JL, Parfrey LW, Knight R. Defining the human microbiome. Nutr Rev. 2012 Aug;70 Suppl 1(Suppl 1):S38-44. doi: 10.1111/j.1753-4887.2012.00493.x. PMID: 22861806; PMCID: PMC3426293. 

2. Zhao, Q., Chen, Y., Huang, W. et al. Drug-microbiota interactions: an emerging priority for precision medicine. Sig Transduct Target Ther 8, 386 (2023). https://doi.org/10.1038/s41392-023-01619-w 

3. Hitchings, Reese et al. Predicting and Understanding the Human Microbiome’s Impact on Pharmacology. Trends in Pharmacological Sciences, Volume 40, Issue 7, 495 – 505. 

4. Maier L, Goemans CV et.al. Unravelling the collateral damage of antibiotics on gut bacteria. Nature. 2021 Nov;599(7883):120-124. doi: 10.1038/s41586-021-03986-2. Epub 2021 Oct 13. PMID: 34646011; PMCID: PMC7612847. 

5. Gulliver EL, Young RB et.al. Review article: the future of microbiome-based therapeutics. Aliment Pharmacol Ther. 2022 Jul;56(2):192-208. doi: 10.1111/apt.17049. Epub 2022 May 24. PMID: 35611465; PMCID: PMC9322325. 

6. Edward Hamer, Sebastian Kwisda, and Kevin Kalinka Small bugs with major commercial potential The accelerating rise of microbiome-based therapeutics. Strategy & part of pwc published on: October 09, 2023 Accessed on : October 09, 2023.  

URL: https://www.strategyand.pwc.com/de/en/industries/pharma-life-science/impact-microbiome therapeutics.html

About the Author:

Shruti Talashi

Ms. Shruti  Talashi  boasts a dual mastery of lab research and writing. Her doctoral study outcome as M.Phil in biomedical science while studying breast cancer and an extraordinary masters degrees dissertation work on exploring role of Gal-lectin in cancer metastasis fuels her extensive research interests. She has gained few publication in journals. Bridging the science-public gap is her passion, aided by expertise in diverse techniques. From oncology to antibiotic/drugs production, she's led and managed complex projects, even clinical trials. Now, as a freelance Content Coordinator for Sinoexpo Pharmasource.com, her industry knowledge shines through valuable insights on cutting-edge topics like GMP, QbD, and biofoundry.