Yeast fungi may play important role in chronic bowel inflammation, study finds

Chronic bowel inflammation arises from an overactive or misguided inflammatory response. Researchers suspect that the immune system’s reaction to microorganisms in the gut, which don’t typically trigger inflammation in a healthy state, plays a pivotal role. However, the specific microorganisms responsible and the precise immune cell responses remain largely unknown.

A breakthrough has emerged from the Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI), with scientists from Kiel University (CAU) and the University Hospital Schleswig-Holstein (UKSH), Campus Kiel, shedding light on a potential culprit – yeast fungi. Their findings, published in Nature Medicine, suggest that these fungi could significantly contribute to the problem.

The human body hosts trillions of microorganisms, primarily viruses and bacteria, but also fungi, especially in the gut. This microbiome maintains a delicate balance with our body, crucial for overall health. The immune system must walk a tightrope, tolerating these microbes while preventing overgrowth.

Current research indicates that in Crohn’s disease, a chronic inflammatory bowel condition, this balance goes awry. Immune cells become overly responsive to specific microbiome components, leading to recurrent gut inflammation. Individuals with Crohn’s experience symptoms like pain, diarrhea, fever, and more. It’s estimated that around one in 500 people in Germany is affected by this condition.

Yeast fungi as an inflammation trigger

T cells hold a critical role in the disrupted immune tolerance observed in Crohn’s disease. These immune warriors possess a specific receptor, the T-cell receptor, on their surface that allows them to recognize particular microbial components, known as antigens, triggering a tailored immune response.

The quest was to pinpoint which microorganisms spark this altered T-cell response in Crohn’s disease. Gabriela Rios Martini, a doctoral candidate in Professor Petra Bacher’s research group at the Institute of Immunology and the Institute of Clinical Molecular Biology at CAU and UKSH, clarifies, “We aimed to identify these triggers by studying how certain T cells respond to various microbes in blood and tissue samples from patients versus healthy individuals.”

Initially, the focus was on examining reactions to specific bacteria, given their prevalence in the microbiome. However, no discernible differences were observed between sick and healthy individuals with the bacterial species studied thus far. Rios Martini elaborates, “Then, we turned our attention to T-cell responses regarding yeast fungi, including various Candida and Saccharomyces species. Astonishingly, we discovered a significantly heightened T-cell response in Crohn’s disease patients.” Their investigation encompassed responses to yeasts both naturally occurring in a healthy microbiome and those introduced to the intestine primarily through dietary sources.

Cross-reactivity: T cells react to many different yeast fungi

To delve deeper into the functional traits of T cells and explore the intricacies of T-cell receptors, the researchers embarked on a journey of sequencing the T cells engaged in combat with yeast fungi. Through this investigation, Professor Petra Bacher, the lead senior author hailing from the Institute of Immunology and the Institute of Clinical Molecular Biology at CAU and UKSH, and her team made a noteworthy observation.

They discerned that patients primarily harbor T cells armed with T-cell receptors capable of responding to a broad spectrum of Candida and Saccharomyces species. “Evidently, these T cells possess the ability to recognize a specific element common to many of these closely related yeast fungi,” Professor Bacher elucidates.

This signifies that these T cells aren’t limited to reacting to just one yeast species; instead, they can be activated by numerous Candida and Saccharomyces yeasts. This phenomenon, known as cross-reactivity, provides a plausible explanation for how yeast-specific T cells might contribute to the persistent inflammatory response.

“In essence, our data suggests that following an initial T-cell response to yeast, repeated encounters with antigens shared by multiple yeast varieties result in the activation and proliferation of cross-reactive T cells. This cyclic immune response likely plays a pivotal role in the chronicity of inflammation,” Professor Bacher concludes. Notably, this process could be influenced not only by the commensal yeast fungi residing in the gut but also by yeasts ingested daily through dietary sources.

Investigating new therapeutic approaches for Crohn’s disease in the future

Professor Stefan Schreiber, the spokesperson of the Cluster of Excellence PMI and Director of the Department of Internal Medicine I at UKSH, Campus Kiel, as well as the Institute of Clinical Molecular Biology at CAU and UKSH, Campus Kiel, emphasized the potential implications of these discoveries.

“These findings open doors to potential novel therapeutic avenues,” Professor Schreiber notes, highlighting the collaborative effort behind this study.

He stresses the importance of these findings in enhancing our comprehension of the underlying mechanisms in chronic inflammatory bowel conditions like Crohn’s disease. Until now, yeast fungi haven’t received the attention they deserve in this context. This study presents compelling evidence for the involvement of yeast-reactive T cells in the inflammatory response characteristic of Crohn’s disease. Professor Schreiber underscores the need for further research to elucidate their direct role in the disease’s pathophysiology.

In subsequent investigations, the researchers aim to explore the impact of dietary yeast elimination or the targeting of yeast fungi through antifungal therapy in the gut. Another avenue of inquiry involves the specific deactivation of cross-reactive yeast-specific T cells through cellular therapies. The outcomes of these studies will provide insights into whether future therapies that directly address yeast fungi or yeast-specific T cells could be clinically effective, as per the research team’s objectives.

Source: Kiel University

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