Alternatives to Antimicrobials: Implications for the Food Chain

As a PhD student and early postdoc working on the intestinal microbiota in the mid to late 1990s, I attended two Rank Prize conferences. These were focused on human nutrition, which had substantial links to my research. I fondly remember spending time in the Lake District with colleagues and making new acquaintances. One of the key positives for me at the time was the multidisciplinary nature of the meetings, which allowed me, as a microbiologist, to engage in discussions with health economists and nutritionists, and to better understand specialist areas outside of my own field.

Fast forward 25 years or so, and I was pleased to be invited to serve on the organizing committee for a Rank Prize Nutrition symposium that was themed to consider alternatives to antimicrobials. The nutrition-based focus of the Rank Prize meetings was still apparent in that the main goal of the meeting was to include the implications of the food chain.

Antimicrobial resistance is now widely recognised as one of the greatest challenges facing humankind but unfortunately, many people take the effectiveness of antibiotics for granted. This is evidenced by the pressure that is put on GPs to prescribe these drugs. Patients are often concerned about the personal side effects of medicines yet may be less aware of the broader implications of antibiotic use and misuse. In this context, the Rank Prize committee called upon us to put together a meeting to explore the link between food and the food chain and alternatives to antimicrobials. This presented an opportunity to bring together several groups of scientists from diverse fields, including intestinal microbiologists, cell biologists, evolutionary biologists focusing on microbial evolution, and environmental microbiologists.

After several pandemic-related delays, the Alternatives to Antimicrobial Implications for the Food Chain symposium commenced on June 6, 2022, at the Wordsworth Hotel in Grasmere, Cumbria, the same location as the meetings I attended all those years ago. The event was organized by four Professors from different universities: Glenn Gibson from the University of Reading, John Mathers from Newcastle University, Anne-Marie Minihane from the University of East Anglia, and me (from the University of Manchester).

The first day of the symposium began with the traditional introductions and welcome remarks by Professor John Mathers. We gathered in the hotel bar in the evening for the opening session, providing an opportunity for attendees to meet in an informal setting with an icebreaker where everybody said something about themselves that the other attendees were unlikely to already know.
On Tuesday, June 7th, the main symposium began with a series of presentations and discussions focused on factors influencing the global burden of antimicrobial resistance and potential ways to reduce it. The day started with Session One, “Factors Influencing the Global Burden of Antibiotic Resistance”, chaired by Professor Glenn Gibson and Ms Katie Robbins. The first speaker, Professor Brendan Gilmore from Queen’s University Belfast, gave a presentation on how antibiotic therapy and the gut microbiome can influence resistance development, and how the delivery route of antibiotics can impact the gut microbiome. This topic is particularly important as even relatively minor changes, such as how the type of administration of an antibiotic drug, can potentially reduce the burden of resistance. Professor Gilmore’s presentation linked several aspects that were to be considered during this symposium. Next, in the morning session, Dr Katarzyna Mickiewicz from Newcastle University spoke about “L-form bacteria”, which are bacteria in which the cell wall has not formed, and how they may contribute to the development of antibiotic resistance. This is another important topic and not a well-trodden path in terms of the microbiology of AMR, but it is generating very interesting results with wide-ranging implications.

Ms Vicky Bennet from the University of Bath followed, defining the role of efflux in bacterial biofilm formation and antibiotic resistance. Efflux pumps have long been identified as potential mediators of AMR, particularly that which can be displayed in cross-resistance, where one type of antimicrobial may have resistance to a chemically unrelated agent. The way this happens is through pumps that are polygamous in terms of the compounds that they extrude from the microbial cell. It is also worth noting that efflux pumps apparently play a role in biofilm formation. Given that biofilms, which are communities of microbial cells growing on surfaces, have been associated with considerable tolerance towards antimicrobial compounds in the absence of any genetic adaptation, this was a particularly relevant presentation to the aim of the symposium.

The next session was titled “reducing antimicrobial resistance by manipulating relevant ecosystems” and was chaired by Professor Bob Rastall and Ms Vicki Bennett. The first speaker was Professor David Graham from Newcastle University. He gave a presentation on the transmission and spread of antimicrobial resistance across environments, discussing environmental factors that contribute to the spread of resistance and potential strategies for reducing transmission. This topic falls on what can be described as a One Health theme linking human animal and environmental health in a holistic manner. Ms Katie Robbins also from Newcastle University then presented on characterizing the sources and drivers of environmental resistance over UK landscapes she discussed how environmental factors such as agricultural-based management can contribute towards the spread of resistance. Dr Stephen Kelly from Queen’s University Belfast concluded the session with a presentation on hospital sinks as a reservoir of antimicrobial resistance and infection and discussed policy to reduce antibiotic use. I found this particularly interesting because one of my first tasks on moving to the University of Manchester in the late 1990s was to develop a laboratory model of domestic sink drain search environments that may be important sources of antimicrobial-resistant bacteria and genes, but they are relatively little studied.

The third session was titled “Potential for Manipulating the Gut Microbial Ecosystem to Produce Antimicrobial Resistance.” Of obvious relevance to both nutrition and human health, this session that I chaired with chaired Dr Carlos Gómez-Gallego. The first speaker, Ms. Briony Sayers from the University of Reading then presented on the topic of novel combinations of probiotics and polyphenols and their effects on gut and cognitive health in active military personnel. This served as an illustration of the progress in intestinal microbiology that has happened since the first Rank Prize meetings, I attended in the mid-1990s. Not only do we have a greater appreciation of the links between the large intestine or microbiota and many aspects of human health, including cognition, but we also now have methods that are actually capable of profiling the intestinal microbiota and other microbial communities with a reasonable level of accuracy. Such methods were not well enough developed back in the mid-90s. Next, Dr Innes Mora from the University of Leeds presented on modelling the effects of xenobiotics on gut health.

The day drew to a close with a refreshing walk around the lake, followed by dinner at the hotel’s outstanding restaurant. As the evening progressed, there was much enjoyable socialising, with scientists from different disciplines exchanging ideas and insights. These kinds of interactions are especially productive in small gatherings like this one, which provided an ideal setting for the cross-pollination of ideas. The meeting was perfectly sized, allowing attendees to connect with everyone who was presenting or involved, which can be more challenging at larger conferences. The intimate location, excellent staff and carefully selected topics made for a highly engaging and fruitful experience.

On the morning of Wednesday, June 8th, Session Four of the symposium began with the title “Potential for Manipulating the Gut Microbial Ecosystem to Reduce Resistance.” The session was chaired by Professor John Mathers and Dr Innes Miura. The first presentation was given by Professor Bob Rastall from the University of Reading on the topic of “Can Dietary Carbohydrates Reduce Infections?” Professor Rastall has been studying this area for several years with the aim of producing carbohydrates with functions that go beyond dietary fibre or prebiotic effects. His presentation was both interesting and informative, highlighting the many potential approaches to mitigating or reducing the need for antibiotics, which are the main driver of antibiotic resistance.

The next presentation was given by Carlos Gomez Gallego from the University of Eastern Finland, who discussed “Microbiota Modulation Strategies to Reduce Antibiotic Resistance.” His presentation covered a range of strategies, including probiotics and other bioactive compounds. This nicely complemented Professor Rastall’s presentation, illustrating the range of different approaches that have great potential in this area.

Dr Andrea Monteagudo-Mera from the University of Reading then presented her research on “Prebiotic Synergy 1: Mitigating Unfavourable Changes in the Gut Microbiota Caused by Iron Supplementation in Healthy Women.” Changes in the intestinal microbiota, referred to in the literature as dysbiosis, can have a number of implications, and in some cases, these changes may eventually require the use of antibiotics. Dr Monteagudo-Mera’s research explored different routes to achieving a healthier composition in the microbiota of the colon and how this could potentially mitigate the need for antibiotics.

Finally, Professor Roberto La Ragione from the University of Surrey discussed novel alternatives to antibiotics for use in the livestock industry and this again showed the interconnectedness of the different topics in this symposium which could also be considered as a One Health theme. We had heard about considered environmental ecosystems, hospital ecosystems human microbiome ecosystems and here we were looking at antibiotic use in the livestock industry.

Session five focused on novel approaches for managing microbial systems with Dr Mato Lagator from the University of Manchester discussing mechanistic approaches to studying resistance evolution. Dr Lagator is one of a group of evolutionary biologists based at the University of Manchester, who apply evolutionary biology theory to consider wider implications for microbial communities. This has great relevance to antibiotic resistance and again illustrates the strength of cross-disciplinary research.
Dr Thomas Thompson from Queen’s University Belfast then presented on the mechanism and evolution of antibiotic resistance in Archaea. This presentation crossed over very nicely between environmental microbiology and the microbiology of a different subset of microorganisms the Archaea and antibiotic resistance showing the strengths of looking beyond immediate and obvious themes.

Dr Rok Krašovec from the University of Manchester then talked about density-associated mutation rate plasticity and antibiotic resistance. This is a fascinating topic where the density of microbial populations has been found to be correlated to rates of resistance evolution and some of the effects that this group has observed appear to apply across all tested domains of life, so this is very fundamental research with direct applications in medical and clinical microbiology and antibiotic resistance.

Session six focused on novel approaches for managing microbial ecosystems. Mr Ahmad Aljohani, from the University of Manchester, presented on how a probiotic bacterium, Escherichia coli Nissle 1917, can inhibit biofilm formation and mitigate virulence without inhibiting planktonic growth. This approach, known as virulence mitigation, aims to downregulate the virulence of a pathogen and convert it into a harmless symbiont. This approach is less likely to select for resistance compared to conventional antibiotics, whose main aim is to stop growth or kill a microorganism. Professor Cath O’Neill, also from the University of Manchester discussed how Lactobacillus rhamnosus can inhibit Staphylococcus aureus adhesion to skin, while Doctor Cecile El Shami presented her research on how Lactobacillus rhamnosus lysate protects organ-cultured human skin from the damaging effects of Staphylococcus aureus. Both of these presentations demonstrated interesting methodological approaches including culturing human skin in the laboratory for many days as a model for interactions between microorganisms and the human host.

The next session focused on novel approaches to managing microbial systems. Dr Dana Gifford from the University of Manchester discussed evolutionary approaches to circumvent resistance, highlighting the application of evolutionary biology to solve the problem of antibiotic resistance. Dr Jai Mehat from the University of Surrey presented on the importance of vaccination in medicine as an alternative to antimicrobial therapy. Dr Bernhard Kepplinger from the University of Wroclaw, Poland presented on the discovery of the antibiotic polyketide, emphasising the need for discovering new antibiotics with novel modes of action. Finally, Dr Anthony Slate from the University of Bath discussed novel approaches to control bacterial biofilms in the catheterised urinary tract, highlighting the importance of considering the environment in the risk assessment of antibiotic resistance.

The day ended with a reception and a gala dinner, which was an extremely enjoyable event with great speeches, food and camaraderie.

On the symposium’s final day, session 8 titled “Future” was chaired by Dr Katarzyna Mickiewicz and Dr Andrea Monteagudo-Mera. The session began with a talk by Professor Mark Wilcox from the University of Leeds titled “A gut model that really works,” where he discussed the use of realistic gut models to identify new alternatives to antimicrobial therapy and highlighted the potential of using microbiome-targeted therapies to prevent and treat infections. Dr Kelly Jobling from Newcastle University spoke about the spread of antimicrobial resistance in community settings and used the example of prisons as isolated communities where resistant bacteria can thrive and spread due to close contact among prisoners, staff, and visitors. Dr Kelly Joblong emphasised the need for effective infection control measures to combat the spread of antibiotic-resistant bacteria.

The talks were followed by a discussion session where the audience had the opportunity to ask questions and share their thoughts on the topics presented. After the discussion, there was a break before the meeting resumed with a summary of the symposium by Professors John Mathers and Glenn Gibson. The award for the best early career speaker was then presented to Dr Cecile El Chami.

As someone who attended two Rank Prize Nutrition symposia in the 1990s, attending this symposium brought back pleasant memories but more importantly, highlighted the excellent work that Rank Prize does in bringing together scientists in a forum that maximises discussion, the generation of new ideas, and furtherment of science. I am confident that many collaborations have developed from these symposia. It was also inspiring to reflect on the significant progress that has been made in microbiology and nutrition since the mid-1990s.

The symposium was an excellent opportunity to learn about novel approaches to managing microbial systems, combatting antibiotic resistance, and promoting infection control measures and perhaps most importantly, to meet people from a range of scientific fields in a friendly, enjoyable and supportive environment. I would like to thank the organisers, Samantha Walker and Philippa Lewis, and of course, Rank Prize, for making this possible.

Professor Andrew McBain, University of Manchester

Professor Andrew McBain (University of Manchester)

Professor Glenn Gibson (University of Reading)

Professor John Mathers (University of Newcastle, Rank Prize Nutrition Committee)

Professor Anne Marie Minihane (UEA, Rank Prize Nutrition Committee)