Authors: Pinaki Panigrahi (Georgetown University, DC, USA)
Dysbiosis of the microbiome and sepsis has been a talked-about topic in the past few years, and with evidence of an association increasing, the focus is turning to how we could harness the microbiome for prevention and treatment of sepsis.
In this interview we speak to Pinaki Panigrahi (Georgetown University, DC, USA) about his work using probiotics for the prevention of sepsis in neonates. In addition, he comments on the impact of probiotics for other infections and some of the skepticism surrounding some microbiome research, find out more below.
Could you just introduce yourself and tell us a bit about your background?
I am a Professor of Pediatrics at Georgetown University Medical Center and I am also the director of microbiome research at Georgetown. I have been doing global health for some time, but the microbiome is my main focus.
Could you just outline the current issues around preventing and treating neonatal sepsis?
Across all age groups, sepsis is a big problem, if you look at the mortality and the money spent it is huge and the current strategy of treating with antibiotics is not good enough. So, people are now looking for alternative and adjunct therapies. We now know that, whether in the neonatal intensive care unit or the adult intensive care unit, treating with antibiotics is proportional to a negative impact on the host over the medium- and long-term, depending on how much and how long you treat with antibiotics. I think physicians are becoming cognizant of treating with antibiotics less and for a shorter period, but we still need alternatives, in addition, I think that prevention is better than cure.
My focus has been to prevent sepsis and if it is blood-derived, which we see particularly in neonatal sepsis in lower-income countries where there is a lot of Gram-negative sepsis, a lot of the infections are gut-derived. This is not a new finding, we knew this from elderly and immunocompromised patients but in a ‘normal’ baby, why should this happen? The answer is that a baby does not have a fully developed immune system, and, in many cases, they’re stressed, so the microbiome can play a big role in the pathogenesis of sepsis.
The microbiome has been linked to many organ systems now including brain, other mucosal surfaces, and the skin – and I like it because I feel that this is the truth! I remember many years ago when I had just finished fellowship training. I was studying necrotizing enterocolitis, a disease of premature infants, and we showed the very first results of our study, which indicated that if you have more bacterial diversity the baby fares better than if there was limited diversity. So, in babies with only 2 or 3 types of bacteria more necrotizing enterocolitis (NEC) was observed compared with those that had 8–10 (in those days bacteria were identified by culture) strains. Many of these babies also had concurrent sepsis.
That was many years ago, but the principle has carried through; after doing next-generation sequencing we see that this is the bottom line, a reduction in diversity allows one particular bacterial species to overgrow and that can cause problems. So how can we fix this? Maintaining the balance should be our aim. Part of this is not to administer too many antibiotics for too long, but for those with microbiome disruption without antibiotics, what can you do?
That leads on to the next question, how do you think probiotics could be used in the prevention of sepsis?
In cases, as I just mentioned, where individuals are getting sepsis without antibiotics, we tried to use probiotics. In my presentation at ASM Microbe (21–24 June 2019, San Francisco, CA, USA) I showed how it took us over 20 years to build this study but we’ve discovered that if you can restore the flora, if you can help the baby by giving probiotics in the first week of life, then they will have a reduction in the rate of sepsis. We also saw that not only were probiotics linked to a lower risk of sepsis but were at a lower risk of respiratory tract infections, which was a surprise! That’s the reason our study was stopped in the middle – we only had enrolled 4500 out of a targeted 8000 infants but because there was enough evidence that the probiotics were working we didn’t have to continue. I have been involved in many studies and usually the time we stop is when there are deaths or other negative impacts. But according to the ethics if you find enough evidence for the intervention then also you should stop because it’s not ethical that not everybody should get the intervention. Moreover, why should you waste money, time and energy if you already have an answer. So, that study showed that probiotics could prevent sepsis in neonates, but now we have to find out how and what the immunological impact(s) of these bacteria are, because the gut is the largest immune organ, and if you’re thinking of modulating immunity then there cannot be a better place than the gut.
You mentioned respiratory tract infections; do you think probiotics could help prevent other infections?
For me, there is no doubt that probiotics could play a role in any infection you can think about. Because infections are immune-mediated, probiotics will affect the gut microbiota and this will impact the immune system, so, there is no question that probiotics could impact other infections, viral, bacterial, or other.
When we started studying the microbiome, people were thinking about bacterial infection and competitive inhibition etc. but we can see that it’s not that simple, it’s pretty complex! Probiotics are defined as organism that have beneficial effect on the host, so by adding a probiotic there may be an overall change in the bacterial milieu that in turn will drive the immune response. I don’t want this to be devalued as ‘snake oil’ because many scientists feel this way and question the mechanisms behind it. Clearly, one probiotic agent may not work for every infection or every individual at any age, but at least there will be specific probiotics that can have specific impacts on the host at specific ages.
In addition, if it were up to me, I would spend my energy not just on infectious disease but also on allergy and autoimmune diseases, which are driven by irregularities of the immune system. Currently there is no cure for any autoimmune disease there are only treatments. The way we treat is to suppress, by giving a dose of steroids or similar, but by suppressing something you are not going to resolve it. The aim should not be to suppress but to prevent the disease in the beginning, and I think with that a good healthy microbiome would help with that.
With regards to the microbiome, you’ve mentioned there have been many associations, could you just comment on correlation and cause?
I’d like to compare microbiome therapeutics with antibiotics and ask: how many years (about 90?) and how many billions of dollars have been spent to come to the stage where we can really make strong statements? So, when we come to microbiome, we are really just at the beginning so it is not fair to say that we can establish causality – correlation is how you start. People might say ‘well you can associate anything with everything’; yes, but still if there are strong associations some of them will pan out to be causative, even if they are not 100% causative. You have to see it in terms of balance, what you gain vs what you lose, how much does it cost, what side effects could it have? And in terms of these questions I think that probiotics are very promising.
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