Understanding how timing and dosage of antimicrobials can affect patient gut health

08 July 2021

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Researchers at the Healthcare Associated Infections Research Group at the University of Leeds and Leeds Teaching Hospitals are investigating how antimicrobial treatments affect gut health.

Dr Jane Freeman, Dr Anthony Buckley, Dr Caroline Chilton, Dr Ines Moura, Dr Suparna Mitra and Prof Mark Wilcox developed a microbial dysbiosis model based on patient clinical and faecal microbiome data. This will facilitate investigations into what factors are involved in dysbiosis and colonisation with pathogenic organisms; and developing novel treatments/preventatives.

Antibiotic-associated diarrhoea (AAD) affects between 5 and 30% of people taking antibiotics. Although diarrhoea is a common side-effect of many antibiotic treatments, in some cases an imbalance of gut micro-organisms is the cause rather than the medications themselves. “It is important to make the distinction between antibiotic-associated diarrhoea and antibiotic associated diarrhoea with an infectious cause. About 25% of antibiotic associated diarrhoea (AAD) cases are caused by the pathogen Clostridium (Clostridioides) difficile,” explained Dr Freeman. 

The team looked at antibiotic use in patients with antibiotic associated diarrhoea with and without C. difficile infections and characterised the microbiomes in these patients. They were then able to design different antibiotic dosing regimens and assess them for their propensity to detrimentally affect the gut microbiome (dysbiosis) in an in vitro gut model They found that broad-spectrum antibiotics, including amoxicillin, ciprofloxacin and piperacillin/tazobactam contributed to the loss of colonisation resistance, whereby the gut microbiota protect against invasion from pathogenic micro-organisms.

The gut microbiota is a complex community of micro-organisms which maintain balance through competition for nutrients and space. A diverse range of microbes present in the gut prevents opportunistic pathogens like C. difficile from becoming dominant and causing disease. When presented with a healthy, diverse microbiota, C. difficile is not able to colonise and cause infection. Antibiotic treatment can kill or harm parts of the microbiota, allowing C. difficile to grow and produce toxins that cause inflammation resulting in diarrhoea or even more severe disease.

Paradoxically, C. difficile infections (CDI) are conventionally treated with antimicrobials, but treatment options are limited and there is the added challenge of high rates of recurrent disease despite initial clinical cure. “The biggest challenge in treating CDI to my mind is preventing recurrence,” said Dr Freeman. “Infection recurs in about 30% of people after their primary episode. Unfortunately, if you are unlucky enough to have a recurrence, your risk of another one increases to 50%. Recurrence partly occurs because of long term disruption of the bowel microbiota (dysbiosis) providing an ideal environment for CDI and because C. difficile produces hardy spores that are not killed by the antibiotics we use to treat CDI – they can survive and germinate again to cause disease.”

Sometimes antibiotics are essential treatments, so maintaining a diverse and functioning microbiome and a healthy gut might help to prevent or reduce dysbiosis when they are necessary. Understanding the patients who may be more prone to dysbiosis of the gut microbiome – and therefore C. difficile-associated diarrhoea because of antimicrobial treatment – could help doctors tailor treatments and reduce the likelihood of patients getting AAD. “In the future, I hope we might be able to develop laboratory tests that will help us identify patients at risk, for example those that have a high degree of dysbiosis. Better, more targeted antibiotics and microbiome therapeutics to help the restoration of our gut microbiota are some of the exciting developments that we should see starting to emerge in the coming years,” said Dr Freeman.

Dr Jane Freeman will present the team’s data at the Microbiology Society’s Focused Meeting Anaerobe 2021: The Microbiota and Beyond. Her talk, titled ‘Guess poo: modelling antibiotic-mediated dysbiosis’ will take place at 13:05 on Friday 16 July.


Image: iStock/Dr Microbe..