Does microbiome disruption lead to sepsis? – an interview with L Clifford McDonald

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Sepsis, a condition associated with significant morbidity and mortality, has been increasingly associated with the gut microbiome. In this interview L Clifford McDonald from the Center for Disease Prevention and Control (CDC; GA, USA) talks about the role the microbiome might have in mediating sepsis and how this association could be harnessed for the frontline of care in the future.

 First, could you introduce yourself and tell me a bit about your background?

I am the Associate Director for Science and the Division of Healthcare and Quality Promotion at CDC. The Division of Healthcare and Quality Promotion is responsible for preventing healthcare-associated infections and antibiotic resistance associated with healthcare-associated infections. I am by training a physician, with specialization in internal medicine, infectious diseases, medical microbiology and epidemiology.

Could you outline the current issues in diagnosing and treating sepsis?

Sepsis has a major impact on human health, amounting to approximately 270,000 deaths and 1.7 million cases – from bacteremia in neonates to pneumonia in older individuals. The definitions of sepsis have been challenging, with burden estimates, traditionally based on discharge or administrative codes. CDC recently led development of new estimates of sepsis burden using electronic health records based on new consensus clinical definitions; we have greater confidence in this new estimate.

The challenges in addressing sepsis are many. One is that the microbiology of underlying infections is different in children than adults. The main focus for prevention to-date has been surviving sepsis, and not necessarily preventing it. CDC shares in emphasizing the early recognition and treatment of patients with sepsis, which clearly has a major impact on morbidity in US hospitals – but we are moving more and more towards also thinking about how to better prevent the infections that lead to sepsis. Though the majority of these infections have their onset outside healthcare facilities, there are likely opportunities to both prevent these infections as well as better manage them to present progression to sepsis.

What role could the microbiome play in mediating sepsis?

One study demonstrated that patients who were previously hospitalized with an infectious diagnosis, and presumably those taking antibiotics, were more likely to be readmitted with sepsis. Now, some people would worry this increased risk is just because the patients have underlying predisposition to recurrent infection, rather than this risk being related to antibiotic-related microbiome disruption. These investigators addressed this concern  by showing that patients who did not have an infectious diagnosis during an index hospitalization were least likely to be readmitted with sepsis, if they had an infectious diagnosis other than C. difficile infection they more were likely, and if they had a C. difficile infection they were even more likely. They further looked to see if this increasing risk accross these three categories of index hospitalization was for any readmission or only for sepsis readmissions – and they found that it was for only sepsis readmissions.

This has been looked at further in a study by Baggs et al., where we were actually able to look at exposure to antibiotics as a risk factor for readmission with sepsis. We were able to show a dose effect; if patients were given antibiotics that were designated as high risk for C. difficile on a previous hospitalization they were more likely to get readmitted for sepsis within 90 days. In contrast there was a decreased likelihood with low-risk antibiotics and the group who didn’t receive antibiotics showed lower risk still If a patient was given more classes of antibiotics, they were at an increased risk of being readmitted for sepsis. Likewise, being given antibiotics for a longer period of time was also associated with increased risk of being readmitted for sepsis.

We looked at any readmission, so not specifically sepsis, and general readmissions didn’t have this same dose effect. So again, we know antibiotics disrupt the microbiome, and this study suggests this might lead to higher chance of sepsis.

Other studies support this association by demonstrating underlying mechanisms. One of these involved a mouse model where mice are given an antibiotic cocktail and also a drug that causes a mild colitis, called dextran sulfate. The dextran sulfate impacted the mice, but it didn’t cause anything like what the researchers saw when they gave the mice antibiotics along with the dextran, here they saw these mice dying of sepsis-like death and they called this phenomena an inflammasome. They traced it back and found that there was an E. coli in the gut microbiome of these mice that was resistant to the administered antibiotics. They termed this a pathobiont – these are members of microbiome that normally don’t function as pathogens, but if antibiotics or something else disrupts the microbiome, they begin to behave as pathogens. In fact, this strain of E. coli was in these mice all the time, but it didn’t cause infection until the microbiome was disrupted. This emphasizes that there are bacteria that are usually suppressed by an interaction between the microbiome and immune system, usually controlling these pathobionts.

Our microbiome is pretty resilient. You can take antibiotics and it will come back to its stable state, but sometimes we might push it too far. While the natural flora are displaced, you probably have some increased risk of infection, for C. difficile we know the risk is elevated for around 2–3 months and for sepsis we haven’t really looked after 90 days, but we think it’s probably similar.

It’s a combination of increased risk of infection, for example through the breakdown of the mucosal barrier or dysregulation of the immune system that is triggered by this imbalance of the microbiota. With regards to immuno-regulatory functions of the microbiome, they might manifest very distant from the gut. There are some data suggesting certain commensal microbiota produce, for example, short-chain fatty acids, which maintain the integrity of the gut. Moreover, usually we are colonized with bacteria that are very fit for purpose, if you introduce antibiotic prophylaxis that disrupts it, this could impact the pathobionts that the microbiome usually is directly inhibiting.

There have been some conflicting results in microbiome literature regarding whether dominance is associated with infection. On study demonstrated that if over 30% of microbiome is represented by a single species in hematologic stem cell transplant patients, infection was more likely. There have been other studies too; in long-term acute care hospitals, ventilator patients had an association between having over 20% of their microbiome dominated by a highly antibiotic-resistant bacteria (carbapenem-resistant Enterobacteriaceae) and bloodstream infection caused by the organisms. Another study from Cornell University (NY, USA), also showed dominance associated with mortality.

However, there are other studies that have failed to demonstrate this; for example, a study was just published this year that included 15 bacteremias and the point of the study was to be able to show how you could find the organism causing the bloodstream infection in the gut. However, only two of those 15 individuals were dominant with the infecting organism. So, there is not a uniform metric suggesting dominance leads to infection, but there is clearly a pathway through which microbiome disruption does lead to infection in some cases.

What research are you currently working on?

At CDC we have been funding and working towards supporting the development of microbiome indices. We broadly defined these as a public health indices or health indices for infection control, for infection prevention, for drug development and for diagnostics. The concept is that there are certain microbiome indices that are associated with each antibiotic – because there’s specific characteristics of that antibiotic and how the drug affects the microbiome – so, could this be translated to the patient, using a microbiome diagnostic to evaluate how likely it is a patient will become colonized?

There are some that are some indices that are already fairly developed, for example, the bile metabolism indices as a metric for risk of infection caused by C. difficile. However, other indices could be more dynamic and context specific; for example, dominance as a risk factor for infection. Understanding all this would be very helpful! We have funded several studies to look at the microbiome disruption associated with specific antibiotics but also working towards in vitro models, helping to develop diagnostics and, as much as we can, support development of therapeutics.

Animal models and human data do suggest that there is a route to sepsis from the microbiome, perhaps via increased infection risk that is in turn through the loss of mucosal barrier function or immune regulation. The questions to think about now is, is it too early to consider randomized trials for a microbiome protectant (e.g. a small molecule that blocks the effect of antibiotics on the gut microbiome) or restorative (e.g. a defined, live therapeutic)?

Do you think that manipulation of the microbiome could be used to prevent sepsis?

Yes, I think that would be a future possibility. The question is, is it too early to even think about that? It’s probably too early to think about the tremendous resources that we require to use sepsis prevention as an endpoint – why? Because readmission with sepsis is so rare, this occurs in only about 0.17% of patients, and you can’t feasibly do a clinical trial powered to detect even sizable impacts on such a rare outcome as that. You could probably enrich the cohort by also including patients at higher risk. In some ways, some of this is being worked out by this focus on hematopoietic stem cell transplant patients, a very debilitated population, and I think there’s also a lot of interest in organ transplant patients.

And do you think more broadly microbiomes are going to sort of really impact frontline care in the coming years?

Yes, it’s associated with a lot of conditions. Although, the only place that I believe right now where there’s an almost routine impact is recurrent C. difficile infection that is being treated with fecal microbial transplant (FMT), even in this case FMTs are being done under enforcement discretion, so there’s no US FDA approval.

I think having something FDA-approved that has a fairly broad activity in a microbiome, probably approved for a specific indication, would be great. One challenge I see is that the main indication that people are driving towards, management of multiply recurrent C. difficile infection, already has a lot of different treatments that are being developed so I worry about a lack of significant investment from industry in live biotherapeutics – because the perceived need on the part of investors may not be sufficient.

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