Escherichia coli is arguably the most commonly used bacterial host for metabolic engineering. Our current work is focused on engineering E. coli for the production of useful chemicals. Previously, when we were performing the experiments on butanol production in E. coli, we found that some short-chain fatty acids (SCFAs) (e.g. acetate and butyrate) and lactate are really recalcitrant to engineering. Even though all the well-known related pathway genes were knocked out to remove these byproducts, they were still produced at detectable levels. Although our target product was produced at a very high level, this imperfect process always bothered me.
One day, my supervisor talked to me and said “Hey, why do you always view these compounds as byproducts, they could be positive products under certain conditions”. Suddenly, my conventional thinking way was challenged and I began to view this question in another way. After further discussion, he suggested us to study gut microbiota as E. coli is also a common bacterium in the human intestines. And so, the literature searches for another subject area began! Surprisingly, we found that the by-products we used to dismiss are really important molecules in the human intestines. SCFAs can be used as energy sources and can improve inflammation while lactate can function as a signaling molecule and downregulate pro-inflammatory responses.
So far, we know that some SCFA-producing bacteria may act as probiotics and are a positive component of the gut microbiota. Later, we found a research paper identifying SCFA-producing bacteria via key genes involved in SCFA production . As mentioned above, E. coli is able to produce SCFAs through other pathways. Therefore, we proposed that more SCFA-producing bacteria could be identified via atypical genes. Using E. coli as a model, we designed an experimental procedure and identified more genes contributing to the synthesis of SCFAs and lactate. Furthermore, protein sequence alignment indicated that many of these genes are present in gut microbiota. Some bacteria even only contain the novel genes instead of the well-known ones. Thus, our work provides more genetic targets for researchers to discover more SCFA- and lactate-producing probiotics.
Hence, I recommend you try to break through your conventional thinking and never stop thinking about the significance of your work.
 Zhao, L. et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 359, 1151-1156 (2018).