25 examples of research with impact: Unravelling the secrets of microbiomes

“Microbiomes are central to human health as changes to the human microbiome are linked to a panoply of human diseases ranging from cancer to neurodegeneration. Microbiomes represent key systems of study as they directly link sustainability to ecosystem, environmental, and human health with the important potential for developing novel solutions for a sustainable and healthy future. Once we know how to rationally control microbiomes, they can be harnessed for new solutions including novel bioprocesses for energy production, the synthesis of sustainable materials, drugs or dietary regimens. ”

Prof Dr Paul Wilmes Systems Ecology Group at the University of Luxembourg’s Luxembourg Centre for Systems Biomedicine and the Department of Life Sceinces and Medicine within the Faculty of Science, Technology and Medicine.

Paul Wilmes returned to his native country Luxembourg in 2010 from the University of Berkeley, thanks to an FNR ATTRACT Fellowship, which offers 5 years of funding up to 2 MEUR for promising young researchers to establish a research group in the country. Next to grants from various FNR funding instruments in the years that have followed, Wilmes also secured an ongoing ERC Consolidator Grant alongside funding from other European and international funding bodies.

Advances enabling deeper study of microbiomes

Over the past two decades, major advancements have taken place in the field of molecular microbial ecology, thanks to interdisciplinary approaches.

“Through the advent of molecular methods, we were for the first time able to probe deeply into the structure and function of complex microbial communities ranging from environmental to host-associated microbiota. This allowed us to study microbiomes without the need for traditional culturing techniques. This represented an essential paradigm shift as culture-based methods introduce important biases and lead to non-representative pictures of microbial diversity and function.”

The application of high-throughput DNA sequencing to microbiomes, also referred to as metagenomics, has revolutionised our understanding of the extent of microbial genomic diversity, especially in relation to the overall Tree of Life. This approach also paved the way for important discoveries such the use of CRISPR-Cas9 for gene editing, the subject of the 2020 Nobel Prize in Chemistry, a more complete understanding of biogeochemical cycles, and even the first genome sequence of SARS-CoV-2 through metatranscriptomics.

“Thanks to a growing appreciation for the critical role of microbes in ecosystems coupled to technological advancements, the field of molecular microbial ecology has significantly evolved in the last two decades. Our research group and many others continue to explore novel approaches to unravel the complexities of microbial communities and their impact on environmental sustainability and human health. ”

Prof Dr Paul Wilmes Systems Ecology Group at the University of Luxembourg’s Luxembourg Centre for Systems Biomedicine and the Department of Life Sceinces and Medicine within the Faculty of Science, Technology and Medicine.

Pioneering tools for molecular measurements over space and time

When first establishing the lab in the context of the ATTRACT programme, Wilmes’ research group pioneered wet- and dry-lab tools that enabled systematic molecular measurements of microbial consortia over space and time.

“The tools have allowed my group, in collaboration with others, to define the lifestyles of distinct microbial populations in the environment and to link these to their genetic and functional traits. Most recently, it has allowed us to predict the dynamics of microbiomes to a surprisingly high degree of determination. Such forecasting models will inform control strategies for microbial ecosystems which, in turn, will lead to new problem-directed applications for sustainable management practices such as integrated water reclamation and resource recovery from wastewater streams.”

Using this methodology to study the human gut microbiome in diseases like Parkinson’s disease showed that the functions of the gut microbes are disrupted even if the overall structure of the microbiome appears the same. It also showed that when a child is born by vaginal birth, important immune system-stimulating bacteria pass from the mother to the baby, which could explain why babies delivered by caesarean are more prone to diseases linked to the immune system.

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“The observation that overall microbiome-based functional differences are critical in the context of gut microbiome-linked, chronic diseases represents an essential paradigm shift in Biology and Medicine. These kinds of functional shifts may be triggered by factors which impact the gut microbiome, such as exposure to microorganisms or an unhealthy diet, which in turn may provide the ecological context for the development of diseases. ”

Prof Dr Paul Wilmes Systems Ecology Group at the University of Luxembourg’s Luxembourg Centre for Systems Biomedicine and the Department of Life Sceinces and Medicine within the Faculty of Science, Technology and Medicine.

HuMiX and microGut: Organs-on-a-chip

Looking at the microbiome with a new software tool which the group has developed (PathoFact) revealed that certain genetic elements play particular roles in, for example, bacteria becoming resistant to antibiotics. This tool also helped show an increased infective competence in COVID-19. In order to better understand the human impacts of functional shifts in microbiomes, Wilmes’ group pioneered an “organ-on-a-chip” gut model called HuMiX alongside the expanded microGut system.

“HuMiX allows the co-culture of microbial and human cells under biomimetic conditions. It provides a platform for microbiome-focused mode of action studies against specific human disease backgrounds. It also allows for the in vitro study of essential characteristics which impact human health and disease such as the impact of diet and exposure to drugs on human physiology.”

“Our future research agenda will focus on understanding the molecules and molecular pathways by which the microbiome may trigger or exacerbate disease processes. This knowledge is essential for laying the foundation for establishing the microbiome as a therapeutic and preventative target. Once we have identified critical molecules and pathways, key research will be directed at how we might be able to steer microbiomes back to a balanced, healthy state. ”

Prof Dr Paul Wilmes Systems Ecology Group at the University of Luxembourg’s Luxembourg Centre for Systems Biomedicine and the Department of Life Sceinces and Medicine within the Faculty of Science, Technology and Medicine.

Microbiome imbalances: Cause or effect of disease?

Microbiomes still hold much to be uncovered: In the context of the human microbiome, the major unanswered question is whether disease-linked microbiome shifts are a cause or an effect of disease. Researchers have established that there are imbalances in the microbiome in patients with, for example, cancer or neurodegenerative diseases, such as Parkinson’s Disease, but it remains to be determined whether these disturbances happen because of the disease, or if they could be a consequence of the disease occurring in the first place.

“All the findings highlighted here resulted from FNR-supported research projects. Four of our papers on the human microbiome were listed as milestones in the field by the journal Nature in 2019. It is fabulous to get such independent recognition for one’s own work and impact on a field of research. ”

Prof Dr Paul Wilmes Systems Ecology Group at the University of Luxembourg’s Luxembourg Centre for Systems Biomedicine and the Department of Life Sceinces and Medicine within the Faculty of Science, Technology and Medicine.

In terms of microbiomes that underpin environmental systems, which are at the heart of sustainable resource management and a circular economy, Wilmes explains that rational control strategies will also have to be developed.

“We aim to unravel causal relationships and the linked mechanisms driving interactions within microbiomes and with their environment. Our field will evolve from being largely descriptive to proposing and implementing tangible solutions for human health and environmental sustainability. Through our wet- and dry-lab methodologies, including machine learning and AI, we aim to continue to play key roles in this exciting research and development field.”

Publications related to this article

Pioneering metaproteomics: Wilmes & Bond, 2004, Environ Microbiol 6:911-20

Wet & dry lab tools:

• ISME J 2013, ISME Comm 2021a, Genome Biol 2016, Microbiome 2021
• Nat Comm 2014, ISME J 2015, Nat Comm 2020, Nat Microbiol 2021
• Nat Ecol Evol 2024
• Mov Disord 2017
• Nat Microbiol 2017, Microbiome 2022
• Front Microbiol 2017, Nat Comm 2018, ISME Comm 2021
• Trends Microbiol 2018, Cell Host Microbe 2022a,b
• Cell 2016, eLife 2019, Cell Rep 2023

New software tool:

• PathoFact; Microbiome 2021
• ISME Comm 2021a, Nat Comm 2022, eLife 2022
• Microbiome 2023 (Infective competence in COVID-19)

HuMiX:

• HuMiX; Nat Comm 2016
• Cell Rep 2019; Nat Metab 2022
• Adv Healthc Mater 2024