By Kyle Phong
Published 5:30 EST, Mon December 20th, 2021
The urinary tract infection (UTI) is considered the most common infection and causes around 8 million trips to the clinic and emergency department every year in the US. This infection is more common in women and is also known to affect many elders. A UTI is caused when bacteria from the skin or rectum enter the urinary tract. While the most common UTI is a bladder infection, kidney infections are a more severe form of UTI. The typical symptoms of a UTI consist of a burning sensation while urinating, pain in the groin or lower abdomen, and a fever.
CDC, “Urinary Tract Infection.”
After recurring UTIs, bacteria is infamous for growing resistant to antibiotics, which constantly pushes scientists to develop new forms of treatment. A research team at Baylor College of Medicine and Washington University School of Medicine found a new use of a familiar medicine to treat UTIs by analyzing how the body naturally fights back against E. coli, which causes more than 85% of UTIs. They noticed that a specific pathway greatly contributed to the elimination of E. coli as well as the protection of bladder tissue and wanted to see how they could use this to treat UTIs.
With around 5,600 lab-grown urothelial cells, cells inside the lining of the bladder, the team infected them using E. coli bacteria and allowed them to proliferate. These cells were also stained with a fluorescent dye to indicate the presence of active compounds known as reactive oxygen species (ROS). In response to the growing bacteria population, the urothelial cells produced ROS that killed the E. coli bacteria, which the researchers confirmed through immunofluorescence staining. However, this increase in ROS levels was dangerous as ROS damages urothelial cells alongside E. coli bacteria, causing significant issues with the bladder. Then, the Baylor researchers found that the high levels of ROS led to an anti-ROS response called the NRF2 pathway. Nuclear factor erythroid 2-related factor 2 (NRF2) is a protein in the cytoplasm that is bound to another protein called Kelch-like ECH-associated protein 1 (KEAP1). After a certain level of ROS accumulates, NRF2 separates from KEAP1 and enters the nucleus, where it activates a series of genes. Some of these genes reduce the inflammation in the bladder, and others reduce ROS levels. One activated gene, RAB27B, expels E. coli from the urothelial cells. The NRF2 pathway’s dual ability to protect the bladder tissue and fight off bacteria suggested a new treatment of UTIs. On the other hand, the scientists found that the loss of NRF2 resulted in an increase in ROS, bacteria levels, and inflammation.
With this new information, the team searched for an NRF2 pathway activator and found one FDA-approved drug called dimethyl fumarate (DMF). DMF is typically used to treat relapsing multiple sclerosis, but the scientists believed DMF would be effective in treating UTIs as well. A related study showed that a high concentration of DMF can directly kill bacteria, so the scientists treated their lab-grown cells with lower levels of DMF. Additionally, the team tested DMF on mice with UTI and observed the activation of NRF2 in both experiments, which in turn mitigated the damage from the ROS and increased RAB27B expression to eliminate the E. coli. The mice had fewer bacteria in their urine, reduced damage to their bladder tissue, and reduced inflammation.
Cell Reports, “Graphical abstract.”
Continued use of antibiotics not only develops resistant bacteria but also harms the “good bacteria,” or microbiome, of the body. However, the professor of molecular virology and microbiology at Baylor, Dr. Mysorekar, commented, “The most exciting part about this work was identifying a non-antibiotic-based therapy that contained the infection and reduced inflammation.” Since the DMF treatment does not utilize antibiotics, it eliminates the concern of the bacteria becoming resistant. The researchers at Baylor realized that the activation of NRF2 is critical for our body’s defense against UTIs. They recognize the long process before this treatment can be applied clinically and hope that this experiment will open up the possibility of DMF treatment to aid women who suffer from recurrent UTIs. The team also hopes that future efforts focus on identifying additional NRF2 modulators like DMF. It is imperative that we continue to search for more effective methods of treatment in order to continue revolutionizing the world of medicine.
Kyle Phong, Youth Medical Journal 2021
Cell Reports, “NRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expression”, 19 October 2021
https://www.cell.com/cell-reportNRF2 promotes urothelial cell response to bacterial infection by regulating reactive oxygen species and RAB27B expressions/fulltext/S2211-1247(21)01323-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124721013231%3Fshowall%3Dtrue
News Medical Life Sciences, “Study reveals potential new approach to fight urinary tract infections,” 19 October 2021
CDC, “Urinary Tract Infection,” 6 October 2021