More Precise Treatment

150 million people worldwide are affected by urinary tract infections every year, often recurrent. The standard treatment is antibiotics, but these do not always help and can lead to resistance. Antibiotics also damage the 'good' bacteria that are part of the microbiome in the urinary and intestinal tract. 'We now want to harness this microbiome in the treatment of urinary tract infections,' says Professor Thomas Kessler, senior physician in neuro-urology at Balgrist University Hospital.

The new treatment will be developed under the auspices of the mTORUS project (microbiome-based Therapeutic Options for Recurrent Urinary Symptoms) funded over the next five years by The LOOP Zurich. It's a new step on two fronts for the researchers from the University of Zurich, ETH Zurich, Balgrist University Hospital, University Hospital Zurich and EPFL in Lausanne. Firstly, they plan to fight the disease-causing bacteria with genetically adapted bacteriophages (called phages for short). Secondly, they will then transplant healthy microbiomes into patients' urinary tracts to prevent future infections - this too is a novel procedure.

What is a healthy microbiome?

Before they can begin treating patients, however, the researchers need to get back to basics. 'As a medical student, I was taught that the bladder is sterile and contains no bacteria,' says Kessler. Nowadays we know that like the gut, the urinary tract has its own microbiome, which is altered in people with a urinary tract infection. Little is known, in contrast, about what makes up a healthy microbiome in the urinary tract. This will therefore be the initial focus of the team's research, along with the interaction between bacteria and the immune system. With the help of artificial intelligence, the researchers will analyze vast amounts of data from a great number of patients so that in the future, personalized therapies can be offered.

Old tradition

The new treatment will consist of two parts. First, the infection-causing bacteria will be destroyed by genetically altered phages. Phages are viruses that attack specific bacteria without damaging the rest of the microbiome. This method is over 100 years old, but following the introduction of antibiotics its use fell. It is still employed in a few countries, such as Georgia, and due to increasing antibiotic resistance, phages are now also enjoying a comeback elsewhere.

In recent years, the research team around Thomas Kessler and Martin Loessler at ETH Zurich has managed to genetically alter phages to make them target the bacteria that cause urinary tract infections. The researchers are also working on improving phages' ability to support the immune system. The phages are currently being tested in studies with animals, and by the end of 2023 should be ready to be trialed in clinical studies with humans.

Replacing the microbiome

Even once infection-causing bacteria have been killed off, patients still run the risk of getting new infections. This is because the microbiome of people who suffer recurring urinary tract infections is altered. This seems to affect the immune system, making it less effective at fending off infection.

If the mTORUS group succeeds in determining the composition of a healthy microbiome, the stage will be set for the next part of the planned therapy: transplanting a healthy microbiome into patients who suffer recurring urinary tract infections or are predisposed to them. The principle will be tested in an initial clinical study as part of the mTORUS project.

If all goes well, it could lead to a paradigm change in the treatment of urinary tract infections, as well as other types of bacterial infections: 'We want to see medicine move away from antibiotics and toward the use of phages and healthy microbiomes,' says Kessler..

More targeted treatment for obesity

The second project to receive support from The LOOP Zurich for the next five years is dedicated to another widespread health issue: obesity. Severe obesity can lead to a host of other problems - from diabetes and high blood pressure to an increased risk of tumors. 'These secondary disorders pose a greater problem medically than obesity itself,' says Felix Beuschlein, UZH professor and director of the Department of Endocrinology, Diabetology and Clinical Nutrition at the UniversityHospital Zurich. While there are a few medications to treat obesity, and gastric bypass operations can help people lose weight, no precision therapies are available to date.

Led by Beuschlein, a consortium of researchers from UZH, ETH Zurich and the University Hospital Zurich now aims to change that with the LOOBesity project. Their research will focus on a subgroup making up around 10 percent of obese people. People in this group are particularly at risk of developing secondary disorders due to the way their metabolism functions. In these patients, the stress hormone cortisol is more active than usual and causes damage to fat cells in particular. The cortisol leads to inflammation in the fat cells, thus increasing the likelihood of further diseases.

There are drugs that can slow down this increased cortisol activity, but until now they have not been used for obese patients, because physicians have no way of knowing who will benefit. 'That's why it's important to develop a method of accurately and easily identifying patients with increased cortisol activation,' says Beuschlein.

From biopsies to MRIs

The LOOBesity research team plans to take biopsies of patients' adipose tissue to investigate what effect cortisol actually has on fat cells at the level of individual cells - at present, little is known about this. In addition to the biopsies, the patients will undergo MRI scans. The researchers want to know whether the altered metabolism can also be precisely identified in the MRI images by algorithms - if so, it would no longer be necessary to conduct biopsies, which are costly and time-consuming.

Following the diagnostic stage, the second part of the project will focus on treatment. A clinical study will investigate whether the existing cortisol-modulating medications - which have not been used for obesity until now - actually bring any improvement for this group of patients.

A large amount of data will be gathered during the project. 'In that regard, we are a typical LOOP project,' says project leader Beuschlein. 'The aim is to use the data for further developments in precision medicine so that we can help those obese patients who are particularly affected by secondary disorders.'

'Our goal is to combine complex molecular analyses with imaging techniques and thereby enable personalised obesity therapy and successfully bring it into application,' says Christian Wolfrum, who has just been appointed ETH Vice President for Research and is involved in LOOBesity as a researcher. 'The project is a fine example of close cooperation with university and clinical partners, which ETH intends to strengthen even further in the future.'

Research consortia

mTORUS: Microbiome-based Therapeutic Options for Recurrent Urinary Symptoms

Main applicant: Prof. Thomas M. Kessler (Balgrist/UZH) with Prof. Gunnar Rätsch (ETH Zurich), Prof. Shinichi Sunagawa (ETH Zurich), Prof. Emma Wetter Slack (ETH Zurich), Prof. Martin J. Loessner (ETH Zurich), Prof. Onur Boyman (USZ/UZH), Prof. Nicola Zamboni (ETH Zurich), Dr. André Kahles (ETH Zurich), Dr. Lorenz Leitner (Balgrist/UZH), Dr. Shawna McCallin (Balgrist/UZH), Dr. Alaz Oezcan (USZ/UZH), Prof. John McKinney (ETH Lausanne)

LOOBesity

Main applicant: Prof. Felix Beuschlein (UZH/USZ) Joint applicants: Prof. Thomas Frauenfelder (UZH/USZ), Prof. Ender Konukoglu (ETH Zurich), Prof. Milo Puhan (UZH), Prof. Christian Wolfrum (ETH Zurich)

This is a slightly modified version of an article by Adrian Ritter that appeared in UZH News. Adrian Ritter is a freelance journalist.