Gut Microbiome in Acute Pancreatitis

[00:00:01] Speaker A: Good morning. My name is Professor Vikram Mitra. I'm the chair for the Pancreas clinical section of British Society Gastroenterology. I would like to introduce Professor Pramod Kirg, who is the president of the Indian Society of Gastroenterology and a very eminent pancreatologist from India. We are going to use the next few minutes discussing about microbiome in pancreatitis and look forward to the discussions. Professor Gag. [00:00:34] Speaker B: Thank you, Vikram and it's my pleasure to be here. [00:00:37] Speaker A: Thank you. So if we can begin with the gut microbiome obviously has been linked to almost every disease outside the GI tract. And is there a relationship between gut microbiome and pancreatitis? [00:00:54] Speaker B: So I think the obvious answer here is yes, because as we know that humans and microbes have evolved together. And I think it's a symbiotic relationship between humans and microbes, be it GI tract, lungs, skin, everywhere. And it's beneficial both ways. It's beneficial relationship. So it is quite understandable that if there is dysbiosis, that means the normal patient bacterial flora is disturbed, what we call as dysbiosis, then there are chances that it will affect human health. And as you rightly said, that it is associated in some cases causally also to many diseases. And pancreas is no exception. It has been associated both with acute pancreatitis and chronic pancreatitis and also pancreatic cancer in many ways. [00:01:45] Speaker A: Thank you so much. Can gut microbiome actually predict the severity of acute pancreatitis? [00:01:54] Speaker B: So I would say perhaps yes, because there are now a few studies which have looked at the severity of the disease and the admission gut microbiome. That means a patient is admitted with us within a few days of the pain onset and acute pancreatitis. And we find there is difference between mild and severe acute pancreatitis. There was a large study from Europe, a multicenter study, which had looked at about 400 plus patients and they showed that there was differences in the gut microbiome at admission between mild and severe disease. There was another study from the Dutch group many years ago which also showed the same. In our own prospective study, we have found that there are differences, what we call as beta diversity between sample differences in the gut microbiome between those with mild disease and severe disease. So there is definite data on that. [00:02:48] Speaker A: Thank you. Are there any specific organisms that has been linked to the outcomes of acute pancreatitis that you are aware of? [00:02:57] Speaker B: I think it's a bit difficult question. So Let me first tell the audience that there are many classes of bacteria which is taxonomic classification, like starting from phylum and then family and genus species. So in the human gut, the predominant bacteria belong to Firmicutes, which is now called as Basilota. Then you have Bacteritis, then you have Actinomycetes, then you have Proteobacteria and there are many others. So among these, Proteobacteria is something which has many organisms which have been linked to disease, for example, E. Coli, Shigella, Klepsula, Pseudomonas, others. While Firmicutes and bacterioides, some of the bacteria might be pathogenic, others not. So. In the European study that I mentioned earlier, they have shown that short chain fatty acid producing bacteria were higher in those with severe disease, which was a little surprising because the earlier Dutch studies showed that Proteobacteria and Enterococcus were more were significantly increased in those with Sibo disease compared to mild pancreatitis. And our own results have been consistent with that Dutch study where we are seeing that Proteobacteria, particularly E. Coli, Shigella, Klebsella are increased in patients with severe disease. So I think that's what you were referring to. Which particular bacteria class is important. [00:04:24] Speaker A: That's right. So moving on to the next question. How is the gut microbiome related to the pathogenesis of acute pancreatitis? [00:04:33] Speaker B: That's really difficult to answer. So first of all, let me admit that we don't have very good studies on that. A couple of studies had shown earlier that some bacteria may produce certain products, for example, lps, which is a known molecule which incites inflammatory reactions. So LPS is something which is there if you have infection in the bloodstream and it can cause inflammation in an animal model done many, many years ago, they had shown that if you feed animals with mice, for example, with alcohol, they don't develop chronic pancreatitis, but you feed them. Mice feed the mice with LPS and alcohol, they develop chronic pancreatitis. So it is possible that many of these bacterial products may affect rather negatively or sometimes even positively the pancreatic cells and pancreatic microenvironment to cause the disease. But I think let's admit as pancreatic researchers that our understanding is rather limited in this regard. [00:05:41] Speaker A: Thank you. And do you think, is there any role currently in clinical medicine of identifying the gut microbiome through the buccal swab or the rectal swab or through the blood? There has been some studies. [00:05:53] Speaker B: So I Think your previous questions answer that. So, for example, we are now beginning to understand that gut microbiome, or even oral buccal microbiome, may be associated with the severity and the outcome of acute pancreatitis. And in that regard, at least from a prediction point of view, it might be helpful, if you know the bacteria right in the beginning, what kind of microbiome is there in a particular patient? But having said that, the turnaround time today for the microbiome studies is fairly large. For example, it will take at least a week for us to have answers to that, because you can't do on an individual sample here because the techniques which are available you need to do in batches. We have other clinical markers which tell us about the severity much earlier. But I think going forward we will definitely have news pipelines and platforms where we can have the results very early and we can actually find out whether it's going to predict the clinical outcomes or not. More important than prediction will be that if we understand the pathophysiology, as you asked earlier, that a particular class of bacteria, if they are there, likely the course will be severe, we can then intervene early. And that's what brings me to the next point. Will blood microbiome tell us more about the pathogenesis of the disease? And I think this is again an area where not much data exists, but there is a possibility that because of the increased gut permeability, there could be bacteria in the blood which might actually contribute to the disease pathogenesis. So surely this is an area of further research. [00:07:31] Speaker A: Thank you. And what are the major confounders that could potentially affect the relationship of gut microbiome and pancreatitis? [00:07:39] Speaker B: Again, a very important question from the point of view of not only pancreatitis, but in general about the microbiome research, ethnicity, geography, diet, your alcohol intake, certain drugs, for example antibiotics, proton pump inhibitors, which suppress acid, There are multiple factors which can affect microbiome. When we talk about, say, pancreatitis, etiology of the disease itself is a big confounder. For example, those with alcohol related disease and other etiologies may have different microbiome or different classes of bacteria. So I think very important point from the point of research. Whenever we do microbiome research and we identify difference in the microbiome between two groups of patients, we have to do and take into account the variables, the confounders, for example, age, sex, etiology of the disease, the diet, the confounding effects of drugs into account before we say this is related to the disease or not. [00:08:46] Speaker A: And do you think that gut microbiome can predict the post discharge outcome of acute pancreatitis patients like mortality, morbidity, development, diabetes? [00:08:54] Speaker B: Yeah, I, perhaps, yes. So the European study I mentioned to you, the multicenter study, they actually did a follow up study on those patients who recovered from acute pancreatitis and I think their sample size was somewhere around 280 or something where they showed that they followed up those patients and studied development of recurrent pancreatitis, chronic pancreatitis and diabetes. And they found admission microbiome could predict development of diabetes in the long term. But there was no difference in terms of chronic pancreatitis, exocrine insufficiency and other complications. So I think there is some data, but we need further confirmatory data and more prospective studies. [00:09:40] Speaker A: Sure. And we currently don't advocate antibiotics routinely in acute pancreatitis. Knowing that gut microbiome can be associated, is there a role or should we just direct it with procalcitonin related approach? [00:09:52] Speaker B: So my short answer is that as you said, there is currently no role for prophylactic antibiotics. Now the reason for that is 80% of patients have mild disease and they don't develop infected necrosis, other infectious complications. And that's the reason antibiotics are not really helpful. But as you mentioned earlier, in those with predicted severe disease, if they have leaky gut, they have microbes going into the blood which might contribute to disease. There could be a subgroup of patients who might benefit from antibiotics. But I think we need more data before we can advocate that. [00:10:27] Speaker A: Thank you. And what are the interventions that we can advocate to restore the gut microbiome in acute pancreatitis? If we are linking this to the severity of acute pancreatitis and organ failure? [00:10:39] Speaker B: So I would say couple of things we know are beneficial for gut microbiome. One is early enteral nutrition. So many patients with acute pancreatitis, for example, are kept nil by mouth, they're not given anything. But that's not the right strategy. There is no role for bowel rest. So today what is recommendation is start early enteral oral nutrition. So that will help maintain gut integrity and also the gut microbiome. In addition, do not give unnecessary antibiotics because these antibiotics are going to affect the beneficial bacteria as well. And that is the reason why antibiotics may be harmful. Third thing is that don't give too much of proton pump inhibitors, acid suppressors, that again has its own negative effects and that is not recommended to be given. But beyond that we really don't know whether microbial manipulation, some interventional strategy will be helpful or not. For example, a study published last year, a randomized trial on rifaximine, which is an oral, non absorbable antibiotics and has been found useful in patients with liver disease and bacterial peritonitis, was not shown to be beneficial in preventing infected pancreatic necrosis in patients with acute pancreatitis. But these are early days and I think we need more studies and data on that. [00:12:01] Speaker A: And where should we focus on research in this area in future? [00:12:05] Speaker B: I think whatever we have discussed actually has shown up some areas. For example, again, we need confirmatory data about the specific classes of bacteria in the gut microbiome which could be associated with the severity of the disease and the outcome disease. We need to know the transmission dynamics. If these pathogenic bacteria, which are increased in patients with severe disease, can they cause infected necrosis, how can we then identify these bacteria and start prophylactic antibiotics or other measures to prevent infected necrosis? Third area of research could be microbial manipulation. Can we have strategies where we can make the gut microbiome healthy so that their outcomes are better? I think there are many areas which require in depth study going forward. [00:12:50] Speaker A: Thank you. And for people who are listening to this, how can what one maintain a healthy gut microbiome? [00:12:57] Speaker B: I think that's a million dollar question. So this is not only for physicians watching this or I think patients in general public. So gut microbiome, to keep it healthy, many things we need to do. One is eat healthy. So a nutritious diet, predominantly vegetarian diet, is very healthy. Physical exercise, very important. Do not take unnecessary antibiotics. And like acid suppressor drugs like proton pump inhibitors, many people start taking these and then they take it for years together. Not very good. And good in general, good lifestyle habits are going to keep your gut healthy. [00:13:39] Speaker A: Thank you. And what are the major preventive measures to reduce the risk of acute pancreatitis and, and its severity? I know it's. [00:13:47] Speaker B: I wish I knew, I wish I knew. But let me tell you two things. One is if you look at the causes of acute pancreatitis, two major causes. One is alcohol abuse and second is gallbladder stones. So obviously we need to cut down on alcohol. This is something which is easily doable. And particularly those who are at risk of pancreatitis, they have family history of pancreatitis or some other risk factors, I would strongly recommend, recommend them not to take too much of alcohol, which is very important. Second is gallbladder stones. There is some data that gallbladder stones are increasing in prevalence. Perhaps you've got lifestyles and obesity and other factors, maybe gut microbiome. And I think somebody knows that they have gallbladder stones which are symptomatic. I think they should not delay surgery and go for cholecystech, particularly those who have had pancreatitis in the past. Please go for cholestectomy. Don't delay it. So go by the advice of your doctor. But I think these are the two measures we should take. And again, eat healthy, exercise, you'll be fine. [00:14:53] Speaker A: Well, thank you so much for helping us with this. Very grateful. And we had a lot of insight. [00:14:59] Speaker B: Thank you, Vikram, for doing this. It was a pleasure. Thank you. Namaskar.