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An international research team has provided valuable new information about what drives the global spread of genes responsible for antimicrobial resistance (AMR) in bacteria. The collaborative study, led by researchers at the Quadram Institute and the University of East Anglia, brought together experts from France, Canada, Germany and the UK and will provide new information to combat the global challenge of AMR. [caption id="attachment_27431" align="alignright" width="300"] E. coli. Image by Raphaelle Palau, the Quadram Institute[/caption] By examining the whole genome sequences of around two thousand resistant bacteria, predominantly Escherichia coli collected between 2008 and 2016, the team found that different types of AMR genes varied in their temporal dynamics. For example, some were initially found in North America and spread to Europe, while for others the spread was from Europe to North America. Not only did the study look at bacteria from different geographic regions but also from diverse hosts including humans, animals, food (meat) and the environment (wastewater), to define how these separate but interconnected factors influenced the development and spread of AMR. Understanding this interconnectivity embodies the One Health approach and is vital for understanding transmission dynamics and the mechanisms by which resistance genes are transmitted. The study, published in the journal Nature Communications, was supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), a global collaboration spanning 29 countries and the European Commission that is tasked with turning the tide on AMR. Without concerted efforts on a global scale, AMR will undoubtedly make millions more people vulnerable to infections from bacteria and other microorganisms that can currently be tackled with antimicrobials. The team focussed on resistance to one particularly important group of antimicrobials, the Extended-Spectrum Cephalosporins (ESCs). These antimicrobials have been classed as critically important by the World Health Organization because they are a ‘last resort’ treatment for multidrug resistant bacteria; despite this, since their introduction, efficacy has declined as bacteria have developed resistance. Bacteria that are resistant to ESCs achieve this through the production of specific enzymes, called beta-lactamases, that are able to inactivate ESCs. The instructions for making these enzymes are encoded in genes, particularly two key types of genes: extended-spectrum beta-lactamases (ESBLs), and AmpC beta-lactamases (AmpCs). These genes may be found on the chromosomes of bacteria where they are passed to progeny during clonal multiplication, or in plasmids, which are small DNA molecules separate to the bacterium’s main chromosome. Plasmids are mobile and can move directly between individual bacteria representing an alternative way of exchanging genetic material. This study identified how some resistance genes proliferated through clonal expansion of particularly successful bacterial subtypes while others were transferred directly on epidemic plasmids across different hosts and countries. Understanding the flow of genetic information within and between bacterial populations is key to understanding AMR transmission and the global spread of antimicrobial resistance. This knowledge will contribute to the design of vitally needed interventions that can halt AMR in the real world where bacteria from diverse hosts and environmental niches interact, and where international travel and trade mean that these interactions are not limited by geography. Professor Alison Mather, group leader at the Quadram Institute and the University of East Anglia, said: “By assembling such a large and diverse collection of genomes, we were able to identify the key genes conferring resistance to these critically important drugs. We were also able to show that the majority of resistance to extended spectrum cephalosporins is spread by only a limited number of predominant plasmids and bacterial lineages; understanding the mechanisms of transmission is key to the design of interventions to reduce the spread of AMR”. Lead author Dr Roxana Zamudio said “Antimicrobial resistance is a global problem, and it is only by working collaboratively with partners in multiple countries that we can get a holistic understanding of where and how AMR is spreading”. Read Roxana's Nature Community Blog about why international collaboration is crucial for tracking antimicrobial resistance   Reference: Dynamics of extended-spectrum cephalosporin resistance genes in Escherichia coli from Europe and North America. Roxana Zamudio, Patrick Boerlin, Racha Beyrouthy, Jean-Yves Madec, Stefan Schwarz, Michael R. Mulvey, George G. Zhanel, Ashley Cormier, Gabhan Chalmers, Richard Bonnet, Marisa Haenni, Inga Eichhorn, Heike Kaspar, Raquel Garcia-Fierro, James L. N. Wood, Alison E. Mather. Nature Communications DOI: 10.1038/s41467-022-34970-7 This project was supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), through the Medical Research Council (MRC, MR/R000948/1), the Canadian Institutes of Health Research (CFC-150770), and the Genomics Research and Development Initiative (Government of Canada), the German Federal Ministry of Education and Research (BMBF) grant no. 01KI1709, the French Agency for food environmental and occupational health & safety (Anses), and the French National Reference Center (CNR) for antimicrobial resistance. Support was also provided by the Biotechnology and Biological Sciences Research Council (BBSRC) through the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent project BBS/E/F/000PR10348 (Theme 1, Epidemiology and Evolution of Pathogens in the Food Chain)

Dr Matthew Gilmour and Dr Evelien Adriaenssens from the Quadram Institute in Norwich, UK, have each been granted prestigious partnership awards to collaborate with researchers in Canada. The UK’s Biotechnology and Biological Sciences Research Council (BBSRC) funded awards will involve a variety of activities over the duration, including seminars, workshops, and exchange visits. The BBSRC Canada Partnering Awards are four-year awards to a maximum of £50,000 over the course of the project. The partnering awards encourage the long-term collaboration of scientists internationally, sharing skills and experiences across disciplines to strengthen the scientific approaches to the respective control of infectious diseases in the UK and partner countries. Dr Gilmour’s partnership will focus on the advancement of genomic tools to study the foodborne transmission of Listeria monocytogenes, the cause of the foodborne infection, listeriosis. Partnering with the Public Health Agency of Canada’s National Microbiology Laboratory and Health Canada’s Food Directorate, the collaboration will enable the exchange of ideas and approaches towards Listeria and facilitate the development of bioinformatic tools to study key genetic elements of Listeria, which will help to contribute improved evidence during food safety interventions. This will include focusing on genetic traits responsible for antibiotic and biocide resistance, and the formation of biofilms, which play an important role in the pathogen’s ability to grow and survive in food processing facilities and ultimately cause human illness. Dr Gilmour’s research group works to understand the microbial traits that contribute to the significant risk posed by Listeria. Dr Gilmour said: “The people in this collaboration have already done much work to bring genomic technologies into the mainstream to investigate foodborne illnesses, including listeriosis. We have recognised that there are still many gaps in our understanding of how Listeria survives and then spills into the food chain. Between our coalition of Canadian and UK experts, we are very excited to work together to further advance our toolset and improve our investigation into the reasons for these continued illnesses.” “Early detection of Listeria in the food chain is crucial, as it helps reduce the frequency of food-borne illness outbreaks. Health Canada is proud to have our very own Dr Pagotto partner with Dr. Gilmour and the National Microbiology Laboratory to advance food safety research and improve outbreak response,  said Dr Martin Duplessis, Director of the Bureau of Microbial Hazards at Health Canada’s Food Directorate. Because the Bureau of Microbial Hazards works to minimize public health risks from the consumption of foods contaminated by bacterial, parasitic, viral, and prion-disease agents, this is a great opportunity to collaborate with national and international partners.” Dr Adriaenssens’ partnership is with Agriculture and Agri-Food Canada (AAFC), a department of the Canadian government concerned with farm and agri-based products, to focus on a one health approach to understanding and using bacteriophages in the control of enteric pathogens and their effects on the gut microbiome. The award will facilitate the exchanging knowledge and expertise on the food chain application of bacteriophages, their genomic diversity, bioinformatics and the gut microbiome. Dr Adriaenssens’ and her research group at the Quadram Institute study the role of bacteriophages in gut health and disease. Dr Adriaenssens said: “I am very excited to start this collaboration with Dr Hany Anany at AAFC which will allow us to increase our knowledge on bacteriophages in that crucial interface between food applications and the human microbiome, supported by excellence in bioinformatics through our Co-Investigator Dr Andrea Telatin. We predict that bacteriophages will be important players in the future fight against antimicrobial resistance, both in the food chain and in human therapies.” Dr Hany Anany, research scientist at the Guelph Research and Development Centre, AAFC, said: “I am thrilled to be part of the Canada Partnering Award and work with Drs Adriaenssens and Telatin in this interesting research project. The outstanding experience of our UK partners in bacteriophage biology and viromics will definitely help us to have a better understanding of the enormous diversity of bacteriophages throughout the food supply chain and their host interaction. This will lead to the development of novel phage-based approaches to control and detect foodborne bacterial pathogens to enhance food safety."  

“Our gut is populated with trillions of microbes, collectively known as the gut microbiota. In a healthy state our body helps to regulate the gut microbiota. We often see the response in our bodies to gut microbiota, but we don’t fully know what is interacting on the cell surface level. Innate immunity is the first defending barrier between us and microbes, from cell to cell. It intrigues me. I'm interested in understanding the mechanism of how gut microbiota interact with a protein superfamily that is found in our bodies’ immune cells. Are lectins a link between our immune system and gut microbiota? The proteins I’m interested in are called lectins. Some lectins are found on the surface of important immune cells in our body. Lectins is a broad term that describes proteins that can bind to sugars. We know that lectins on our immune are linked to either increasing or reducing inflammation. We also know that gut microbes are coated in sugars. My hypothesis is that some lectins stop inflammation getting out of control in our body, and certain gut microbiota coated in specific sugars interact with these lectins to maintain a healthy state. The specific lectins I’m interested in are called Siglecs (Sialic acid-binding immunoglobulin-like lectins) and are found mostly on immune system cells. Siglecs are known to inhibit inflammation. A few researchers have looked at how disease-causing microbes interact with Siglecs. But nobody has looked at how Siglecs interact with friendly microbes. I am hoping to identify novel interactions and something new about how our immune system is regulated in a healthy state. I hope that by understanding how a healthy microbiota is maintained it will help develop therapeutics to prevent a disease state. A career in science from cancer microbiology to flow cytometry I’m very curious. The unknown has always intrigued me and I was drawn to science. I joined the Institute of Food Research, the predecessor to the Quadram Institute, for my PhD where I studied lectins and microbiota in cancer progression'. I started by screening the interaction of cancer associated bacteria with a wide range of cancer inducing proteins. Through these experiments I found that Siglecs bind to colon cancer associated bacteria called Fusobacterium. After my PhD, I went to the University of Alberta in Edmonton in Canada to join researchers also working on Siglecs. Their research focused on the role of Siglecs in the immune system. There are fifteen Siglecs and they coat different immune cells. In Edmonton I learnt more about their host interactions inside the human body. I liked Siglec biology even more. After my postdoctoral position in Canada, I returned to the UK and joined the Quadram Institute. I joined to work as the manager of the Flow Cytometry facility. Flow cytometry allows us to analyse and sort single cells based on their size and characteristics. Currently, I am also working on a Bowel Cancer UK funded project to identify Siglecs and antibodies in the blood that are linked to microbes associated with colorectal cancer. The idea is that we might be able to identify markers in the blood for colon cancer. The hope is that if you have the blood and faecal (FIT) sample data, you can reduce the number of false positives so less people have an invasive colonoscopy unnecessarily. Studying lectins in a healthy gut microbiome In my fellowship I’m linking together lots of areas that I know and have experience of, on a project that will hopefully be helpful and insightful. First, I’m going to isolate the microbial cells from colon tissue and faecal samples. We have cell lines where we express just the Siglec protein, so we have the Siglec protein itself. We can then tag the Siglec, and incubate with tissue microbiota to see which interact. It’s nice in my fellowship, because I’ve kept collaboration with researchers from the University of Alberta. Through BBSRC’s International Partnership funding I have been to Canada to learn more techniques on how to knock down the Siglec on the immune cells. The idea is that in the model I’ll have the cells that express Siglec but also the knocked down cells that don’t, so I will have a negative control. Using my expertise of flow cytometry, I will have the microbiota and the Siglecs and put them together. Using the facility I will identify the microbiota that bind to Siglecs because we can sort them in the machine. Then using the sequencing facility here at the Quadram Institute I will characterise the specific bacteria, so I can find the signature of a healthy gut and which microbes interact with Siglecs. I’ll be looking at fungi and viruses too, as well as bacteria, to learn about the whole microbial community. That could involve other expertise here at the Quadram Institute with other researchers who focus on viruses and bacteriophages. At the moment, we know very little about how viruses and fungi interact with Siglecs. Through my fellowship I hope to explore in more depth the mechanism of how Siglecs and microbes interact. I’m going to use the gut-on-chip models we have at the Quadram Institute. The gut on chip technology can simulate the conditions inside the human body. I hope to identify immune responses to understand better the mechanism of how Siglecs and microbes interact. I’m so excited to understand the first interaction between gut microbiota cells and human cells. Although my fellowship is focused on the healthy state, down the line it could help us understand cancer and other disease states too."

Recently a group of our nutritionists, scientists and technology transfer staff from the Quadram Institute visited the United States to share knowledge and build collaborations with global nutrition experts. Here our Research Scientist Dr Liangzi Zhang explains more. “International collaboration is important to improve health through nutrition. In March 2023, I joined Dr Maria Traka, deputy Head of our Food & Nutrition National Bioscience Research Infrastructure (F&N NBRI) together with Professor Martin Warren’s group in a visit to the US to attend the 2023 “UC Davis/Quadram Collaboration on Biofortification, B12, and More: from Nutrition to Food Biotechnology". Biofortification describes the process of improving the nutrition of plant-based foods. The two-day conference focused on biofortification was held at University of California, Davis campus and brought us together with researchers, clinicians and nutritionists from UC Davis as well as a small number of companies and investors together with and the Innovation Institute for Food & Health at the University of California. Public and planetary health The first day of the conference focused on health, nutrition and biofortification. We learnt about the concept of Personalised Public Health from Professor Sean Adams, Vice Chair for Basic Research at UC Davis. This concept is tailoring public health interventions to the individual characteristics and needs of a person, including their unique genetic, environmental and lifestyle factors. Professor Adams explained this concept by focussing on the variation in human physiological responses to food. Then Dr Maria Traka and I gave a talk on how we provide and update data and knowledge on food composition and intake in the UK, to deliver nutritional policy and high-quality science through the F&N NBRI based here at the Quadram Institute. Vitamin B12 In our talk, Maria and I explored the balance between human and planetary health, using the example of our research into vitamin B12 in milk. Vitamin B12 is an essential micronutrient important for our health. It’s a topic that researchers in Professor Martin Warren’s group study too. At the F&N-NBRI and together with the Warren group we have conducted research projects on the nutritional quality of plant-based food products and British cow milk. Milk is currently the main source of vitamin B12 for the UK population. We found that the levels of vitamin B12 in cow milk are lower than 20 years ago and the population intake of B12 is even more concerning as more people switch to plant-based, which can lack vitamin B12. This conference provided an ideal platform to share our findings with the vitamin B12 community and forge connections with food science experts, technology transfer experts, interested companies and investors. The day also included presentations on vitamin B12 and neurological complications by experts from the University of California, San Francisco, and vitamin B12 as a health barometer and microbial modulator from UC Berkeley. We ended the first day with a collective discussion about the need for vitamin B12 fortification and current ways we can increase vitamin B12 in foods through biofortification. [caption id="attachment_28966" align="alignright" width="300"] Researchers from the Warren Group, F&N NBRI and Business Development team at the Biofortification Collaboration meeting[/caption] Innovation and Technology On the second day, the discussions centered around the potential of new technology and data science in understanding food, nutrition, and the environment. Dr Danielle LeMay from USDA ARS Western Health and Nutrition Research Center explored the significant advancements that Artificial Intelligence (AI) can bring to the field of food and nutrition research. She highlighted how AI can facilitate precise and data-driven approaches in understanding the intricate relationships between diet, health, and diseases. We learnt about a new initiative called “the Periodic Table of Food”. The initiative aims to create a worldwide system that offers tools, data, and training to catalogue the biomolecular composition of the global food supply. Dr Mariana Barboza and Professor Bruce German from UC Davis explained how such a comprehensive database could transform the agriculture, food, and health industries. Insight from industry The conference was not only a platform for research presentations but also an opportunity for industry partners like Meati and TurtleTree to share their visions on commercialising new plant-based products developed from precision fermentation technology. Following the conference, we took part in honey tasting event organized by Amina Harris, Ph.D., Director of Honey and Pollination Center. This event provided a unique sensory experience, allowing us to fully immerse ourselves in the aroma, flavor, texture, and color of three beautiful local honeys. The conference was a resounding success, featuring a range of discussion not only on the topic of biofortification and vitamin B12, but also broader conversations surrounding technology, food systems, and the health of both people and the planet. Forging future collaborations For us in the UK’s Food and Nutritional National Bioscience Research Infrastructure (F&N NBRI) team, the conference allowed us to establish ties with the FoodData Central (FDC), the USDA's online integrated food and nutrient data system. We visited the FDC in person, in Beltsville Human Nutrition Research Center, Maryland where we had two days of discussions and saw their Human Studies Facility too. Together, we discussed the research and methodology development of analysing components within food, including plant bioactives. During our visit we were struck by the differences in research focus between FDC in the US and F&N-NBRI here in the UK. The FDC places a greater emphasis on fundamental research, given their abundant resources and expertise. In contrast, our team at F&N-NBRI is more focused on adapting our data for practical use and exploring its interdisciplinary applications beyond nutritional information. With these divergent approaches, we found the opportunity to share ideas and learn from each other extremely valuable. We were able to identify common interests and explore potential areas for collaboration that could benefit both our organisations.”

“Clostridium perfringens is a bacterium that can be found in the intestinal tract of humans and animals, in soil and in poorly prepared food. This bacterium can cause food poisoning, intestinal necrosis and tissue disease in humans and animals. We are interested in this bacterium because it can affect the most vulnerable people. I am from a rural community in the Boyacá region of Colombia, in South America. When I was a child, I always dreamed of becoming a doctor. The possibility of becoming a doctor seemed slim because my family did not have the money to pay for training. But my dream came true when I received a scholarship from the Universidad de Boyacá for being an outstanding student. With this scholarship, I studied medicine for six years. Then I spent a year as a doctor working in rural areas, which is part of medical training in Colombia. In Colombia there are some places, especially in rural areas of Boyacá, where there is a lot of poverty. There is a lack of access to drinking water, refrigerators and sanitation measures. These places have higher rates of transmission of microbes such as C. perfringens and it is the elderly and children who are most at risk of getting sick. This is why I want to learn more about the biology of this bacterium, how to prevent it and share the knowledge with my community. One day, while working as a doctor in these rural areas, the Universidad de Boyacá contacted me to offer me an opportunity to do a PhD at the Centro de Investigaciones en Microbiología y Biotecnología de la Universidad del Rosario (CIMBIUR) under the direction of Dr. Marina Muñoz Diaz and Dr. Juan David Ramírez. I accepted and it was then that I started my research on C. perfringens. A One Health approach to studying Clostridium perfringens I am the principal investigator of a project that focuses on the identification and characterisation of circulating C. perfringens in humans, animals and food in the Colombian Cundiboyacense Altiplano area. I believe that the whole ecosystem is important in the transmission of infectious diseases. If you study humans, animals, and the environment together, you can learn more about how to prevent disease. My parents are teachers in rural schools. They teach about life and nature. They taught me that all life is connected and that the best way to help is to educate. I think my project is inspired by that and uses a unique approach to health. My father also loves my research and has helped me collect samples with his students, who will also be great scientists one day. When we visit rural communities there is a lot of poverty, animals drink water from the same places as humans, people cannot refrigerate their food, floors are dirty, and there are other conditions that can help the bacteria spread. Together with other researchers from my university in Colombia, we take microscopes, leaflets and videos to farms to teach about bacteria. During these visits we take samples of human and animal faeces and food to learn more about how bacteria spread between organisms. We have collected around 700 samples from healthy humans, patients with gastrointestinal symptoms, animals and food in various municipalities in Boyacá. Building bioscience skills When I started my PhD, I read a lot of papers on C. perfringens and came across research from Professor Lindsay Hall's group based at the Quadram Institute. They study bacteria in babies and I found that fascinating. I told my supervisor Marina that my dream was to visit the Quadram Institute. The possibility seemed very low because we did not know anyone and coming to England from Colombia is very expensive. But through a shared contact from Marina, my research was mentioned to Lindsay Hall and they talked about the possibility of me coming to the Quadram Institute. Lindsay is wonderful and she accepted my academic visit and thanks to the support of the University of Boyacá, my group CIMBIUR, the Universidad del Rosario and the Ministry of Sciences of Colombia - Minciencias; I got a scholarship to come here to the Quadram Institute to the Lindsay Hall group. I am working with Dr. Raymond Kiu in the Hall group to learn bioinformatics skills on how to analyse C. perfringens genomic data. They have taught me many tools to analyse DNA sequences. In the lab I am also learning about the colon model. I love the colon model! I joined the Quadram Institute in January. The cold weather was a shock, but it was fascinating to see a snowy day in Norwich! I think the Quadram Institute is a great institute, the research here is excellent, the building is wonderful, and the people are friendly. Communicating with communities in Colombia Thanks to funding from Minciencias and partner universities, we visit farms, hospitals and rural schools in Boyacá and teach children and adults to wash their hands and handle food. We take the children to visit the laboratories of the University of Boyacá and use microscopes to see the bacteria. We have made videos about our research and also share them through social media. Together with the children, we have made radio programmes to further spread the message. Radio is an important way to communicate our research because it is one of the main ways that people in rural communities in Colombia obtain information. When I return to Colombia, I will visit hospitals and visit universities to share the results of this research. In the future, after my PhD I would like to continue this and other research in my country. I am interested in the intestinal microbiota and those associated with bacterial infections. When I finish my doctorate, I will also continue teaching at the University of Boyacá on topics such as infectious diseases and medicine. I am interested in the intestinal microbiota and those associated with bacterial infections. I want to continue to seek funding to reach out to communities and teach underprivileged children and youth that they too can become great scientists. We are the size of our dreams. I love my research because through science I can help people and I have the opportunity to study, travel, get to know different cultures and grow not only as a scientist but as a person. I have not done this alone, all thanks to the support from my family, my teachers and my colleagues who have taught me that the sky is the limit. I think this quote from Isaac Newton sums up our research: "If I have been able to see beyond, it has been because I have stood on the shoulders of giants”."