Decoding Two-Way Brain-Gut Communication Unveils New Insights into Neurological Diseases

Cells move from the brain to the gut and back. – A new paper by Rhonda McFleder et al. reveals a groundbreaking discovery in the intricate world of brain-gut communication. Published in “Nature Communications,” the study challenges the conventional wisdom that communication between the brain and the gut is a one-way street.

“In our latest study, we demonstrate that brain-to-gut communication is a dynamic two-way process. Cells can migrate from the brain to the gut, influencing the spread of diseases,” explains neurobiologist Professor Rhonda McFleder, who lead the study alongside Professor Chi Wang Ip.

The research focuses on the role of immune cells, particularly macrophages, in the progression of Parkinson’s disease. The team discovered that proteins linked to Parkinson’s, specifically α-Synuclein (αSyn), migrate from the brain to the gut, causing disruptions. Notably, these protein accumulations were found in macrophages, not the neurons controlling the gut’s autonomous nervous system.

“To definitively test the migration of macrophages from the brain to the gut, we developed a method to label brain cells and track their migration,” says Rhonda McFleder, who teamed up with the Beilhack lab to uncover a unique communication between the brain and gut, suggesting its involvement in Parkinson’s disease spread.

Professor Chi Wang Ip adds a crucial finding: “We observed that macrophages not only migrate in Parkinson’s but also under control conditions, broadening the relevance to other neurological diseases. Just as these cells drive pathology in Parkinson’s, they may also promote disease spread in other neurological conditions.”

Next steps involve fully characterizing these migrating cells and identifying homing molecules guiding them to the gut. “Once identified, we can develop therapeutics targeting these molecules, potentially halting the progression of Parkinson’s and other neurological diseases,” says Rhonda McFleder.

The study involved collaboration from various research groups and received support from the Alexander von Humboldt Foundation, the Bavarian Ministry of Economic Affairs, the German Research Foundation (DFG), the Interdisciplinary Center for Clinical Research (IZKF) at the University of Würzburg, the VERUM Foundation, and the former EU Horizon 2020 research and innovation program.

McFleder RL, Makhotkina A, Groh J, Keber U, Imdahl F, Peña Mosca J, Peteranderl A, Wu J, Tabuchi S, Hoffmann J, Karl AK, Pagenstecher A, Vogel J, Beilhack A, Koprich JB, Brotchie JM, Saliba AE, Volkmann J, Ip CW. (2023). Brain-to-gut trafficking of alpha-Synuclein by CD11c+ cells in a mouse model of Parkinson’s disease. Nature Communications, 14(1):7529.

This research article was also highlighted in Nature Reviews Neurology.

Link to press release from Würzburg University Hospital, Germany (in German).

Dr. Stefanie Schwinn Awarded Top Thesis Award

Dr. Stefanie Schwinn, who specialized in her experimental medical thesis in Group 3 Medulloblastoma, was honored with the prestigious Klug & Sichler Doctoral Prize in Cancer Research by the Faculty of Medicine at the University of Würzburg on Monday at this year’s Dies Academicus.

As a dedicated doctoral candidate under the mentorship of Prof. Matthias Wölfl at the University Children’s Hospital and Prof. Andreas Beilhack at the Department of Medicine II, Dr. Schwinn embarked on extensive research to explore innovative treatment options for the highly aggressive subgroup of pediatric brain tumors known as Molecular Subgroup 3 Medulloblastoma. Her groundbreaking work led to the discovery of a highly effective treatment combination – Gemcitabine, a cytostatic agent, along with Axitinib, a VEGF receptor inhibitor – against Medulloblastoma cells. To closely mimic patient conditions, she conducted her experiments with exceptional skill and dedication on a demanding mouse model, employing advanced techniques such as light sheet fluorescence microscopy (LSFM).

The results unveiled that Dr. Schwinn’s chosen treatment option was not only at least as effective as the standard therapy but also better tolerated. Her pioneering research was published as the lead author in the journal Scientific Reports. Additionally, Dr. Schwinn contributed as a co-author to eight more scientific publications in the field of experimental oncology.

Dr. Stefanie Schwinn’s exceptional work has made a significant contribution to the development of potential therapy approaches for children with this highly aggressive brain tumor. Her findings now provide a solid foundation for clinical research and hold the potential to enhance treatment options for this patient group.

Linoleic Acid Unleashes Potent Antitumor Immunity in CD8+ T Cells

In a groundbreaking study published in the prestigious journal Cell Metabolism, lead author Theresa Manzo supported by an international research team unveiled key findings that could revolutionize cancer immunotherapy. The study highlights the profound impact of linoleic acid on cytotoxic T cells, showcasing its potential to enhance the effectiveness of antitumor immune responses.

The Beilhack lab explores novel concepts in immunotherapy against cancer, infections and inflammatory diseases. Würzburg University Immunology Program, GermanyRecently it has been recognized that the metabolic state of CD8+ cytotoxic T cells is a key player in the immune response against tumors. Our interdisciplinary team, in this project under the leadership of Theresa Manzo,   discovered that specific lipids, when improperly regulated, can compromise CD8+ T cell mitochondrial integrity, leading to impaired antitumor responses. Notably, the newly published study demonstrates that linoleic acid emerges as a major positive regulator, bolstering CD8+ T cell activity and overcoming metabolic hurdles. By mitigating exhaustion, cytotoxic CD8+ T cells become capable of sustaining potent and prolonged antitumor responses, offering new possibilities for overcoming challenges in cancer treatment.

The study also shed light on the ability of linoleic acid to induce a memory-like phenotype in CD8+ T cells. This transformation equips the cells with superior effector functions, suggesting that linoleic acid treatment could play a crucial role in enhancing the longevity and effectiveness of immune responses against cancer. A deeper exploration into cellular dynamics revealed that linoleic acid treatment enhances the formation of ER-mitochondria contacts. This action promotes calcium (Ca2+) signaling, optimizes mitochondrial energetics, and boosts the effector functions of CD8+ T cells. 

As linoleic acid-instructed CD8+ T cells exhibited superior antitumor potency both in vitro and in vivo, this new study suggests linoleic acid treatment as an enhancer for more effective adoptive cellular immunotherapy against cancer. 

This work was supported by our German Research Council (DFG) research consortium  TRR221 GvH-GvL.

Reference:

Nava Lauson CB, Tiberti S, Corsetto P, Conte F, Punit T, Machwirth M, Ebert S, Loffreda A, Scheller L, Mokhtari Z, Sheta D, Peters T, Raman AT, Greco F, Rizzo A, Beilhack A, Signori G, Tumino N, Vacca P, McDonnell L, Raimondi A, Greenberg PD, Huppa JB, Cardaci S, Caruana I, Rodighiero S, Nezi L, Manzo T. (2023). Linoleic acid potentiates CD8+ T cell metabolic fitness and anti-tumor immunity. Cell Metabolism 35(4):633-650.e9.

Young Investigator Award for Antonio Solimando

Former postdoctoral fellow and now young principal investigator at Bari University Dr. Antonio Solimando receives the IMS Young Investigator Award in Vienna, Austria.

Young Investigator Award for Antonio Solimando, 18th International Myeloma Workshop, Vienna 2021, Andreas Beilhack research lab, Würzburg UniversityClinician-Scientist Dr. Antonio Solimando will present our award winning research project on cell adhesion-regulated epithelial-mesenchymal-transition resulting in extramedullary multiple myeloma disease manifestation at the 18th International Myeloma Workshop in Vienna, Austria, on September 10th, 2021. This is a wonderful reward for our continuing fruitful scientific collaboration on the mechanisms and new therapeutic targets in adhesion mediated cancer progression. In the past years the basic science of this research project has been generously supported by the DFG µbone consortium and the therapeutic research aspects by the Bayerische Forschungsstiftung.

18th International Myeloma Workshop Vienna Austria, Young Investigator Award Group Picture 2021 Antonio Solimando, AG Beilhack Research Lab, Würzburg University, Germany

Image courtesy: International Myeloma Society

 

And the award goes to…

The European Society of Blood and Marrow Transplantation awarded our research on the protective function of host intestinal macrophages in acute graft-versus-host disease with this year’s Basic Science Award.

At the EBMT presidential symposium on March 15, 2021, postdoctoral fellow Dr. Duc-Dung Le presented our work and received this prestigious award together with his co-first author Dr. Ana-Laura Jordán Garrote on behalf of our entire team at University Hospital Würzburg and our national and international collaboration partners. Many thanks go to all the enthusiastic team members and especially to our partners within the DFG Transregio 221 consortium on GvH and GvL for the excellent support!

Read more about this award here.

Postdoctoral fellow Dr. Duc Dung Le receives EBMT Basic Science Award 2021 on behalf of the Beilhack lab
Prestigious research award to Dr. Duc Dung Le, Dr. Ana-Laura Jordán Garrote, Maria Ranecky and the entire team of the Beilhack lab and our collaboration partners of the DFG TRR221 consortium at Würzburg, Erlangen and Regensburg as well as Bern, Bonn, Harvard and Marseille.

Watch the interview with postdoctoral fellow Dr. Duc Dung Le here or on Youtube here.

A new potent approach to treat steroid-refractory acute Graft-versus-Host Disease?

Clinical studies suggested that endothelial dysfunction and damage can be involved in the development and severity of acute graft-versus-host disease (aGvHD), a complication in patients undergoing allogeneic hematopoietic cell transplantation. In a new paper under the lead of Olaf Penack from the Charité Berlin we show extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Subsequently, therapeutic intervention with an already clinical approved endothelium-protecting agent improved outcome in a mouse model of steroid-refractory aGvHD.

Sildenafil steroid-refractory acute GvHD, GvH-GvL, Andreas Beilhack laboratory, Würzburg University Immunology Program, Immunotherapy research Germany

Sildenafil protects from endothelial damage in experimental steroid-refractory acute GvHD

Allogeneic hematopoietic stem transplantation (allo-HCT) is the only curative treatment option for many patients suffering from blood cancers. However, there are still risks for patients undergoing allo-HCT. One major complication is acute graft-versus-host disease (aGvHD) occuring in more than two thirds of patients. This inflammatory condition primarily affecting the skin, liver, and intestines. Although treatment with steroids is successful in most patients, about the 20%-25% of patients fail initial steroid treatment resulting in a very high mortality rate. Currently, no standard treatment for this steroid-refractory aGVHD is available and its pathobiology remains poorly understood, thereby hindering the development of novel therapeutic approaches.

The endothelium is the first contact for immunological effector cells in the blood and a key regulator in various inflammatory processes. The endothelium was shown to be relevant for early complications after allo-HCT such as transplantation-associated-microangiopathy, veno-occlusive disease, capillary leak syndrome and diffuse alveolar hemorrhage. Recent studies also suggested a critical role of the endothelium in aGvHD. Accordingly, we found increased percentage of apoptotic Casp3+ blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGvHD. 

Light sheet fluorescence microscopy, LSFM, Andreas Beilhack laboratory Würzburg University Immunology Program

Pathologic vascular restructuring in intestinal acute GvHD

In mouse models of experimental aGvHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. Employing light-sheet fluorescence microscopy revealed structural changes in the colonic vasculature including increased vessel branching and vessel diameter. Human biopsies and murine tissues from steroid refractory aGvHD revealed extensive tissue damage but low levels of alloreactive T cell infiltration in target organs, providing the rationale for T-cell independent steroid refractory aGvHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental steroid refractory aGvHD. The study by Steffen Cordes et al. demonstrates extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Consequently, therapeutic intervention by endothelium-protecting agents, such as sildenafil, appear attractive to treat steroid refractory aGvHD complementing current anti-inflammatory treatment options. 

 

This work resulted from a strong collaborative effort between clinicians and scientists from different European medical centers: The Charité Berlin and the University Hospitals of Barcelona (Spain), Hannover, Heidelberg and Würzburg. Our lab was supported for this study be the DFG collaborative research center TRR221 GvH-GvL (project B11).

 

Reference:

Cordes S, Mokhtari Z, Bartosova M, Mertlitz S, Riesner K, Shi Y, Mengwasser J, Kalupa M, McGeary A, Schleifenbaum J, Schrezenmeier J, Bullinger L, Diaz-Ricart M, Palomo M, Carrreras E, Beutel G, Schmitt CP, Beilhack A, Penack O. (2021). Endothelial damage and dysfunction in acute graft-versus-host disease. Haematologica 106(8):2147-2160.

Breaking a vicious cycle in multiple myeloma

Multiple myeloma is a malignant disease of antibody producing plasma cells. As this devastating type of cancer locates to the bones it seems that multiple myeloma highly depends on close interactions with the bone marrow microenvironment. In our new paper by clinician-scientist Dr. Antonio Solimando et al. we describe our new discovery that multiple myeloma cells use an adhesion molecule called JAM-A (Junctional-adhesion-molecule A) to interact with blood vessel lining endothelial cells. It appears as these endothelial-multiple myeloma interactions feed into a vicious cycle propagating disease progression.

Multiple myeloma, bone marrow environment, adhesion molecules, JAM-A, Andreas Beilhack laboratory, cancer immunotherapy, Antonio Solimando, vicious cycle, new treatment
Our projected started with our initial observation that the expression level of JAM-A by malignant plasma cells can predict disease outcome. Subsequently, we discovered that elevated membrane expression of JAM-A also on bone marrow endothelial cells of patients with newly diagnosed or relapsed-refractory multiple myeloma cells predicted poor clinical outcome.

Based on this finding we investigated how elevated JAM-A levels would contribute to more aggressive disease. We discovered that direct contact of endothelial cells with multiple myeloma cells would enhance JAM-A levels. Then it got even more interesting, as the cell adhesion molecule JAM-A has remarkable features: it can interact with itself if expressed on two opposing cell types. Furthermore, if JAM-A is shed by a cell, the soluble form of the JAM-A molecule can bind to cell-bound JAM-A, which in turn even enhances its binding capacity. What ensues is a vicious cycle of malignant plasma cells expressing and shedding JAM-A, increasing JAM-A expression on endothelial cells and stimulating blood vessel formation. In turn, increasing numbers of JAM-A-overexpressing endothelial cells can now better bind malignant plasma cells, which now find more interaction partners and by increasing the multiple myeloma niche space can produce more JAM-A. Consequently, using different experimental models we found that blocking the adhesion molecule JAM-A would inhibit blood vessel formation, reduce JAM-A interactions and impair multiple myeloma disease progression. These therapeutic effects of blocking JAM-A were observed in preclinical models not in patients and, therefore, must be interpreted with caution. Nevertheless, our new findings may point towards a potential Achilles’ heel of multiple myeloma that might be exploited therapeutically in the future.

This work was generally supported by the Bavarian Research Foundation within the research consortium FORTiTher and the German Research Council (DFG) consortium µbone.

Reference:

Solimando AG, Da Vià MC, Leone P, Borrelli P, Croci GA, Tabares P, Brandl A, Di Lernia G, Bianchi FP, Tafuri S, Steinbrunn T, Balduini A, Melaccio A, De Summa S, Argentiero A, Rauert-Wunderlich H, Frassanito MA, Ditonno P, Henke E, Klapper W, Ria R, Terragna C, Rasche L, Rosenwald A, Kortüm KM, Cavo M, Ribatti D, Racanelli V, Einsele H, Vacca A, Beilhack A. (2021). Halting the vicious cycle within the multiple myeloma ecosystem: blocking JAM-A on bone marrow endothelial cells restores the angiogenic homeostasis and suppresses tumor progression. Haematologica 106(7):1943-1956.

Nature Reviews Microbiology features our recent research paper

Nature Reviews Microbiology, Andreas Beilhack lab, host-pathogen interactions, Würzburg University, Germany, Imaging, Light-sheet fluorescence microscopy, immunotherapyIn its current issue, the journal Nature Reviews Microbiology reports about our recent mBio research article advancing light-sheet fluorescence microscopy (LSFM) to study host-pathogen interactions within the 3D environment of the lung. In the news section Under the Lens, Manish S. Kushwah and Stephen Thorpe from Oxford University highlight our research article by former postdoctoral fellow Dr. Jorge Amich, postdoctoral fellow Zeinab Mokhtari et al. in their report A clearer picture of microbial biogeography.

Amich J*, Mokhtari Z*, Strobel M, Vialetto E, Sheta D, Yu Y, Hartweg J, Kalleda N, Jarick KJ, Brede C, Jordán-Garrote AL, Thusek S, Schmiedgen K, Arslan B, Pinnecker J, Thornton CR, Gunzer M, Krappmann S, Einsele H, Heinze KG, Beilhack A. (2020). 3D light sheet fluorescence microscopy of lungs to dissect local host immune – Aspergillus fumigatusinteractions. mBio 11(1): e02752-19

T cells induce interferon-dependent cell cycle regulator pathways in cancer cells as a key immune mechanism to control cancer

A new paper in Nature Communications by Brenner et al. demonstrates in mice and in human patients that cancer control strictly requires the activation of tumour-intrinsic, senescence-inducing cell cycle regulators by the immune system to stably arrest those cancer cells that escape from eradication.

Cancer immunosurveillance, cancer immune senescence-signalling, immunotherapy, Andreas Beilhack research laboratory, immunology program Würzburg university

Mechanisms of cancer immunosurveillance. (A) Conventional and cancer immunotherapies can enhance direct cytolytic effector mechanisms of cytotoxic T cells and NK cells. (B) TNF and interferon released by Th1 T cells can induce and maintain cancer cell senescence. Mutations in the interferon-senescence-signalling pathway in tumor metastases can abolish this important mechanism and result in cancer progression.

Recent advances in cancer immunotherapy allow to efficiently unleash immune effector cells. Consequently, T cells, NK cells and macrophages can kill malignant cells throughout the body in patients with hematologic and solid cancers. Even if these therapies primarily aim to completely eradicate all cancer cells, often enough cancer cell killing remains incomplete and does not sufficiently and permanently control cancer. Moreover, the majority of cancer-related deaths do not result from the primary tumor. Instead, months or even years after initial therapy, cancer metastases arise from reawakened, dormant cancer cells that had been resistant to chemo-, radiation- or immunotherapies.

In a collaborative multidisciplinary effort lead by the team of Prof. Dr. Martin Röcken from Tübingen University and scientists from Tübingen and Würzburg University, we uncovered that IFN-γ/STAT1-dependent activation of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf and p21Cip1 is required to keep cancer cells in a senescent state that had escaped immune cell mediated killing. Conversely, metastases that acquire mutations in the IFN-γ-senescence-inducing signalling pathways become resistant to immunotherapies and progress. In line with this, our study discovered that more than half of the metastases of patients not responding to immune checkpoint inhibitor therapy had at least one defect or genetic alterations in the IFN-dependent senescence-signalling pathway. Consequently, drugs that can re-invigorate the senescence-signalling pathways in cancer cells such as CDK4/6 inhibitors appear promising to be combined with cancer immunotherapy.

This work pinpointing key mechanisms required for protection against cancer cells that escape from cytotoxicity was supported by the German Research Council (Deutsche Forschungsgemeinschaft) in the research consortium FOR2314 Targeting therapeutic windows in essential cellular processes for tumor therapy and the Wilhelm Sander-Stiftung.

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