Study reveals nerve changes linked to pain and urinary frequency in recurrent UTI sufferers

Published

1 year ago

March 7, 2024

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By Vijay Kumar Malesu Mar 7 2024 Reviewed by Lily Ramsey, LLM

In a recent study published in Science Immunology, a group of researchers investigated how sensory nerve sprouting and mast cell activity, driven by nerve growth factor (NGF), contribute to persistent bladder pain and dysfunction in recurrent urinary tract infection (rUTI) cases.

Study: Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity . Image Credit: Rabizo Anatolii/Shutterstock.com Background

Urinary tract infections (UTIs), primarily caused by uropathogenic Escherichia coli (UPEC), lead to numerous clinical visits annually due to their high recurrence rate, especially in women.

Recurrences are often attributed to UPEC persisting within the urinary tract's epithelial cells, causing rUTIs even in individuals with intact immune systems.

Standard UTI treatment involves a short course of antibiotics, with longer prophylactic use in cases of frequent recurrences.

rUTI patients frequently experience symptoms like pelvic pain and increased urination frequency, often treated with antibiotics despite negative urine cultures.

Further research is needed to develop targeted therapies that address the underlying neuro-immunological mechanisms contributing to chronic pelvic pain and bladder dysfunction in rUTI patients. About the study

In the present study, researchers employed a rUTI mouse model to mimic symptoms and phenotypes observed in human clinical settings.

They evaluated voiding behavior, pain-like responses, and nerve anatomy through various techniques such as cystometry, histology, and three-dimensional (3D) model reconstruction.

Additionally, enzyme-linked immunosorbent assay (ELISA) and flow cytometry were utilized to identify proteins and cell types relevant to rUTI pathology.

To validate their findings, the team implemented multiple targeting strategies, including receptor antagonists and neutralizing antibodies against NGF, as well as genetically modified mice lacking specific immune cell receptors or cells. Related StoriesCellectricons expertise in pain research recognized by second EU research grantLow back pain? Theres good and bad newsNew drug targets key mechanism in ALS, protects motor neurons

To further establish the connection between their observations in mice and human patients, the researchers administered NGF, histamine, and bradykinin to naive mice.

This replicated the primary observations from the rUTI model, suggesting a possible translational significance of their findings.

Human bladder biopsies and urine samples were collected from control individuals and rUTI patients experiencing pain to confirm the animal model data with human clinical observations.

These human samples underwent similar analysis protocols to those applied in animal studies, ensuring that the insights gained from the research were grounded in both preclinical and clinical realities.

The study explored nerve growth in rUTI through various methods. Researchers collected dorsal root ganglia (DRGs) from mice, treated them with enzymes for dissociation, and then cultured the cells on coated coverslips. Adding NGF or its antagonist revealed NGF's role in neurite outgrowth.

This was paralleled by in vivo experiments where NGF was instilled into mouse bladders to induce nerve sprouting, contrasting with treatments that neutralized NGF or blocked its receptor, which prevented such growth.

Additionally, monocytes and mast cells were cultured with neurons to demonstrate further NGF's influence on nerve development.

Various techniques were employed to assess pelvic sensitivity and bladder innervation effects, underscoring NGF's central role in sensory nerve sprouting associated with rUTI symptoms. Study results

Patients experiencing rUTI often report persistent symptoms such as pelvic sensitivity and urinary frequency, even after bacterial cultures show no signs of infection. This observation led researchers to investigate the role of bladder sensory nerves and their connection to rUTI symptoms.

Upon examining bladder biopsies from rUTI patients, an increase in Substance P (SP+), a marker for nociceptive sensory nerves, was observed, suggesting alterations in nociceptive activity.

A mouse model of rUTI was employed to explore these clinical findings further, revealing similar symptoms of increased pelvic sensitivity and urinary frequency alongside significant sensory nerve sprouting in the lamina propria.

The investigation into the underlying mechanisms of these observations pointed towards the role of NGF, a key mediator in nerve sprouting and sensitization. Elevated levels of NGF, but not brain-derived neurotrophic factor (BDNF), were identified in the bladders of rUTI mice.

Targeting NGF signaling through the administration of native NGF to naive mice or utilizing NGF-neutralizing strategies replicated the rUTI phenotype or alleviated symptoms, respectively, confirming NGF's pivotal role.

The cellular source of NGF was traced back to recruited monocytes and bladder-resident mast cells, which were identified as primary contributors to the elevated NGF levels during rUTI.

These findings were further confirmed by in vitro experiments showing that monocytes and mast cells induced nerve growth. This process could be blocked by Tropomyosin receptor kinase A (TrkA) antagonism, indicating the specificity of NGF from these immune cells in inducing sensory nerve sprouting.

Exploring the link between sensory nerve sprouting, sensitization, and the observed rUTI symptoms, researchers discovered that the sustained release of NGF-sensitized nociceptors leads to pain-like responses and urinary frequency.

This process involved the activation of Transient Receptor Potential Vanilloid 1 Positive (TRPV1+) nerves, with mast cell products such as histamine and bradykinin playing significant roles in mediating these symptoms.

Interestingly, the administration of histamine or bradykinin directly into the bladder of naive mice induced similar symptoms to those observed in rUTI, suggesting a role for these mast cell products in the pathological process. Journal reference:

Byron W. Hayes et al. Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity. Sci. Immunol. (2024). doi:10.1126/sciimmunol.adi5578. https://www.science.org/doi/10.1126/sciimmunol.adi5578

Entertainment

Terence Stamp, Superman villain and star of The Adventures of Priscilla, Queen of the Desert, has died

Published

2 hours ago

August 17, 2025

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Terence Stamp, Superman villain and star of The Adventures of Priscilla, Queen of the Desert, has died

British actor Terence Stamp – who famously played General Zod in Superman and Superman II – has died at the age of 87.

The Oscar-nominated actor, who was born in London’s East End, also starred in hits such as Theorem, A Season in Hell, and The Adventures of Priscilla, Queen of the Desert.

He formed one of Britain’s most glamorous couples with Julie Christie, with whom he starred in “Far From the Madding Crowd” in 1967.

In a statement, his family said: “He leaves behind an extraordinary body of work, both as an actor and as a writer that will continue to touch and inspire people for years to come.”

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Environment

Mahindra reveals Batman BE 6 EV – and it’s kind of amazing

Published

3 hours ago

August 17, 2025

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Mahindra reveals Batman BE 6 EV – and it's kind of amazing

Mahindra Built A Batman SUV And Somehow It’s Completely Serious

Indian ag and automaker Mahindra has launched a limited-run Batman Edition of its BE 6 Electric Origin SUV, calling it, “a production car that brings to life a rare fusion of cinematic heritage and modern luxury, inspired by Christopher Nolan’s critically acclaimed The Dark Knight Trilogy from Warner Bros. Pictures.”

And, you guys – the new Mahindra BE 6 is. So. Serious.

Someone at Mahindra is very taken with American culture it seems. After launching the Willys MB Jeep-inspired Mahindra Roxor a few years ago, the company followed it up by building a credible line of EVs co-developed with VW. Now, they’re building a limited edition of one of those EVs inspired by another American cultural icon.

“Batman is more than a pop-culture icon — he represents innovation, resilience, and an unyielding drive to push boundaries,” says Vikram Sharma, Senior Vice President, Warner Bros. Discovery Global Consumer Products, APAC. “This collaboration brings that spirit to the road in a bold, electric way. With this limited-edition range, fans in India can now experience the thrill of Batman every time they drive. It’s a collector’s statement on wheels.”

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To separate the Batman Edition from the other Mahindra SUVs, its makers have festooned their EV with Dark Knight logos and branding, inside and out.

Batman Edition features

Exterior

Custom Satin Black Colour premieres on the Batman Edition
Custom Batman Decal on front doors
R20 alloy wheels for an aggressive, athletic stance
Alchemy Gold-painted suspension and brake callipers a bold, premium contrast to the Satin black body
“BE 6 × The Dark Knight”, limited edition, rear badging
The Bat emblem, as seen in The Dark Knight Trilogy, uniquely placed on:
Hub caps
Front quarter panels
Rear bumper
Windows & Rear Windshield
Infinity Roof featuring The Dark Knight Trilogy Bat emblem
Night Trail – Carpet lamps with The Dark Knight Trilogy Bat emblem logo projection
‘Batman Edition’ signature sticker on rear door cladding

Interior

Brushed Alchemy Gold Batman Edition plaque on the dashboard with numbering
Charcoal leather instrument panel (IP) with brushed gold halo around driver cockpit
Suede and leather upholstery with gold sepia accent stitching and integrated The Dark Knight Trilogy Bat emblem for a rich, tactile experience
Gold-accented steering wheel, In-Touch Controller, Electronic Parking Brake, custom key fob with Alchemy gold detailing
The Dark Knight Trilogy Bat emblem embossed on:
The “Boost” button
Seats
Interior labels
Pinstripe graphic and The Dark Knight Trilogy Bat Emblem across the passenger dashboard panel
Race car inspired open straps with Batman Edition Branding Batman Edition welcome animation on the infotainment display
Custom Batman inspired exterior engine sounds

Despite all the Batman branding, the end result is almost tasteful. I could do without the custom Batman decal on the front quarter panels, but the rest of the mods are far less offensive. I even like the little “Bat Signal” puddle lights on the wing mirrors.

Mahindra Batman BE 6

As a car, the special edition Batman Mahindra is based on the top-shelf version of the BE 6, fitted with a 79 kWh battery good for 550 km (about 340 miles) of range according to its WLTP rating. That battery sends power to a rear-mounted 282 hp (210 kW / 286 PS) electric motor generating and 380 Nm (about 280 lb-ft) of torque that sends power to the rear wheels.

The BE6 also features a modern Level 2 ADAS tech and screens everywhere, including in the steering wheel hub – which seems like it might get particularly nasty in an airbag deployment (but no one asked me).

Pricing starts at ₹27.79 lakh (a little under $27,500, as I type this), and production will be limited to just 300 units. Order books are set to open 23AUG.

SOURCE | IMAGES: Mahindra.

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Business

Miniature classic car-maker Hedley Studios revs up rescue deal

Published

5 hours ago

August 17, 2025

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Miniature classic car-maker Hedley Studios revs up rescue deal

A company which makes miniaturised electric versions of classic cars has secured a rescue deal led by an American merchant banking group.

Sky News understands that the future of Hedley Studios – formerly known as The Little Car Company – has been salvaged through a pre-pack administration deal.

FRP Advisory is understood to have acted as administrator before selling the business to an entity controlled by Island Capital Group.

Hedley Studios was founded in 2018, when luxury car-maker Bugatti approached Ben Hedley to see if he could recreate a 1920s Type 35 racing car at half-scale to mark its 110th anniversary.

In a statement issued in response to an enquiry from Sky News, the company said it had built and delivered more than 500 vehicles to clients in more than 60 countries in the last 17 months.

Hedley Studios manufactures its cars at three-quarters the size of the original model, with the resulting vehicles typically costing £75,000 or more.

“We’re thrilled to welcome Island Capital Group as a strategic partner in the next phase of Hedley Studios’ growth,” Mr Hedley said.

“Its investment and belief in our vision mark a pivotal moment for the company as we accelerate our expansion and reach new global audiences.

Hedley Studios makes its cars in partnership with a range of luxury manufacturers, including Aston Martin, Bentley and Ferrari.

Andrew Farkas, founder, chairman and CEO of Island Capital, which initially backed Hedley Studios in 2023, said: “This latest investment is testament to the entrepreneurial spirit of Ben and his team in building a successful British luxury brand in a short period of time.

“Automotive enthusiasts globally are increasingly keen to honour these historic icons, bringing them to new audiences in a new, fully electric way.

“Our broader investment marks the beginning of a new chapter for Hedley Studios, reinforcing its position as a leader in the creation of luxury, driveable artworks, and Island Capital is excited to be part of that growth journey.”