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 develop another. The study, by researchers at Washington University School of Medicine in St. Louis and the Broad Institute of MIT and Harvard, showed that a round of antibiotics eliminates disease-causing bacteria from the bladder but not from the intestines. Surviving bacteria in the gut can multiply and spread to the bladder again, 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, women with recurrent UTIs in the study had less diverse microbiomes that were deficient in an important group of bacteria that helps regulate inflammation, and a distinct immunological signature in their blood indicative of inflammation.

The study is published May 2 in Nature Microbiology.

“It’s frustrating for women who are coming in to the doctor with recurrence after recurrence after recurrence, and the doctor, who’s typically male, gives them advice about hygiene,” said co-senior author Scott J. Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology at Washington University. “That’s not necessarily what the problem is. It’s not necessarily poor hygiene that’s causing this. The problem lies in the disease itself, in this connection between the gut and the bladder and levels of inflammation. Basically, physicians don’t know what to do with recurrent UTI. All they have is antibiotics, so they throw more antibiotics at the problem, which probably just makes things worse.”

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

The researchers studied 15 women with histories 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 the bacterial composition in the stool samples, tested the 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 histories of repeated UTIs. When participants were diagnosed with a UTI, the team took additional urine, blood and stool samples.

The difference between the women who got repeated UTIs and those who didn’t, surprisingly, didn’t come down to the kind of E. coli in their intestines or even the presence of E. coli in their bladders. Both groups carried E. coli strains in their guts capable of causing UTIs, and such strains occasionally spread to their bladders.

The real difference was in the makeup of their gut microbiomes. Patients with repeat infections showed decreased diversity of healthy gut microbial species, which could provide more opportunities for disease-causing species to gain a foothold and multiply. Notably, the microbiomes of women with recurrent UTIs were particularly scarce in bacteria that produce butyrate, a short-chain fatty acid with anti-inflammatory effects.

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

The findings highlight the importance of finding alternatives to antibiotics for treating UTIs.

“Our study clearly demonstrates that antibiotics do not prevent future infections or clear UTI-causing strains from the gut, and they may even make recurrence more likely by keeping the microbiome in a disrupted state,” Worby said

Hultgren has long worked on finding innovative therapies to eradicate disease-causing strains of E. coli from the body while sparing the rest of the bacterial community. His research forms the basis of an experimental drug based on the sugar mannosideand an investigational vaccine, both of which are being tested in people. Another strategy would be to rebalance the microbiome through fecal transplants, probiotic foods or other means.

“This is one of the most common infections in the United States, if not the world,” Hultgren said. “A good percentage of these UTI patients go on to get these chronic recurrences, and it results in decreased quality of life. There is a real need to develop better therapeutics that break this vicious cycle.”

The study is issued by researchers from the University of Illinois Chicago who have been studying the effects of early life binge drinking on health later in life.

In prior research, the UIC team found that binge drinking in adolescence alters brain chemistry at the enhancer region of the Arc gene — for activity-regulated cytoskeleton-associated protein immediate-early gene — and decreases Arc expression in the amygdala of both rodents and humans. This epigenetic reprogramming of the Arc gene in the brain’s emotion and memory center contributes to a predisposition to anxiety and alcohol use disorder in adulthood.

In the new study, the researchers show that this epigenetic reprogramming, which persists throughout life, actually can be reversed with gene editing.

“Early binge drinking can have long-lasting and significant effects on the brain and the results of this study offer evidence that gene editing is a potential antidote to these effects, offering a kind of factory reset for the brain, if you will,” said study senior author Subhash Pandey, the Joseph A. Flaherty Endowed Professor of Psychiatry and director of the Center for Alcohol Research in Epigenetics at UIC.

Pandey and his team used a gene-editing tool called CRISPR-dCas9 in their experiments to manipulate the histone acetylation and methylation processes at the Arc gene in models of adult rats. These processes make genes more or less accessible for activation.

First, the researchers studied adult rats with intermittent alcohol exposure in their adolescence, corresponding to about age 10 to 18 in human years. They observed that when dCas9 was used to promote acetylation, a process that loosens chromatin and allows transcription factors to bind to the DNA, Arc gene expression normalized. And, indicators of anxiety and alcohol consumption decreased.

Anxiety was measured through behavioral testing, such as by documenting the exploratory activity of rats placed in maze tests, and preference for alcohol was measured by monitoring the amount of liquid consumed when the rats were presented with a choice of two bottles consisting of options such as tap water, sugar water and varying concentrations of alcohol (3%, 7% and 9%).

In a second model, the researchers studied adult rats without early alcohol exposure. When inhibitory dCas9 was used to promote methylation, which tightens chromatin and prevents transcription factors from binding to DNA, Arc expression decreased and indicators of anxiety and alcohol consumption increased.

“These results demonstrate that epigenomic editing in the amygdala can ameliorate adult psychopathology after adolescent alcohol exposure,” the authors report.

“Adolescent binge drinking is a serious public health issue, and this study not only helps us better understand what happens in developing brains when they are exposed to high concentrations of alcohol but more importantly gives us hope that one day we will have effective treatments for the complex and multifaceted diseases of anxiety and alcohol use disorder,” said Pandey, who is also a senior research career scientist at Jesse Brown VA Medical Center. “That this effect was seen bidirectionally validates the significance of the Arc enhancer gene in the amygdala in epigenetic reprogramming from adolescent binge drinking.”

The research was supported by the National Institute on Alcohol Abuse and Alcoholism (U01AA019971, U24AA024605, P50AA022538, and F32AA027410) and the Department of Veterans Affairs.

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“The United States is the largest exporter and donor of field corn around the world,” said Felicia Wu, a John A. Hannah Distinguished Professor and an international expert on food safety in the Department of Food Science and Human Nutrition and the Department of Agricultural, Food, and Resource Economics in the College of Agriculture and Natural Resources at MSU. “Here in the U.S., we consume field corn in the form of corn chips, corn flakes, corn grits and corn tortillas; as opposed to sweet corn, which is frozen, canned and eaten off the cob. Field corn is also used for animal feed and for ethanol production.”

The fungi Aspergillus flavus and Aspergillus parasiticus produce aflatoxin which can infect peanuts, tree nuts and corn. Aflatoxin not only degrades corn quality but can also cause health problems for humans and animals depending on the amount and length of time it is ingested. While aflatoxin contamination occurs annually in the southern United States because of the hot and dry climate, it has rarely been a serious problem in the Corn Belt region of the U.S.

“When we ran our near-term climate model scenarios, we found that between 2031-2040, aflatoxin is going to become more of a problem in the U.S. Corn Belt in the Midwest,” Wu said. “The last time there was a serious problem was in 2012 when we had an unusually hot and dry summer throughout the Midwest; particularly Iowa, Illinois and Indiana.”

Wu’s research was published April 5, 2022 in the journal Environmental Research Letters. Co-authors on the paper include her former doctoral student Jina Yu (Hong Kong Baptist University), David Hennessy (Iowa State University) and Jesse Tack (Kansas State University).

Hot and dry conditions encourage fungi spores to be airborne which increases their chances of contaminating crops. Water helps plants withstand stress that makes them vulnerable to harmful fungi. Steps growers, grain elevators and processors can take to reduce the risk of aflatoxin contamination include storing corn harvests in cool, dry conditions and keeping crops irrigated to the extent possible given declining water tables.

Researchers are already using both biotechnological and conventional breeding techniques to develop hybrid crops that can withstand drought, insect damage and fungal infections. In many parts of the world, corn growers are using biocontrol to reduce aflatoxin. Biocontrol infects plants with Aspergillus fungi which is unable to produce aflatoxin because this these fungi competitively exclude the fungi that produce aflatoxin.

Another possibility shifts crop production further north or further south geographically where the climate is cooler or wetter to reduce aflatoxin risk. That, however, impacts farms that have been passed down for generations.

For consumers concerned about eating field corn and their aflatoxin risk, Wu suggests eating your greens and garlic. “Green leafy vegetables are good for your overall health,” Wu said. “Chlorophyll has a sandwich molecular structure that traps aflatoxin molecules so that humans excrete them before the toxin can enter our bloodstream.”

Also, cruciferous vegetables like broccoli, cauliflower, kale and allium vegetables like garlic, onions and leeks can help detoxify carcinogens in our bodies.

“We predict seeing an increase in aflatoxin problems over the next 10-20 years,” Wu said. “So, we need to rely on technologies and a whole suite of interventions that can reduce the problem.”

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Materials provided by Michigan State University. Original written by Emilie Lorditch. Note: Content may be edited for style and length.

The findings, published in The Laryngoscope, show that only 1 in 7 subsequently needed surgery for injuries that weren’t resolved with vocal therapy and other conservative management. Researchers determined which vocal injuries were most common by sex, age, training, and professional/amateur status, and what kinds of treatment these patients subsequently required.

“When you’re an injured singer, especially when you depend on singing for your livelihood, the stakes are really high. Injured singers are often reluctant to talk about their injury or ask questions among their colleagues or community because injuries carry a stigma,” said study leader Lesley Childs, M.D., Associate Professor of Otolaryngology — Head and Neck Surgery and Medical Director of the Voice Center at UT Southwestern. “There are many opportunities for misinformation, so we wanted to gather data to help dispel myths and counsel our patients on the facts.”

Toward that end, Dr. Childs and her colleagues, including UTSW resident physician Ashwin Rao, M.D., and Ted Mau, M.D., Ph.D., Professor of Otolaryngology — Head and Neck Surgery, reviewed charts of all singers who sought care for vocal injuries at the Voice Center between 2011 and 2019. A total of 438 patients between ages 8 and 78 who had never undergone prior surgery to correct vocal fold injuries were seen during this period.

Searching for patterns, the researchers discovered that the most prevalent injury by far was nodules, a callous-like injury that affected 58% of these singers, followed by blister-like injuries called pseudocysts, as well as polyps, cysts, and vocal fold hemorrhages. Although female singers were more likely to develop nodules and pseudocysts, polyps and cysts were more common in male singers. Polyps developed more frequently with age in female patients, while young male singers were more likely to develop nodules.

Dr. Childs and her colleagues found that professional status and a lack of prior vocal training were the greatest risk factors. Professional singers who had not taken voice lessons were eight times more likely to need surgery than amateur singers with prior voice lessons.

Although the increased risk among professional singers is probably due to the greater amount of singing time overall, the link with vocal training is unclear, Dr. Childs said. Training may increase vocal proficiency, and a history of voice lessons might make it easier for the injured to follow vocal therapy protocols.

Regardless, she added, the data can help physicians reassure patients who seek help at the Voice Center.

“For amateur and professional singers alike, vocal injuries can be devastating, but our study suggests that these injuries need not be career-ending,” Dr. Childs said. “With conservative management, most singers can get back on track.”

UT Southwestern’s Voice Center, one of the largest in the South, employs a collaborative, multidisciplinary team of passionate voice care specialists to care for injured singers. Several members of the Voice Center are singers themselves: Dr. Childs is a classically trained soprano with experience in various professional chamber ensembles as well as recording for Walt Disney Records, and all six of the Voice Center’s speech language pathologists are singers.

“We’re very proud that we can offer this personal experience to our patients and speak the unique language that singers use,” she said.