The Application of Bioengineered Microbes & Therapeutic Probiotics

The future of medicine could be microbial. As microbiome research continues to expose the rich array of symbiotic and biological functions of the microbes that inhabit human bodies (functions that then lead to noteworthy changes in human host physiology), we are discovering that it may be the function(s), rather than the composition, that dictates the health of one’s microbiome. Although the composition can vary greatly amongst communities that consume vastly different diets, the microbiomes of these communities may share the same functions despite these compositional differences. Some of the biological functions these microbes are capable of include improving blood glucose control / regulating glucose homeostasis, increasing GLP-1 secretion, producing GABA, digesting insoluble fiber, synthesizing vitamin K, and more.

Is it possible to bio-engineer strains of bacteria that have a specific biological action in the human body? Is it possible to then administer these strains to patients to effectively treat metabolic disease (obesity, diabetes, etc.), as well as other conditions? Can we strategically manipulate the microbiome to improve digestion and modulate hormone secretion? Can we understand the rapid rate of bacterial evolution, the abundance of microbe-microbe interactions, and the complexity of microbe-host interactions enough to harness the power of bacteria to treat human diseases? Early research indicates the answer to these questions may be yes.

For example, Levilactobacillus brevis LB01, as well as other probiotic strains, were found to efficiently produce GABA from monosodium glutamate in vitro.¹ Because low levels of GABA are thought to play a role in anxiety, depression, and other mental health conditions, increasing the synthesis of this inhibitory neurotransmitter via an upstream bacterial strain could prove to be a potential treatment for these conditions. It seems that the gad operon is responsible for the GABA synthesis, but the gad genes may be inactivated/methylated and/or might require specific signals to be activated and transcribed.¹ Just as epigenetics play a role in human genomics and protein synthesis, the epigenome and methylation patterns must also be considered when studying microbial genomes. Although in vivo studies are necessary before the application of this type of bacterial therapy, the in vitro experiments done in this study aimed to mimic the human colonic environment.¹ However, the rapid mutation rates and evolution of bacterial strains must also be taken into consideration, as well as the unknown factor of whether GABA synthesized in the intestines will cross the blood-brain-barrier and/or affect GABA signaling in the brain via the gut-brain axis.

With the popularity of semaglutide - a GLP-1 receptor agonist used to treat diabetes and induce weight loss - another particularly prevalent example has to do with the enhancement of GLP-1 secretion. In a study published by Nature, over a thousand bacterial strains were isolated from the guts of healthy humans, many of which were found to increase GLP-1 secretion.² Specifically, many strains of Staphylococcus epidermis positively modulated GLP-1 secretion by the production of a peptide called Hld.² Further experiments showed Hld to be sufficient at increasing GLP-1 secretion.² Could this bacterial peptide and/or the bacterial strains themselves be used to treat metabolic disease?

Other bacteria may also be capable of increasing insulin sensitivity, regulating glucose homeostasis, and treating metabolic disease via a variety of indirect and direct mechanisms. In another study, Holdemanella biformis proved to modulate enteroendocrine L-cells, leading to an increase in PYY and GLP-1 secretion, via an increase in pyy and proglucagon transcription, LCFA and SCFA production (which are GLP-1 secretagogues), and other indirect mechanisms.³ Another indirect mechanism by which metabolic disease may be improved via microbes of the microbiome is by promoting the strength of the intestinal epithelial barrier and lowering the inflammation caused by disruption to this barrier and the loss of tight junction integrity.

Akkermansia muciniphila, an obligate anaerobe, also enhances GLP-1 secretion from intestinal L-cells.⁵ One mechanism is mediated by propionate production via mucin degradation, which is then converted to the well-known SCFA butyrate by secondary fermenters that are also located in the large intestine. In human clinical trails, Akkermansia muciniphila, in combination with other bacterial strains, was found to lower glucose total area under the curve (AUC) in diabetic individuals.⁴ Despite the conflict of interest involved in this specific study (it was conducted by a company who sells a probiotic with the formulation being tested), other studies have also highlighted Akkermansia muciniphila’ s potential ability to induce weight loss or play a role in metabolic disease.

Given the many mechanisms by which bacteria can exert an effect on human physiology, one can understand the difficulty in understanding the intricacies of microbe-host interactions and all the functions of the human microbiome. Although more research is needed before the application of bio-engineered microbes to treat disease, I remain hopeful that microbes will become a foundation for a new type of medicine.

References

1. Monteagudo-Mera A, Fanti V, Rodriguez-Sobstel C, Gibson G, Wijeyesekera A, Karatzas K-A, et al. Gamma aminobutyric acid production by commercially available probiotic strains. J Appl Microbiol [Internet]. 2023 [cited 2023 Dec 30];134(2):lxac066. Available from: https://academic.oup.com/jambio/article/134/2/lxac066/6918826  

2. Tomaro-Duchesneau C, LeValley SL, Roeth D, Sun L, Horrigan FT, Kalkum M, et al. Discovery of a bacterial peptide as a modulator of GLP-1 and metabolic disease. Sci Rep [Internet]. 2020 [cited 2023 Dec 30];10(1):1–12. Available from: https://www.nature.com/articles/s41598-020-61112-0  

3. Romaní-Pérez M, López-Almela I, Bullich-Vilarrubias C, Rueda-Ruzafa L, Gómez Del Pulgar EM, Benítez-Páez A, et al. Holdemanella biformis improves glucose tolerance and regulates GLP‐1 signaling in obese mice. FASEB J [Internet]. 2021;35(7). Available from: http://dx.doi.org/10.1096/fj.202100126r  

4. Perraudeau F, McMurdie P, Bullard J, Cheng A, Cutcliffe C, Deo A, et al. Improvements to postprandial glucose control in subjects with type 2 diabetes: a multicenter, double blind, randomized placebo-controlled trial of a novel probiotic formulation. BMJ Open Diabetes Res Care [Internet]. 2020 [cited 2023 Dec 30];8(1):e001319. Available from: https://pubmed.ncbi.nlm.nih.gov/32675291/  

5. Yoon HS, Cho CH, Yun MS, Jang SJ, You HJ, Kim J-H, et al. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nat Microbiol [Internet]. 2021 [cited 2023 Dec 30];6(5):563–73. Available from: https://pubmed.ncbi.nlm.nih.gov/33820962/