“By teasing out the microbial changes that occur in the small bowel with age, medication use and diseases, we hope to identify unique components of the microbial community to target for therapeutics and interventions that could promote healthy aging,” said Ruchi Mathur, MD, the study’s principal investigator.

Research exploring the gut microbiome, and its impact on health, has relied predominantly on fecal samples, which do not represent the entire gut, according to Mathur. In their study, investigators from Cedars-Sinai’s Medically Associated Science and Technology (MAST) Program analyzed samples from the small intestine-which is over 20 feet in length and has the surface area of a tennis court-for examination of the microbiome and its relationship with aging.

“This study is the first of its kind to examine the microbial composition of the small intestine of subjects 18 years of age to 80. We now know that certain microbial populations are influenced more by medications, while others are more affected by certain diseases. We have identified specific microbes that appear to be only influenced by the chronological age of the person,” said Mathur, an endocrinologist and director of the Diabetes Outpatient Treatment & Education Center.

The 21^st century has been referred to as the “era of the gut microbiome” as scientists turn considerable attention to the role trillions of gut bacteria, fungi and viruses may play in human health and disease. The microbiome is the name given to the genes that live in these cells. Studies have suggested that disturbances in the constellations of the microbial universe may lead to critical illnesses, including gastroenterological diseases, diabetes, obesity, and some neurological disorders.

While researchers know that microbial diversity in stool decreases with age, Cedars-Sinai investigators identified bacteria in the small bowel they refer to as “disruptors” that increase and could be troublesome.

“Coliforms are normal residents of the intestine. We found that when these rod-shaped microbes become too abundant in the small bowel-as they do as we get older-they exert a negative influence on the rest of the microbial population. They are like weeds in a garden,” said study co-author Gabriela Leite, PhD.

Investigators also found that as people age, the bacteria in the small intestine change from microbes that prefer oxygen to those that can survive with less oxygen, something they hope to understand as the research continues.

“Our goal is to identify and fingerprint the small intestinal microbial patterns of human health and disease. Given the important role the small bowel plays in absorption of nutrients, changes in the microbiome in this location of the gut may have a greater impact on human health, and warrants further study,” said Mark Pimentel, MD, director of the MAST program and a co-author of the study.

This research is part of Cedars-Sinai’s ongoing REIMAGINE study: Revealing the Entire Intestinal Microbiota and its Associations with the Genetic, Immunologic, and Neuroendocrine Ecosystem.

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Women who participated in the study were critical of healthcare providers for failing to understand their experiences while over-prescribing antibiotics as a treatment option.

“We were inspired to conduct the study due to the large number of women coming to us feeling hopeless and helpless when it came to the management of their UTIs,” said lead author Victoria Scott, MD, a urologist at the Female Pelvic Medicine and Reconstructive Surgery clinic at Cedars-Sinai.

To help give voice to those suffering with recurrent urinary tract infections, researchers led a focus group study of 29 women who experienced recurrent UTIs to learn about gaps in their care. UTIs are infections of any part of the urinary tract, including the kidneys, ureters, bladder or the urethra. The term is most commonly used to describe a bladder infection.

One of the biggest concerns expressed by study participants revolved around the frequent prescribing of antibiotics and fears of the potential adverse and long-term effects of the medication.

“Many of the participants were aware of the risks of bacteria developing resistance to antibiotics,” Scott said. “They also were aware of the ‘collateral damage’ of antibiotics and disruption they can have on the normal balance of good and bad bacteria throughout the body.”

The focus group discussions also reported concern with the medical system and limited research efforts to investigate new non-antibiotic management strategies.

Participants voiced frustration and resentment toward their medical providers for “throwing antibiotics” at them without presenting alternative options for treatment and prevention, and for not understanding their experience. In addition, many women described seeking advice from herbalists and acupuncture practitioners, as well as from peers in online forums and chatrooms.

Treatment and Prevention

Although studies show that antibiotics are often the most effective treatment option for urinary tract infections, research also shows that up to 40% of bladder infections can be cleared with non-prescription steps that can include increased water intake and pain relief medications such as ibuprofen.

Taking these steps when UTI symptoms initially develop and urine test results are pending can be important for avoiding unnecessary antibiotics and ensuring that appropriate antibiotics are prescribed when needed.

Among steps women can take to avoid a urinary tract infection are drinking water, taking cranberry supplements or a low-dose antibiotic after sexual intercourse, and using vaginal estrogen for those who are postmenopausal.

While over-the-counter treatments are preferred by many, Scott recommends seeing a doctor if a fever develops or symptoms persist beyond a day, as antibiotic therapy can be crucial for some infections to ensure they don’t spread from the bladder to the kidneys.

“Antibiotics are amazing drugs and in certain settings are lifesaving,” Scott said. “There are absolutely some instances in which antibiotics are necessary, but it’s also important for women to be educated regarding all their options.”

Those who experience recurrent urinary tract infections should seek evaluation by a specialist. Some women will benefit from undergoing a kidney ultrasound or a cystoscopy, which uses a small camera that can be inserted into the urethra to give a view of the urethra and bladder to rule out anatomic abnormalities.

Scott notes that while less common, men also can experience urinary tract infections.

Improving Care

Some healthcare providers might not think that a single episode of a urinary tract infection could have a significant impact on a patient’s life. But when UTIs recur, often without warning, they can have a negative impact on social life, work, families and relationships.

The study recommended that physicians modify management strategies to address women’s concerns and to devote more research to improving non-antibiotic options for prevention and treatment of recurrent urinary tract infections, as well as management strategies that better empower patients.

“Unfortunately, we see many women who blame themselves for developing UTIs. It’s important to understand that UTIs are a very common problem and should not invoke shame” Scott said. “If you are experiencing recurrent UTIs I encourage you to connect with a doctor who specializes in female pelvic medicine and reconstructive surgery to work together to come up with individualized prevention and management strategies.”

The new analysis suggests that 78% to 92% of lung cancers in patients who have never smoked can be treated with precision drugs already approved by the Food and Drug Administration to target specific mutations in a patient’s tumor. The researchers found that most never-smokers’ lung tumors had so-called driver mutations, specific mistakes in the DNA that fuel tumor growth and that can be blocked with a variety of drugs. In contrast, only about half of tumors in people who smoke have driver mutations.

The study appears Sept. 30 in the Journal of Clinical Oncology.

“Most genomic studies of lung cancer have focused on patients with a history of tobacco smoking,” said senior author Ramaswamy Govindan, MD, a professor of medicine. “And even studies investigating the disease in patients who have never smoked have not looked for specific, actionable mutations in these tumors in a systematic way. We found that the vast majority of these patients have genetic alterations that physicians can treat today with drugs already approved for use. The patient must have a high-quality biopsy to make sure there is enough genetic material to identify key mutations. But testing these patients is critical. There is a high chance such patients will have an actionable mutation that we can go after with specific therapies.”

In the U.S, about 10% to 15% of lung cancers are diagnosed in people who have never smoked, and that proportion can be has high as 40% in parts of Asia.

The researchers analyzed lung tumors from 160 patients with lung adenocarcinoma but no history of tobacco smoking. They also compared data from these patients to data in smokers and never-smokers from The Cancer Genome Atlas and the Clinical Proteomic Tumor Analysis Consortium, projects led by the National Institutes of Health (NIH) to characterize different types of cancer. The scientists verified never-smoker status by examining the mutation patterns in these patients and comparing them to mutation patterns in lung cancers of patients who had smoked. Past work led by Govindan and his colleagues found that smokers’ lung tumors have about 10 times the number of mutations as the lung tumors of never-smokers.

“Tobacco smoking leads to characteristic changes in the tumor cells, so we can look for telltale signs of smoking or signs of heavy exposure to secondhand smoke, for example,” said Govindan, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “But very few of these patients’ tumors showed those signs, so we could verify that this was truly a sample of lung cancer tumors in patients who had never smoked or had major exposure to tobacco smoke.”

The researchers also found that only about 7% of these patients showed evidence of having mutations present at birth that raised the risk of cancer — either inherited or arising randomly — furthering the mystery of what causes lung cancer in never-smokers.

“There appears to be something unique about lung cancer in people who have never smoked,” Govindan said. “We didn’t find a major role for inherited mutations, and we don’t see evidence of large numbers of mutations, which would suggest exposure to secondhand smoke. About 60% of these tumors are found in females and 40% in males. Cancer in general is more common among men, but lung cancer in never-smokers, for some unexplained reasons, is more common among women. It is possible additional genes are involved with predispositions to cancers of this kind, and we just don’t know what those are yet.”

The study also shed light on the immune profiles of these tumors, which could help explain why most of them do not respond well to a type of immunotherapy called checkpoint inhibitors. Unlike the smokers’ lung tumors studied, very few of the never-smokers’ tumors included immune cells or immune checkpoint molecules that these drugs trigger to fight the cancer.

“The most important finding is that we identified actionable mutations in the vast majority of these patients — between 80% and 90%,” Govindan said. “Our study highlights the need to obtain high-quality tumor biopsies for clinical genomic testing in these patients, so we can identify the best targeted therapies for their individual tumors.”

This work was supported by the National Institutes of Health (NIH), grant numbers 2U54HG00307910 and U01CA214195; and the Mesothelioma Biomarker Discovery Laboratory.

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Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.

The study — which covers more than 1,500 cases in the Dallas area since May 2020 — offers a snapshot of what doctors believe is happening in communities across the country. The research shows the proportion of pregnant COVID-19 patients requiring hospitalization increased to 10 to 15% in late August and early September, more than double the percentage of last year before the emergence of the Delta variant.

“This is a concerning trend, and we’re primarily seeing these cases in unvaccinated women,” said Emily Adhikari, M.D., Assistant Professor of Obstetrics and Gynecology, and a lead author of the study published in the American Journal of Obstetrics and Gynecology.

Dr. Adhikari said the findings offer the first objective evidence that the case number and severity of illness in pregnant women rose with a spike in the Delta variant. The study included 1,515 pregnant women diagnosed with COVID-19 who received care from Parkland Health & Hospital System — Dallas County’s public hospital — from May 2020 through Sept. 4, 2021.

Overall, 82 patients had severe or critical illness, including 10 requiring ventilators, and two deaths. The proportion of severe or critical cases was around 5% until after the new year, and were then largely nonexistent in February and most of March.

However, the rise of the Delta variant coincided with a new wave of hospitalizations that peaked this August and early September, including more than a third of COVID-19 cases the week of Aug. 29. By this time, genetic sequencing conducted at UT Southwestern showed nearly all the local variants sequenced were the Delta B.1.617.2 strain.

Of the 82 patients hospitalized since May 2020, all but one were unvaccinated.

Dr. Adhikari acknowledged that some women fear the vaccine may not be safe to take during pregnancy, but said research has debunked those concerns. She co-authored a JAMA article earlier this year that elaborated on the issue of vaccines and pregnancy.

Dr. Adhikari said pregnant women are at greater risk for complications with any type of severe respiratory infection, so these findings further emphasize the need for pregnant and lactating women in all communities to get vaccinated for COVID-19.

“If they are exposed and infected, they run a higher risk of severe illness from this most recent Delta variant,” said Dr. Adhikari, Medical Director of Perinatal Infectious Diseases at Parkland. “Pregnant women should get immunized as soon as possible.”

The genomic sequencing that revealed nearly all the local SARS-CoV-2 variants were Delta was performed in the McDermott Center Next Generation Sequencing (NGS) Core with analysis performed by the McDermott Bioinformatics Lab, both under the supervision of Helen H. Hobbs, M.D., a Howard Hughes Medical Institute investigator and Professor of Internal Medicine and Molecular Genetics, who directs the Eugene McDermott Center for Human Growth and Development at UT Southwestern. Jeffrey SoRelle, M.D., Assistant Professor of Pathology and a co-author on the study, is collaborating with Dr. Hobbs by providing all positive COVID-19 samples tested at UT Southwestern and interpreting sequencing results with support from a rapid, focused PCR-based test. The collaboration with the McDermott Center Next Generation Sequencing (NGS) Core at UT Southwestern allows whole genome whole sequencing of SARS-CoV-2 virus in a state-of-the-art facility that performs NGS coupled with bioinformatic analysis.

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In a recent study published in Frontiers in Immunology, Prof. Chiharu Nishiyama, Kazuki Nagata, and Ayumi Okuzumi from the Tokyo University of Science and Prof. Hiroshi Nagase from the University of Tsukuba attempted to understand the effects of opioids on the immune system. They tested the effects of KNT-127 — an artificially synthesized opioid that activates delta opioid receptors — on immune responses in live animal and cell culture experiments.

When mice with inflammatory bowel disease (IBD) were treated with KNT-127, they showed a reduction in the severity of colitis — a form of colon inflammation — indicated by lower weight loss and colon atrophy and improved disease activity scores. Similar results were also obtained in a recovery model, confirming the beneficial effects of KNT-127 against colonic inflammation.

Although these results were promising, an important caveat still loomed. “Before proceeding with additional experiments, we had to rule out the role of CNS opioid receptors in the anti-inflammatory effects of KNT-127,” says Prof. Nishiyama, the lead researcher on the study. To address this, the researchers performed similar experiments with YNT-2715, a peripheral KNT-127 that cannot cross over from the blood to the brain. The results were similar to those observed with KNT-127, confirming that its anti-inflammatory effects were indeed CNS-independent.

Encouraged by this, the group examined other immune-related effects of KNT-127 treatment in the colitis model. They found that during disease progression, the opioid reduced the serum levels of IL-6, a pro-inflammatory factor, while also decreasing the number of macrophages in the mesenteric lymph nodes (MLNs). Interestingly, they also observed an increase in the number of regulatory T cells (Tregs) in MLNs. Together, their results showed that KNT-127 suppresses the inflammation caused by macrophages during disease progression and enhances the anti-inflammatory response due to Tregs during recovery.

Finally, to understand the direct effects of KNT-127 on immune cells, the researchers performed in vitro experiments in which they treated macrophages derived from bone marrow or T cells from spleen with the drug. The results were consistent with those from animal experiments, revealing increased secretion of the pro-inflammatory signals as well as enhanced development of Tregs in response to KNT-127 treatment.

Altogether, the findings demonstrated that KNT-127 can directly act on immune cells and reduce the severity of inflammation, making it a good candidate for the treatment of IBD. “Several people around the world suffer from diseases related to colon inflammation, and so far, optimal treatment strategies are lacking. Our findings show that KNT-127 and other activators of opioid receptors could be promising therapeutic options for such diseases,” comments Prof. Nagase, the chief drug developer behind the synthetic opioid, while also cautioning of the road ahead. “Of course, before these drugs are used clinically, additional experiments will be required to elucidate how they exert their immunomodulatory functions and what their effects on other immune diseases are,” he adds.

Nevertheless, Prof. Nishiyama and her team are confident that their study represents an important milestone, not only towards the treatment of IBD but also towards our understanding of the “brain-gut axis” — the interrelationship between brain and gut function — which has received increasing attention in recent years. “Today, we know that poor mental health has physical manifestations. For example, stress worsens inflammation in the gut, which in turn affects the health of the brain. Our results on the immune-related effects of opioids, which commonly act on the brain, is a step toward unraveling the biological mechanisms that govern the reciprocative relationship of gut health and the immune system with the CNS,” mentions Prof. Nishiyama, excited about what the future holds.

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