Gut Microbiome-Related Recurrent UTIs, Chronic Inflammation – Washington University School of Medicine in St. Louis

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Antibiotics may increase the risk of new UTIs by disrupting the microbiome

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One of the biggest frustrations with urinary tract infections (UTIs) is that they recur so often. UTIs are caused by bacteria in the urinary tract and characterized by frequent and painful urination. A round of antibiotics usually eliminates symptoms, but relief is often temporary: a quarter of women develop a second UTI within six months. Some unfortunate people have UTIs repeatedly and need antibiotics every few months.

A new study suggests that women who get recurrent UTIs may be caught in a vicious cycle in which antibiotics given to eradicate one infection predispose them to developing another. The study, conducted by researchers from Washington University School of Medicine in St. Louis and the Broad Institute of MIT and Harvard, showed that a series of antibiotics kills disease-causing bacteria from the bladder but not the intestines. Surviving bacteria in the gut can multiply and spread back into the bladder, causing another UTI.

At the same time, repeated cycles of antibiotics wreak havoc on the community of helpful bacteria that normally live in the intestines, the so-called gut microbiome. Similar to other disorders in which gut microbes and the immune system are linked, the women with recurrent UTIs in the study had less diverse microbiomes that were deficient in an important group of bacteria that help regulate the inflammation, and a distinct immunological signature in their blood indicating inflammation.

The study is published May 2 in Nature Microbiology.

“It’s frustrating for women who come to the doctor with recurrence after recurrence after recurrence, and the doctor, who is usually a man, gives them hygiene advice,” said the co-senior author. Scott J. Hultgren, Ph.D., Helen L. Stoever Professor of Molecular Microbiology at the University of Washington. “That’s not necessarily the problem. It is not necessarily poor hygiene that is the cause. The problem lies in the disease itself, in this connection between the intestine and the bladder and the levels of inflammation. Basically, doctors don’t know what to do with recurring UTIs. All they have are antibiotics, so they throw more antibiotics at the problem, which probably only makes things worse.

Most UTIs are caused by Escherichia coli (E.coli) bacteria from the intestines that enter the urinary tract. To understand why some women get infection after infection and others get one or none at all, Hultgren teamed up with Broad Institute scientists Ashlee Earl, PhD, senior group leader of the Bacterial Genomics Group at Broad and co-author principal of the article, and Colin Worby, PhD, computational biologist and principal author of the article.

The researchers studied 15 women with a history of recurrent UTIs and 16 women without. All participants provided urine and blood samples at the start of the study and monthly stool samples. The team analyzed bacterial composition in stool samples, tested urine for the presence of bacteria, and measured gene expression in blood samples.

Over the course of a year, 24 UTIs occurred, all in participants with a history of repeated UTIs. When participants were diagnosed with a UTI, the team collected additional urine, blood and stool samples.

The difference between women who had repeated UTIs and those who didn’t, surprisingly, wasn’t just about the type of E.coli in their intestines or the presence of E.coli in their bladder. Both groups wore E.coli strains in their intestines capable of causing UTIs, and these strains sometimes spread to their bladder.

The real difference was in the makeup of their gut microbiomes. Patients with repeated infections showed a decrease in the diversity of healthy gut microbial species, which could provide more opportunities for pathogenic species to take hold and multiply. Notably, the microbiomes of women with recurrent UTIs were particularly sparse in bacteria that produce butyrate, a short-chain fatty acid with anti-inflammatory effects.

“We believe that women in the control group were able to clear bacteria from their bladders before they caused illness, and women with recurrent UTIs were not, due to a distinct immune response to bacterial invasion of the bladder potentially mediated by the gut microbiome,” said Worby.

The results highlight the importance of finding alternatives to antibiotics for the treatment of UTIs.

“Our study clearly demonstrates that antibiotics do not prevent future infections or eliminate the strains responsible for UTIs, and they may even make recurrence more likely by keeping the microbiome in a disrupted state,” said Worby.

Hultgren has long worked to find innovative therapies to eradicate pathogenic strains of E.coli of the body while sparing the rest of the bacterial community. His research forms the basis of an experimental drug based on mannoside sugar and an experimental vaccine, both of which are being tested on humans. Another strategy would be to rebalance the microbiome through fecal transplants, probiotic foods, or other means.

“It’s one of the most common infections in the United States, if not the world,” Hultgren said. “A good percentage of these patients with UTIs have these chronic recurrences, which lead to a decreased quality of life. There is a real need to develop better therapies that break this vicious circle.”

Worby CJ, Schreiber HL, Straub TJ, van Dijk LR, Bronson RA, Olson BS, Pinkner JS, Obernuefemann CLP, Muñoz VL, Paharik AE, Walker BJ, Desjardins CA, Chou WC, Bergeron K, Chapman SB, Klim A, Manson AL, Hannan TJ, Hooton TM, Kau AL, Lai HH, Dodson KW, Hultgren SJ, Earl AM. Longitudinal multi-omics analyzes link gut microbiome dysbiosis to recurrent urinary tract infections in women. Natural microbiology. May 2, 2022. DOI: 10.1038/s41564-022-01107-x

This project was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), grant number U19AI110818; the NIH Mucosal Immunology Studies Team Consortium, grant number U01AI095542; NIH, grant numbers T32GM007067 and T32GM139774; and the Center for Women’s Infectious Disease Research at Washington University School of Medicine.

Washington University School of MedicineThe 1,700 doctors of the faculty are also part of the medical staff of Barnes-Jew and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching, and patient care, and is currently #4 in National Institutes of Health (NIH) research funding. Through its affiliations with Barnes-Jewish and St. Louis Children’s Hospitals, the School of Medicine is linked to BJC Healthcare.

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