Formic Acid Drives Novel Electron Transfer in the Gut Bacteria

Researchers at Goethe University Frankfurt have discovered a surprising role for formic acid in the human gut: The small molecule acts as a kind of “taxi” for electrons – both within bacteria and, likely, also between different microorganisms. The gut bacterium Blautia luti produces formic acid as part of a metabolic trick that allows it to respond flexibly to what is available in the gut. In addition to carbohydrates, the bacterium can also metabolize toxic carbon monoxide derived from the body’s own hemoglobin degradation.

Among the many trillions of microorganisms in the human gut is Blautia luti. Like many gut bacteria, it metabolizes indigestible dietary components, such as fiber in the form of carbohydrates. This process produces, among other things, acetic acid (acetate), an important energy source for our intestinal cells and a signaling molecule that can even influence our well-being via the gut-brain axis.

Taxis for Electron Transport

B. luti lives in the gut without oxygen and cannot respire, but only ferment. During this process, carbohydrates are converted into lactate, succinate, ethanol, carbon dioxide, and hydrogen, which are excreted as metabolic end products. Too much hydrogen in the gut is unhealthy because it inhibits further fermentation. Therefore, small single-celled organisms known as archaea consume the hydrogen, convert it into methane, and thus regulate hydrogen levels in the gut. Hydrogen thus acts, so to speak, as an electron taxi within a bacterium and between different bacteria. However, this process involves a substantial loss of energy and is therefore disadvantageous for the bacteria.

B. luti has an additional, better option. Raphael Trischler and Prof. Volker Müller, Chair of Molecular Microbiology and Bioenergetics at Goethe University Frankfurt, found that B. luti produces formic acid (formate) instead of carbon dioxide (CO₂) and hydrogen, with hydrogen bound to CO₂. In this case, formic acid is the electron taxi, allowing the energetically costly production of hydrogen to be bypassed.

Formic Acid as an Electron Store

To produce formic acid, B. luti uses the enzyme pyruvate formate lyase. This enzyme is rather unusual in acetogenic bacteria. "The electrons are essentially stored in the formic acid," explains Trischler. However, formic acid is also unhealthy at high concentrations.

B. luti detoxifies formic acid together with CO₂ via a special metabolic pathway, the Wood-Ljungdahl pathway (WLP), converting it into acetate. In the WLP, CO₂ is transformed via two different "branches" and ultimately assembled into acetic acid. In the first branch, CO₂ is normally converted into formic acid by a specific enzyme - formate dehydrogenase - using hydrogen. "But B. luti completely lacks formate dehydrogenase," explains Raphael Trischler, who studied the bacterium for his doctoral thesis. Instead, B. luti uses formic acid directly. Sugar breakdown on one side and acetic acid production on the other are thus linked via formic acid - a clever strategy that gives the bacterium an energetic advantage.

Useful Side Effects

In the laboratory culture studied, B. luti excretes formic acid. In the complex food web of the gut, however, the situation is different, and formic acid does not accumulate there. Methane-producing archaea can convert formic acid into methane, but B. luti has another trick up its sleeve. Reducing formic acid in the WLP requires electrons that originate from carbohydrate fermentation. But B. luti can also use gases produced by other bacteria for this purpose. "In the presence of hydrogen, the formic acid disappears completely," reports Trischler.

Particularly remarkable is B. luti's ability to utilize carbon monoxide. This highly toxic gas is produced in the human body during the natural breakdown of hemoglobin, the red blood pigment. "Bacteria like B. luti can thus detoxify carbon monoxide produced by the body itself using formic acid," explains Müller. This also explains why so many gut microbes possess the enzyme carbon monoxide dehydrogenase.

B. luti has yet another property beneficial to humans: In addition to acetate, it produces succinate (succinic acid). Succinate promotes the growth of other beneficial gut bacteria, stimulates the immune system, and is also an industrially valuable raw material for biotechnological applications.

The study highlights how diverse metabolic strategies in the gut are.

Even within related groups of bacteria, there are fascinating differences. Understanding this helps us better decipher the interactions between different gut bacteria and their role in human well-being." 

Prof. Volker Müller, Chair of Molecular Microbiology and Bioenergetics, Goethe University Frankfurt