PhD students

Ludwig-Maximilians-Universitaet Muenchen
Mikrobiology
Großhaderner Str. 2-4
82152 Martinsried

Supervisor
Prof. Dr. Kirsten Jung (P08)

Description

coming soon

Deciphering the role of the gut microbiota in the success of radiation therapy for colorectal cancer

Technical University of Munich
Klinikum rechts der Isar
Center for Translational Cancer Research (TranslaTUM)
and Department of Internal Medicine II
Ismaninger Str. 22, 81675 Munich

Supervisor
PhD Markus Tschurtschenthaler (P11)

Description
Radiation is a widely-used approach for the treatment of colorectal cancers (CRC), yet its overall therapeutic benefit varies considerably between patients. This may be due to biological or patient-specific factors. One biological factor that may affect the anti-tumour efficacy of radiotherapy is the gut microbiota, which is defined as the collective body of microorganisms resident in the intestine. Previous research as part of Project P11 identified differential microbial compositions in murine models that faithfully recapitulate human subtypes of CRC. In addition, survival of mice that had been orthotopically transplanted with intestinal adenoma organoids differed between specific-pathogen-free (SPF) and germ-free (GF) conditions. However, the mechanisms leading to these different outcomes are unclear. It is therefore of great interest to functionally examine these differences in microbial composition in the molecular subtypes of CRC and to determine whether they affect the success of radiation therapy.

In my PhD project, I aim to shed light on the role the gut microbiota may play in influencing responses to radiation therapy by taking a multifaceted approach. Firstly, GF and SPF mice will be subjected to a wide range of microbial interventions (including faecal microbiota transplantation), prior to orthotopic xenotransplantation of tumour organoids. These mouse models will then be subjected to radiotherapy to identify how the microbial interventions affect the anti-tumour efficacy of radiotherapy. Secondly, the data generated from the microbial intervention studies will be analysed together with microbiota signatures identified from the IMMENS clinical study in order to identify specific bacterial metabolites to investigate further. The impact of the chosen metabolites on tumour radiosensitivity and regeneration will be investigated in vitro using different tumour organoid lines, prior to being validated in vivo using mice orthotopically transplanted with the organoids. Through this PhD project, I hope to provide a rationale for the clinical investigation of microbiota-based interventions that could potentially improve responses to radiotherapy in colorectal cancer patients.

Defining intestinal microbiota orchestrating immune tolerance to intervene with allergic reactions to food and beyond

Technische Universität München
TUM School of Life Sciences
Lehrstuhl für Biotechnologie der Nutztiere
Liesel-Beckmann-Straße 1, 85354 Freising-Weihenstephan

Supervisor
Dr. rer. nat. Konrad Fischer (P06)

Description

Alpha-gal is a carbohydrate that is ubiquitously expressed in almost all mammals besides humans. In humans, tolerance to alpha-gal is caused by the nutrition and the bacteria present in the gastrointestinal tract. This tolerance can be broken by tick bites. The resulting sensitization, shown by alpha-gal specific IgE antibodies, can cause severe allergic reactions to mammalian meat and certain drugs.

In the second funding phase of Project 06, we will focus on germ free pigs, that are either susceptible or resilient to alpha-gal allergy, dependent on the microbial consortia. By using faecal microbiota transfer (FMT) from healthy human donors to our germ free- and normal-housed,  GGTA1-deficient pigs, we will evaluate the potential of a pre-selected microconsortium to promote resilience.

Furthermore, we will establish a standardized FMT treatment in GGTA1-deficient pigs, that will undergo an antibiotic pre-treatment to „re-set“ their microbiota. The treated pigs and controls will then be sensitized to alpha-gal by intradermal injection and subsequently challenged with alpha-gal. Additionally to alpha-gal, we will investigate the potential of „bacterial therapeutics“, also against oxazolone-induced atopic dermatitis-like skin inflammation.

Institute of Medical Microbiology
Functional Microbiome Research Group
University Hospital of RWTH Aachen

Supervisor
Dr. rer. nat. Thomas Clavel (P14)

Description

The initial aim of this project is to develop libraries of personalised reference microbiomes through high-throughput anaerobic cultivation and to establish comprehensive strain collections for the species Escherichia coli, Enterococcus faecalis, and Phocaeicola vulgatus using samples from healthy donors and patients with inflammatory bowel diseases and colorectal cancer. These isolate libraries will be thoroughly characterized to understand metabolic profiles and will also be used to create customized synthetic microbiomes. This project will then use molecular techniques, continuous culture, and gnotobiotic mice to test phage-bacterial interactions as well as the utilisation of phages for highly specific modification of SYN to build on personalised medicine research.

Host-microbe communication – the influence of dexamethason on Desulfovibrio

Ludwig-Maximilians-Universitaet Muenchen
Mikrobiologie
Großhaderner Str. 2-4
82152 Martinsried

Supervisor
Prof. Dr. Kirsten Jung (P08)

Description

Our bodies carry more bacterial than human cells. Massive efforts have been made to understand which changes bacterial communities undergo between health and disease. A particular challenge is not only to quantify these changes, but to explain the causes triggering population shifts, such as the exposure to drugs. The microbiome is key to many physiological reactions of the host, yet our poor understanding of its mechanisms gives an urgent need for unravelling their molecular basis.

My PhD proposal unites the highest-performance techniques of modern microbiology and chemical biology to explain how drugs affect the gut microbiome. I will characterize anaerobic Desulfovibrio gut bacteria and will establish strategies to genetically modify them to study their stress adaptation and sensory systems. I will also directly investigate host-microbiome interactions using in vivo disease-models of mice, allowing us to bridge the gap between Molecular and Systems Biology.

Altogether, the strategies I will develop will be key to advance the fields of microbiome research to immunology and personalized medicine. By uniting classic characterisation approaches with in vivo models of disease they will help unravel how hormones and drugs affect the gut microbiome to regulate essential host-microbiome interactions.

Ludwig-Maximilians-Universität München
Div. Pediatric Gastroenterology and Hepatology
Dr. von Hauner Children’s Hospital
Lindwurmstr. 4, 80337 Munich

Supervisor
Dr. med. Tobias Schwerd (P01)

Description

coming soon

Phage induced Strain Replacement within Microbiomes

Ludwig-Maximilians-Universität München
Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology
Pettenkofenstr. 9a, 80336 Munich

Supervisor
Prof. Dr. rer. nat. Barbara Stecher (P14)

Description

Within the last decades microbiome research became more and more relevant to the field of public health. It vastly contributed to understanding the pathogenesis of major human diseases but also generated knowledge on the emergence and spread of antibiotic resistances (ABR). Nevertheless, new insights always open up more questions. An important one is: How can we use this knowledge to specifically eliminate harmful or ABR bacteria from the human gut without harming or disrupting overall microbiota composition?

To address this question, we focus on a new strategy termed “phage induced strain replacement within microbiomes”, which aims at combining phage- and probiotics-based therapy within one treatment. The idea behind this approach is to pose a fitness disadvantage on the targeted strain by a strain-specific phage cocktail and introduce a second, closely related, but phage-resistant competitor that competes for the same niche within the gut environment as the target strain. Ideally, this approach leads to strain replacement and elimination of the targeted strain without disturbing the overall gut microbiota composition. We focus on the three species Escherichia coli, Enterococcus faecalis and Phocaeicola vulgatus (formerly Bacteroides vulgatus). These species were chosen due to their clinical relevance, genetic diversity and high prevalence in the human gut.

We confirmed our theory in batch culture setups for E. coli and E. faecalis, showing that phage induced strain replacement is possible. Currently, we are establishing phage and competitor strain libraries for E. faecalis and P. vulgatus for subsequent experiments in a range of different environmental conditions in vitro and in vivo to further evaluate the potential efficiency of strain replacement as a new therapeutic approach to combat ABR and chronical intestinal diseases.

Specialized metabolites from Desulfovibrio sp. and their effects on inflammatory bowel disease

Technische Universität Dresden
Faculty of Chemistry and Food Chemistry
Chair of Technical Biochemistry
Neubau Chemische Institute
Bergstraße 66, Raum: 333
01069 Dresden

Supervisor
Prof. Dr. Tobias Gulder (P16)

Description

Inflammatory bowel disease (IBD) is characterized by damaged mucosal structure, altered gut microbial composition and systemic biochemical abnormalities. Although the exact cause of the disease is unknown, it is thought to be related to reduced microbial diversity of the gut microbiota and significant microbial imbalance. Furthermore, there is an upregulation of certain intestinal bacteria, which, among others, belong to the genus Desulfovibrio. 

The reasons for the high colonisation of the gut of IBD patients with Desulfovibrio sp. and the role of these organisms in disease development and progression are largely unclear. A better understanding of the triggers and direct consequences of this dysbiosis would provide valuable contributions to the diagnosis and treatment of IBD. Of particular interest within my PhD project is investigating the possible effects of specialized metabolites from Desulfovibrio sp. that could play crucial roles in these processes. 

The observation that Desulfovibrio sp. are more abundant in IBD patients can be functionally linked to the inflammatory processes raises the question of whether low-molecular-weight compounds produced by these microbial intestinal inhabitants also fulfil important functions in pathogenesis in this case.

Lipid metabolism as critical link between gut microbiota and colorectal cancer: analysis of genetic models and patient samples

Technical University of Munich
Klinikum rechts der Isar
Department of Surgery
Ismaninger Str. 22, 81675 Munich

Supervisor
Prof. Dr. rer. nat. Klaus-Peter Janssen (P13)

Description

Deregulated lipid metabolism is a hallmark of cancer cells, but its causal contribution to tumor initiation and progression, as well as the functional connection with the gut microbiota and microbial metabolites is largely unclear.

In the first funding period of CRC 1371, we have gathered evidence that the gut microbiome interacts with the host’s lipid metabolism at multiple and non-redundant layers. Gut microbiota promote host lipid synthesis in the regenerating liver by providing short-chain fatty acids, and they limit intestinal lipid absorption.  In fact, levels of dietary-derived polyunsaturated fatty acids (PUFA) in blood plasma, liver and intestine were clearly associated with the presence of gut microbiota. Moreover, expression of the fatty acid desaturase SCD1 was significantly increased in human and mouse CRC, and was positively regulated by gut microbiota.

Project (P13) is based on key findings of the first funding period of CRC1371 (P10 and P13). We hypothesize that a) the gut microbiota causally impact on premalignant and cancer cell lipid metabolism, and b) the host enzyme SCD1 is a critical link between microbiota and cancer. We aim to address the following main topics in the second funding period of CRC 1371. Firstly, what is the contribution and relevance of dietary versus de novo synthesized fatty acids as energy source and cell membrane components for colorectal cancer, with a focus on PUFAs?
Secondly, how does the gut microbiota impact lipid metabolism in pre-malignant intestinal epithelia, as well as in cancer cells, and are these effects relevant for tumor initiation and progression? Thirdly, we will investigate whether fatty acid desaturation by SCD1 forms a critical link between microbiota and cancer that could yield potential therapeutic targets.

Title: Microbial triggers of intestinal inflammation in hosts deficient in X-linked inhibitor of apoptosis protein

Technical University of Munich
University Hospital rechts der Isar
Institute for Molecular Immunology
Ismaninger Straße 22, 81675 Munich

Supervisor
PhD Monica Yabal (P02)

Description

Inflammatory bowel diseases (IBD) have been suggested to result from defective host immune responses to the gut microbiota in genetically susceptible hosts. However, little is known about specific microbial triggers of inflammation and their interactions with host susceptibility genes. Previous work (from us and others) in this area reported mutations in X-linked inhibitor of apoptosis protein (XIAP) as the genetic origin of a Mendelian form of IBD. We observed that XIAP deficiency promoted TNF-dependent death of Paneth and dendritic cells, which correlated with a microbial dysbiosis. Specifically, we could link intestinal inflammation in Xiap^–/– mice to the presence of flagellated Helicobacter spp. and the loss of butyrate-producing Clostridium species. With this background, we look to further investigate and define the host and microbial requirements of intestinal inflammation in XIAP-deficient mice.

One of the aims of my project is to develop a consortium of bacteria (and evaluate specific microbial products) that could ameliorate and prevent intestinal inflammation. I also aim to look into the role of flagellin and other microbial drivers of inflammation in the context of the gut epithelium. This would involve studies of the signaling cascades and cell death pathways of myeloid immune cells at a molecular level.

Overall, this work will elucidate pathways of microbiota-dependent intestinal inflammation in XIAP deficiency, develop strategies for microbial targeting, and investigate microbial drivers of inflammation in human IBD.

Technical University of Munich
ZIEL - Institute for Food & Health
Gregor-Mendel-Str. 2, 85354 Freising-Weihenstephan

Supervisor
Prof. Dr. Dirk Haller (P01)

Description

Crohn's disease (CD), one of the two major types of inflammatory bowel disease (IBD), is marked by chronic inflammation in any region of the gastrointestinal tract and is becoming increasingly prevalent worldwide. Exclusive enteral nutrition (EEN) with a fiber-free formula is a first-line induction therapy for pediatric CD in Europe. The first funding phase of P01 has confirmed that an EEN-like diet induced protective changes in patient-derived microbiota using an ex vivo continuous culture system combined with subsequent patient gut microbiota transfer into IBD-related germ-free mouse models.

In the second funding phase of P01 project, the same combination of ex vivo and mouse models will be used to characterize the functional adaptation of patient-derived microbiota to EEN treatment at the bacterial strain level using integrative multi-omics analysis. The transcriptional, metabolomic, and bacterial functional activity associated with EEN-induced changes in the gut microbiome of pediatric CD will be analyzed to characterize their compositional and functional dynamics in different clinical scenarios (pre-EEN active disease, post-EEN remission, and post-EEN relapse).

Previous studies showed that the re-introduction of a fiber-rich diet post-EEN results in the recurrence of inflammation in CD patients; however, its role in provoking relapse is not clearly understood. In this project, we aim to characterize the effects of different soluble and insoluble fibers on modulating the microbiota functionality and metabolites production using an ex vivo continuous fermentation model system. The impact of specific dietary components on tissue inflammation and cell proliferation and viability will be confirmed using immune cell cultures, intestinal organoids, and gnotobiotic mouse models. The final goal is to identify protective EEN-relevant minimal consortia for future standardized microbial therapy and/or define dietary strategies relevant for the maintenance of remission in pediatric CD patients.

Ludwig-Maximilians-Universität München
Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology
Pettenkofenstr. 9a, 80336 Munich

Supervisor
Prof. Dr. rer. nat. Bärbel Stecher (P08)

Description

The mammalian gut is colonized by diverse microbial communities that provide its host with different functions, e.g. nutrition or protection against invading pathogens. These microbiota functions are dependent on the microbial community composition (who is there?) and inter- and intraspecies interaction networks (what do they do?). 

Profound understanding of individual species interactions and their consequences for the mammalian host is often hindered by the microbiome´s diversity and difficulty in conducting experimental manipulations. Here, synthetic communities (Syncoms) can serve as tool to analyze bacterial ecology in detail by reducing complexity and increasing experimental manipulability. We previously used the Oligo-Mouse-Microbiota Syncom (OMM¹²) to gain a mechanistic understanding of microbiome-mediated colonization resistance against pathogens (Eberl et al. 2021), bacterial interactions networks (Weiss et al. 2022) and the systematic investigation of bacterial keystone species (Weiss et al. 2023). 

Building on our expertise, we now aim to generate a synthetic community to model the human neonatal gut microbiota (NeoSyn). The microbiota plays a crucial role in various aspects of early development and health. NeoSyn is intended to mimic the highly variable neonatal gut microbiome both functionally and taxonomically. 

The variations in the neonatal gut microbiome are driven by many different factors, such as the mode of delivery, the type of feeding or the use of medication (especially antibiotics). 

Using MiMiC (Kumar et al. 2021), a tool which aids the design of minimal microbial consortia based on the functional potential identified in a given metagenomic sample, we designed different variants of NeoSyn consisting of 12 members to mimic an infant's microbiota of vaginally-born (NeoVaSyn) and caesarean-born (NeoCeSyn) infants. This core composition can be complemented with additional species of interest to perform research specific experiments. These NeoSyns will be used alongside our well-established and characterized OMM¹² model to address P08 related questions: What is the role of primary metabolites, in particular polyamines, in the intestinal ecosystem under normal and inflamed conditions? Moreover, we plan to further investigate and understand e.g. differences in microbial ecology and microbiome functions or apply them for studying different antimicrobial compounds.

References

Eberl C, Weiss AS, Jochum LM, Durai Raj AC, Ring D, Hussain S, et al. E. coli enhance colonization resistance against Salmonella Typhimurium by competing for galactitol, a context dependent limiting carbon source. Cell Host Microbe. 2021
Kumar N, Hitch TCA, Haller D, Lagkouvardos I, Clavel T. MiMiC: a bioinformatic approach for generation of synthetic communities from metagenomes. Microbiology. 2021Weiss AS, Burrichter AG, Durai Raj AC, von Strempel A, Meng C, Kleigrewe K, et al. In vitro interaction network of a synthetic gut bacterial community. ISME J. 2022
Weiss AS, Niedermeier LS, von Strempel A, Burrichter AG, Ring D, Meng C, Kleigrewe K, et al. Nutritional and host environments determine community ecology and keystone species in a synthetic gut bacterial community. Nature Communications. 2023

Microbiota-mediated regulation of anti-viral immunity in gnotobiotic mice

Technical University of Munich
Center of Allergy & Environment (ZAUM)
Ingolstädter Landstr. 1, 85764 Neuherberg

Supervisor
Dr. Caspar Ohnmacht (P07)

Description

Infectious diseases are still causing millions of deaths worldwide, COVID-19 being the most recent example. The immune system, including mucosal immunity as an internal barrier, plays an indispensable role in protecting us from pathogens. Defects in both, adaptive and innate immunity can lead to illness such as failed pathogen control or immunopathology.

The immune response following viral infections, vaccination or responsiveness following checkpoint therapy can vary tremendously across individuals. Besides genetic differences, also environmental factors may contribute to this effect. The intestinal microbiome is known to affect various aspects of the immune system including the adaptive immune system.

Based on previous work in P07, I will investigate in my project how anti-viral immune responses, especially T helper cells, are shaped by different bacterial consortia and their metabolites using the LCMV model and gnotobiotic mouse models. This highly controlled system will allow us to shed light on how virus control and immunopathology in acute and chronic viral infections are affected by the intestinal microbiome. Thereby we will not only gain insights on molecular mechanisms involved on the host side but also which bacterial strains or metabolites are responsible for such effects.

Interaction between microbiome and molecular subtypes on the progression of colorectal cancer

Technical University of Munich
TUM School of Life Sciences Weihenstephan
Chair of Livestock Biotechnology
Liesel-Beckmann Str. 1, 85354 Freising

Supervisor
Dr. habil. Tatiana Flisikowska (P12)

Description

Colorectal cancer (CRC) is the second most deadly cancer worldwide with a predicted increasing global incidence and mortality in the next decades. CRC, as a highly heterogenous disease, is reflected by molecular subtypes displaying various genetic mutations in APC, KRAS, TP53, SMAD4 and many more genes. The CRC subtypes respond different to therapy because of diverse microbiome components.

The aim of the thesis is to study the interaction between microbiome and CRC subtypes in the APC¹³¹¹ pig model. Generating different CRC subtypes through germline genome editing tools is a very time-intensive process in pigs. In this work, the somatic genome editing using virus-like particles (VLPs) as a delivery system will be utilized. The VLPs can efficiently deliver proteins and nucleic acids into target cells avoiding undesired viral effects. VLPs derived from murine leukemia virus (Nanoblades technology) packaged with different cargo have been successfully used for in vivo genome editing in mice. Modified VLP delivery protocols enabled efficient genome editing in vitro in pigs.

The VLPs containing Cas9 and guide RNAs for inactivation of different tumor suppressor genes will be used to generate CRC subtypes in vitro in polyp-derived organoids and by in vivo injection into individual polyps during colonoscopies in the APC¹³¹¹ pigs. The progression or regression of the disease will be longitudinally assessed. Tissue samples for spatial and temporal molecular and microbial analyses will be collected. The polyp-derived organoids will be cocultured with immune cells and bacteria to identify interactions between immune system, microbiota and CRC subtypes.

Impact of Desulfovibrio spp. and sulfur metabolism on the pathogenesis of chronic intestinal inflammation and colitis-associated cancer

Technische Universität München
School of Life Sciences Weihenstephan
Chair of Nutrition and Immunology
ZIEL - Institute for Food & Health
Gregor-Mendel-Str. 2, 85354 Freising

Supervisor
Prof. Dr. Melanie Schirmer (P18)

Description

Coming soon

Deciphering the role of the gut microbiota in the success of radiation therapy of colorectal cancer

Technical University of Munich
Klinikum rechts der Isar
Klinik und Poliklinik für RadioOnkologie und Strahlentherapie
Ismaninger Straße 22, 81675 München

Supervisor
Dr. med. sci. Julius Clemens Fischer (P11)

Description

Colorectal cancer (CRC) is the third most common cancer type diagnosed worldwide and top four leading cause of cancer death. Current treatment options of CRC are preoperative therapy including radiation therapy (RT) and chemotherapy, followed by surgery. Within this treatment, RT plays a great role in tumor downstaging before surgery. However, therapeutic efficiency varies substantially between patients and treatment-related toxicity is a major problem. Knowledge based on clinical studies hints towards a role of the intestinal microbiota in influencing response rates and side effects after RT. Previous research in the project P11 identified distinct microbiota compositions in different subtypes of intestinal cancer, as well as microbiota changes during cancer development. However, until now the impact of certain differences in microbial compositions and microbial metabolites on the efficiency of RT is still not known.

In my PhD project, the main goal is to investigate and identify specific microbiota compositions and microbial metabolites that have an impact on the response rates of CRC cells towards RT. To assess the specific effect of different bacterial metabolites on radiosensitivity, murine and human organoids will be treated with selected bacterial metabolites and then irradiated. Additionally, the results generated by these in vitro experiments will be applied in vivo to mice with orthotopically transplanted organoids. Within this PhD project, we aim to find new insights and define microbiota signatures that can serve as a prognostic marker to assess the efficacy of preoperative therapy.

Defining intestinal microbiota orchestrating immune tolerance to intervene with allergic reactions to food and beyond

Technical University of Munich
Klinikum rechts der Isar
Department of Dermatology and Allergology

Supervisor
Prof. Dr. med. Tilo Biedermann (P06)
 

Description

The human gut microbiota plays a critical role in many physiological processes, such as digestion, metabolism, and immune system regulation. Different studies have shown that an imbalance in the gut microbiota is associated with different disorders and diseases, including inflammatory bowel disease, obesity, and allergy. Gut microbiota also plays a significant role in the regulation of immune tolerance. For individuals suffering from allergies a decrease in intestinal bacteria diversity was observed. On the other hand, the beneficial effect of certain bacteria species was detected in groups of healthy donors.
The objective of our study is to examine the microbial composition and mechanisms involved in mitigating allergic reactions in individuals with α-galactose-α-1-3-galactose (α-Gal) allergy. This particular type of allergy can arise in organisms with a non-functional variant of the a-1,3-galactosyltransferase 1 (GGTA1) gene. Humans and old-world monkeys harbor a frameshift mutation in this gene, making them susceptible to sensitization with α-Gal. For our study, we use GGTA1 knockout mice sensitized with α-Gal as a model of allergy to α-Gal. The primary aim is to identify microbiota compositions influencing tolerance to alpha-gal, with the final aim to generate “bacterial-based therapeutics” which will then be tested as therapy or treatment option for food allergy (alpha-gal and OVA) and other allergic skin inflammations such as AD.

T cell skewing in relation to intestinal dysbiosis and graft-versus-host disease in allogeneic stem cell transplantation

Technical University of Munich
TUM School of Medicine
Institute for Medical Microbiology,
Immunology and Hygiene
Trogerstr. 30, 81675 Munich

Supervisor
Prof. Dr. med. Dirk Busch (P04)

Description

Graft-versus-host disease (GvHD) is still the main cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT). Clinically, it affects skin, liver and gastrointestinal (GI) tract, but GI manifestations drive to a large extent aHSCT-related mortality. Antibiotic treatment and damage of Paneth cells by GvHD cause severe dysbiosis in the intestinal microbiota, which associates with increased incidence of GvHD and GvHD-related mortality. A central hypothesis of our clinical tandem is that microbiome-derived antigens and/or their metabolites affect donor T cell activation and skew the reconstitution of an immunoregulatory immune response in the gut. In this project, we take advantage of a globally unique aHSCT patient biosample collection to study the relationship between the intestinal microbiome, mucosal lymphocyte populations and T cell receptor (TCR) diversity in patients with or without GvHD and upon therapeutic interventions such as antibiotic treatment and fecal microbiota transplantation (FMT).

In the last funding period, we established ChipCytometry analysis and a scRNA sequencing pipeline for gastrointestinal biopsies of GvHD patients. We are now able to effectively use these techniques for further in-depth analyses of immune infiltrates in tissue samples. One of our key findings of the first funding phase was that we discovered clonally expanded CD8 T cells in GvHD, indicating a potential new hallmark in the understanding of GvHD pathophysiology. In the next funding phase, we aim at characterizing the antigens that are recognized by T cell receptors associated with GvHD, especially of the clonally expanded T cells. Expanding upon this, we want to evaluate the effect of microbiome modulation by FMT and antibiotic treatment on immune infiltrates and the role of tissue associated microbiota in GvHD and FMT.

Impact of Desulfovibrio spp. and sulfur metabolism on the pathogenesis of chronic intestinal inflammation and colitis-associated cancer

Technische Universität München
School of Life Sciences Weihenstephan
Chair of Nutrition and Immunology
ZIEL - Institute for Food & Health
Gregor-Mendel-Str. 2, 85354 Freising

Supervisor
Prof. Dr. Dirk Haller (P18)

Description

Inflammatory bowel diseases (IBD) are becoming more common and are also associated with an increased risk of developing colorectal cancer (CRC). Several studies show that members of the Desulfovibrionaceae family, particularly Desulfovibrio species, are increased in patients with IBD and CRC. They are among the sulfate-reducing bacteria in the human digestive tract and are capable of converting inorganic sulfates to hydrogen sulfide (H2S) by anaerobic respiration. Increased sulfur metabolism is associated with active disease flares and relapse of IBD. At physiological concentrations, H2S is an important signal mediator and substrate for energy production in cells. However, at elevated concentrations, it is genotoxic, causes severe cell stress, and impairs normal cell function. This project aims to increase the understanding of Desulfovibrio and its metabolism in the context of IBD and CRC. Desulfovibrio isolates will be characterized by their substrate utilization for growth and metabolic changes in in vitro cultures. In addition, the effect of diet on these bacteria will be tested in a more complex environment in a fermenter system. In vivo experiments will provide further insight into the effect of dietary substrates and the depletion and enrichment of Desulfovibrio in the context of inflammation and tumor development.