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schistosome blood fluke

Therapy derived from parasitic worms downregulates proinflammatory pathways

schistosome blood fluke

A therapy derived from the eggs of the parasitic Schistosoma helps to protect against one of chemotherapy’s debilitating side effects by significantly downregulating major proinflammatory pathways, reducing inflammation.

A therapy derived from the eggs of parasitic worms helps to protect against one of chemotherapy’s debilitating side effects by significantly downregulating major proinflammatory pathways and reducing inflammation, indicates the first transcriptome-wide profiling of the bladder during ifosfamide-induced hemorrhagic cystitis.

The experimental model study findings were published online Feb. 7, 2019, in Scientific Reports.

With hemorrhagic cystitis, a condition that can be triggered by anti-cancer therapies like the chemotherapy drug ifosfamide and other oxazaphosphorines, the lining of the bladder becomes inflamed and begins to bleed. Existing treatments on the market carry their own side effects, and the leading therapy does not treat established hemorrhagic cystitis.

Around the world, people can become exposed to parasitic Schistosoma eggs through contaminated freshwater. Once inside the body, the parasitic worms mate and produce eggs; these eggs are the trigger for symptoms like inflammation. To keep their human hosts alive, the parasitic worms tamp down excess inflammation by secreting a binding protein with anti-inflammatory properties.

With that biological knowledge in mind, a research team led by Michael H. Hsieh, M.D., Ph.D., tested a single dose of IPSE, an Interleukin-4 inducing, Schistosoma parasite-derived anti-inflammatory molecule and found that it reduced inflammation, bleeding and urothelial sloughing that occurs with ifosfamide-related hemorrhagic cystitis.

In this follow-up project, experimental models were treated with ifosfamide to learn more about IPSE’s protective powers.

The preclinical models were given either saline or IPSE before the ifosfamide challenge. The bladders of the experimental models treated with ifosfamide had classic symptoms, including marked swelling (edema), dysregulated contraction, bleeding and urothelial sloughing. In contrast, experimental models “pre-treated” with IPSE were shielded from urothelial sloughing and inflammation, the study team found.

Transcriptional profiling of the experimental models’ bladders found the IL-1-B TNFa-IL-6 proinflammatory cascade via NFkB and STAT3 pathways serving as the key driver of inflammation. Pretreatment with IPSE slashed the overexpression of Il-1b, Tnfa and Il6 by 50 percent. IPSE drove significant downregulation of major proinflammatory pathways, including the IL-1-B TNFa-IL-6 pathways, interferon signaling and reduced (but did not eliminate) oxidative stress.

“Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE,” says Dr. Hsieh, a urologist at Children’s National Health System and the study’s senior author. “These preliminary findings reveal several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis in humans.”

When certain chemotherapy drugs are metabolized by the body, the toxin acrolein is produced and builds up in urine. 2-mercaptoethane sulfonate Na (MESNA) binds to acrolein to prevent urotoxicity. By contrast, IPSE targets inflammation at the source, reversing inflammatory changes that damage the bladder.

“Our work demonstrates that there may be therapeutic potential for naturally occurring anti-inflammatory molecules, including pathogen-derived factors, as alternative or complementary therapies for ifosfamide-induced hemorrhagic cystitis,” Dr. Hsieh adds.

In addition to Dr. Hsieh, study co-authors include Lead Author Evaristus C. Mbanefo and Rebecca Zee, Children’s National; Loc Le, Nirad Banskota and Kenji Ishida, Biomedical Research Institute; Luke F. Pennington and Theodore S. Jardetzky, Stanford University; Justin I. Odegaard, Guardant Health; Abdulaziz Alouffi, King Abdulaziz City for Science & Technology; and Franco H. Falcone, University of Nottingham.

Financial support for the research described in this report was provided by the Margaret A. Stirewalt Endowment, the National Institute of Diabetes and Digestive and Kidney Diseases under award R01DK113504, the National Institute of Allergy and Infectious Diseases under award R56AI119168 and a Urology Care Foundation Research Scholar Award.

Dr. Michael Hsieh's clay shield

Innovative urologist Michael Hsieh takes unbeaten path

Dr. Michael Hsieh's clay shield

For an elementary school art project, Michael H. Hsieh, M.D., Ph.D., was instructed to fashion a coat of arms out of clay. In addition to panels for truth, justice and Taiwan, in the shield’s M.D. panel, a snake twists around a rod, like the staff for Asclepius, a Greek god associated with healing.

Children’s urologist Michael H. Hsieh, M.D., Ph.D., knew from age 10 that he would become a doctor. Proof is at his parents’ home. For an elementary school art project, students were instructed to fashion a coat of arms out of clay. In addition to panels for truth, justice and Taiwan, in the shield’s M.D. panel, a snake twists around a rod, like the staff for Asclepius, a Greek god associated with healing.

“I liked science. When I can use it to help patients, that is very rewarding,” says Dr. Hsieh, the first doctor in his family.

These days, Dr. Hsieh’s Twitter profile serves as a digital coat of arms, describing him as “tinker, tailor,” #UTI #biologist, epithelial #immunologist, helminthologist and #urologist.

Tinker/tailor is shorthand for the mystery drama, “Tinker Tailor Solider Spy,” he explains, adding that the “tinker” part also refers “to the fact that I am always questioning things, and science is about experimentation, trying to seek answers to questions.”

While still in medical school during a rotation Dr. Hsieh saw a bladder operation on a young child and thought it was “amazing.” That experience in part inspired Dr. Hsieh to become a urologist and bladder scientist. His training in immunology and study of the bladder naturally led him to study urinary tract infections and parasitic worms that affect the urinary tract. In addition, thanks to R01 funding from the National Institutes of Health (NIH), Dr. Hsieh is co-principal investigator with Axel Krieger, University of Maryland, and Jin U. Kang, Johns Hopkins, on a project to develop imaging robots for supervised autonomous surgery on soft tissue.

The $1 million in NIH funding pushes the boundaries on amazing by using multi-spectral imaging technology and improved techniques to reduce surgical complications.

Anastomosis is a technique used by surgeons to join one thing to another, whether it’s a vascular surgeon suturing blood vessels, an orthopedic surgeon joining muscles or a urologist stitching healthy parts of the urinary tract back together. Complications can set in if their stitching is too tight, prompting scar tissue to form, or too loose, letting fluid seep out.

“The human eye can see a narrow spectrum of electromagnetic radiation. These multi-spectral imaging cameras would see across greater set of wavelengths,” he says.

The project has three aims: figuring out the best way to place sutures using multi-spectral imaging, accurately tracking soft tissue as they model suturing and comparing the handicraft of a robot against anastomosis hand-sewn by surgeons.

“I like challenges, and I like new things. I am definitely not interested in doing permutations of other people’s work,” Dr. Hsieh explains. “I would much rather go on a path that hasn’t been tread. It is more difficult in some ways, but on a day-to-day basis, I know I am making a contribution.”

In another innovative research project, Dr. Hsieh leveraged a protein secreted by a parasitic worm, Schistosoma haematobium, that suppresses inflammation in hosts as a new therapeutic approach for chemotherapy-induced hemorrhagic cystitis, a form of inflammation of the bladder.

Watching his first surgery nearly 30 years ago, he had no idea robots might one day vie to take over some part of that complicated procedure, or that parasite proteins could be harnessed as drugs. However, he has a clear idea which innovations could be on the horizon for urology in the next three decades.

“My hope is 30 years from now, we will have a solid UTI vaccine and more non-antibiotic therapies. UTIs are the second-most common bacterial infection in childhood and, in severe cases, can contribute to kidney failure,” he says.

Globally, parasitic worms pose an ongoing challenge, affecting more than 1 billion worldwide – second only to malaria. People persistently infected by schistosome worms fail to reach their growth potential, struggle academically and lack sufficient energy for exercise or work.


“There is a feeling that the infection prevalence might be decreasing globally, but not as quickly as everyone hopes. In 30 years perhaps with more mass drug administration and additional drugs – including a vaccine – we’ll have it close to eliminated globally. It would become more like polio, casting a slim shadow with small pockets of infection here or there, rather than consigning millions to perpetual poverty.”

Lactobacillis-Bacteria

Does ZIP code factor into genitourinary system health?

Lactobacillis-Bacteria

Clinicians suspect that taking probiotics, such as lactobacillus supplements, and making changes to diet may prevent urinary diseases that occur commonly among pediatric patients. A research team led by Children’s faculty is exploring whether changes in the built environment also affect the urinary microbiome.

Emerging evidence suggests that the variety and volume of bacteria that reside in the bladder – the urinary microbiome – significantly impact whether people’s genitourinary systems remain healthy or become susceptible to disease.

Already, clinicians suspect that taking probiotics and making changes to diet may prevent urinary diseases that occur commonly among pediatric patients. A research team led by Children’s faculty is exploring whether changes in the built environment also affect the urinary microbiome.

Using experimental models, they looked at how stable the urinary microbiome was over time. Then, they measured the potential effect of changing the built environment on the urinary microbiome of preclinical models.

They did this by following six C57BL/6 experimental models for five months, starting from when they were nine weeks old. They collected urine specimens when the study began and repeated sample collections each month. The multidisciplinary team isolated microbial DNA from these specimens to determine the makeup of the bacterial community present in their urinary tracts.

All of the experimental models shared a single cage, drank the same water and ate the exact same chow. At four months, however, they moved the preclinical models to a different facility within the same county. Their chow and bedding remained unchanged, but the water source changed since they received tap water at both locations.

“There were no changes in the proportion of specific bacteria in the urinary microbiomes from month zero through month five, which means the urinary microbiomes of healthy experimental models remain stable over time,” says Michael Hsieh, M.D., Ph.D., a urologist at Children’s National Health System and senior author of the work presented during the Pediatric Urology Fall Conference. “However, the convergence of the Shannon Diversity Index, the clustering seen on Principal coordinate analyses and changes in functional analyses taken as a whole suggest that an overall shift of the urinary microbiome occurred due to a change in the physical environment.”

This work suggests that where patients live could influence which bacteria grow in the urinary tracts, including during urinary tract infections.

The Societies for Pediatric Urology’s Pediatric Urology Fall Conference

  • “Effects of time and the built environment on the stability of the mouse urinary microbiome: implications for clinical utility.”

Catherine S. Forster, M.D., MS, pediatric hospitalist, Children’s National; James Cody, Ph.D., Biomedical Research Institute; Nirad Banskota, MS, Biomedical Research Institute; Crystal Stroud, MS, Children’s National; Ljubica Caldovic, Ph.D., principal investigator, Children’s National; and Michael Hsieh, M.D., Ph.D., urologist, Children’s National.

Staphylococcus

How our bladder’s microbiota affect health

Staphylococcus

The presence of bacteria such as Staphylococcus in the urine is linked to the incidence and severity of urge urinary incontinence as well as treatment success.

About half of the cells in our bodies aren’t really “ours” at all. They’re the microbiota: The vast array of microorganisms that live in our gut, skin, oral cavity and other places. Decades ago, researchers thought that these organisms simply happened to colonize these areas, playing only a tangential role in health, for example, helping to break down food in the intestines or causing cavities. More recent work has revealed the incredibly complex role they play in diseases ranging from diabetes and schizophrenia.

The bladder is no exception. Just a single decade ago, the bladder was thought to be a sterile environment. But that view has shifted radically, with more sensitive cultivation methods and precise 16S rRNA gene-sequencing techniques revealing a significant bladder microbiome that could have an enormous impact on pediatric urologic diseases. These findings have opened brand new fields of research aimed at clarifying the role that the bladder’s microbiome plays in common urological diseases that affect children, according to a review article published online Feb. 22, 2018, by Current Urology Reports.

“There is a growing appreciation for the role of diverse bacteria in contributing to improved health as well as triggering disease processes or exacerbating illness,” says Michael H. Hsieh, M.D., Ph.D., director of the Clinic for Adolescent and Adult Pediatric Onset Urology (CAPITUL) at Children’s National Health System and study senior author. “Already, we know that probiotics and dietary modifications have the potential to play powerful roles in preventing urinary diseases that commonly occur among pediatric patients,” Dr. Hsieh says. This underscores the importance of conducting even more studies to improve our understanding and to identify new therapies for health conditions that resist current treatment options.”

The review conducted by Dr. Hsieh and co-authors highlights the effects of the microbiome on a number of urologic diseases that affect children, including:

  • Urinary tract infection A number of studies point to the association between decreased microbial diversity and the incidence of what is commonly called urinary tract infection (UTI) or “dysbiosis.” This relationship suggests that using probiotics to replace or supplement antibiotics could favorably alter the urinary microbiome. Future research will focus on the pathophysiological role of the microbiome to determine whether it can be manipulated to prevent or treat UTIs.
  • Urge urinary incontinence While data vary by study, the presence of bacteria in the urine, especially certain bacterial species – such as Gardnerella, Staphylococcus, Streptococcus, Actinomyces, Aerococcus, Corynebacterium and Oligella – are linked to the incidence and severity of urge urinary incontinence (UUI) as well as treatment success. Most studies find an association between greater genitourinary biodiversity and reduced incidence and lessened severity of UUI as well as improved treatment response. Future research will focus on further clarifying this relationship.
  • Urolithiasis Calcium oxalate stones, the most common type of kidney stone, have a microbiome that differs from the urinary microbiome leading researchers to question whether the stone’s own bacterial makeup could help to predict recurrence of future kidney stones. What’s more, Oxalobacter formigenes, a gram-negative bacterium, lowers oxalate levels in the blood and are associated with a 70 percent reduction in the risk of kidney stones forming. In an experimental model, fecal transplants with the full microbiome represented had a pronounced and persistent effect on oxalate production. Patients who receive some antibiotics often have reduced rates of formigenes colonization. However, the bacteria are resistant to amoxicillin, augmentin, ceftriaxone and vancomycin, which could point to preferential use of these antibiotics to stave off disease and ward off kidney stone formation.

Additional authors include Daniel Gerber, study lead author, The Georgetown University School of Medicine and Health Sciences; and Catherine Forster, M.D., study co-author, Children’s National.