Talking digestive health and clinical trial considerations in Asia

Vitafoods Insights: 00:06

Welcome to the Vitafoods Insights podcast. Join us as we explore the latest science and innovation, helping the global health and nutrition industry connect, develop and progress. Today's host is Natalia Franca Rocha, content and conference manager.

Natalia: 00:27

Hello and welcome to another Vitafoods Insights Podcast Episode. I’m Natalia Franca Rocha, content & conference manager at Vitafoods. Earlier in the year, as part of our Vitafoods Insights Virtual Expo Asia, we hosted a panel discussion about clinical trial and science considerations for brand owners launching digestive health products in Asia, with Dr. Neerja Hajela, Secretary at the Gut Microbiota and Probiotic Science Foundation in India also Head of Science and Regulatory Affairs at Yakult Danone India, and Dr. Chin-Kun Wang, Distinguised Professor at Chung Shan Medical University. Today we will share some key highlights from that discussion, but first let’s hear from Dr Neerja on why the gut is so important:

Dr Neerja: 01:12

It’s not surprising that more than two thirds of the population suffers from weak intestinal health. We have digestive disorders, constipation, diarrhoea, acidity, bloating, irritable bowel syndrome, and now of course, cancers are on the rise. So, what makes the gut so important? What we already know is that the gut, which is the small intestine, and the large intestine, is responsible for digestion of food and absorption of nutrients. And the large intestine helps in removing all the waste material. We also know that 70% of the immune system is found in the gut in the form of the gut associated lymphoid tissue, and therefore the gut is the largest immune organ of the human body. We have heard of the gut brain axis. So, you have your enteric nervous system and about two thirds of the neurotransmitters in the gut, which also makes it the second brain of the human body. So, the human gut is a complex immunoneutral endocrine organ, it helps in extracting and providing nutrients to the body. It is the largest immune organ with about 70% of the immune cells, we have 100 million neurons.

Natalia: 02:23

And what about the microbes that we have in our gut and body?

Dr Neerja: 02:26

So we've all heard about the human microbiome, we are about 1000 species 100 trillion microbes, which are found in every part of the human body. And you have different species of microorganisms in different parts of the body, like the mouth, the skin, the urogenital tract, and the intestine. The largest consortium of these microbes are found in the in the intestine, and as you can see here, as we go down from the stomach to the duodenum, the jejunum and ileum, and then the colon, the number of microorganisms keep on increasing. In fact, in the colon we have about 10E12 cell forming units per ml of colonic content. And the reason for this is very simple. It is because of a favorable environment in the colon and more substrate availability. Now coming to the role of these microbes cell they have three important roles. One of course, they have a protective function, they have structural functions and metabolic functions. So these microorganisms, they are your first line of defense against pathogens. They help in pathogen displacement by competing for nutrients and receptors. They produce antimicrobial factors like bacterial sins and lactic acid and inhibit the growth of the pathogenic organisms. Also, they help in the induction of secretory IGA and immune system development. Another very important role of these microorganisms is its metabolic function. They ferment non digestible dietary residues and non digestible substrates into what is known as short chain fatty acid, and this short chain fatty acids add a very important source of energy for your colonic epithelial cells. Many of these microorganisms synthesize vitamins, like biotin, and folate, and they help in better absorption of nutrients and salvage of energy. We have all heard about the gut microbiota, the gut and the brain axis. So these microbes, they have their communicate with the brain through a bi directional signalling, which is between the GI tract and the brain through the vagus nerve. So they are vital for maintaining homeostasis, and may be involved in the aetiology of several metabolic and mental disorders. So now the question is, if these microbes are so important, does an imbalance of the microbes in the gut, you know cause disease, so it's a very chicken and egg situation, we know that we have the good, the bad and the ugly, the good here are represented by lactobacillus and Bifidobacteria, which is in the blue box, and the ugly by staphylococcus and Clostridium pathogens. So the balance of these microbes in the gut is very important because the good bacteria help in digestion of food, absorption of nutrients, they help to stimulate the immune system. Also synthesize vitamins, like I've already told you, but this the harmful ones are the ones which are responsible for intestinal putrefaction. They produce carcinogens, and diseases like diarrhoea, constipation and liver damage and also hepatic encephalopathy. So, an imbalance of the gut microbiota with the harmful microbes are in much larger numbers than the beneficial ones are responsible for disease. And like I said, it is a chicken and egg situation, we do not know what comes first, whether the imbalance of the microbes leads to disease or whether the disease is linked to an imbalance in the microbes. But as you can see here, clearly there are differences in the gut microbiota in different disease conditions, like inflammatory bowel disease, metabolic syndrome, allergies, and also infectious disease. And this better represented in this slide, where you can see that even in malnourishment or type two diabetes, or IBD, you will have an imbalance of the intestinal microbes. There are certain species of bacteria or microbes which are over represented, and the others are underrepresented. So even in metabolic disorders, when we have a high fat diet, there's an increase in intestinal permeability, because of increased production of lipopolysaccharide. When they enters into the circulatory system causes tissue inflammation this leads to insulin resistance, and thereby obesity and type two diabetes. There is a concept of replenishing the beneficial microbes. We've all heard about fecal microbiota transplants, which is also basically nothing but stool transplant of fecal bacteria from a healthy individual into a desiccant. Now in a fecal microbiota transplant has been tested in different disease conditions, but in more effectively in Clostridium difficile infection, and as you can see here, 93% of individuals who received FMT, in addition to the antibiotic vancomycin, what you heard of Clostridium difficile infection without relapse, compared to only 31%, who received Banquo medicine. So clearly these microbes help in treatment of disease. And this is a very interesting article in the Times of India In India, where they have shown how Bucha can heal you. So clearly, this shows that some of the diseases which cannot be treated by conventional treatment, possibly could find that you're in the intestinal microbes. So what is important is balance is important. And when it comes to balance there, you have interventions like probiotics, prebiotics, and synbiotics, which are dietary factors to modulate the gut microbiome, the immune system and the factory intervention.

Natalia: 04:44

Balance definitively seems to be of great importance when it comes to gut health, and probiotics, prebiotics and synbiotics are now key terms consumers are becoming more aware of. So let’s all be on the same page about the meaning of these terms. Let’s start with probiotics.

Dr Neerja: 05:00

These are live microorganisms, which when administered in adequate amounts, they confer a health benefit on the host. So this is a definition which was given in 2001 by the food Agriculture Organization and World Health Organization, and 2014, the international scientific association for probiotics and prebiotics gave a consensus statement where they replace the word which with that to make it more inclusive. So they are live microorganisms that when administered in adequate amounts than for a health benefit on the host. So this is the framework for probiotic products, what are probiotic, are your probiotic products your probiotic medical foods foods, non oral probiotics probiotic animal feed, but what are not probiotic fermented foods with an undefined microbial content and an undefined consortia including fecal microbiota transplants. Prebiotics, on the other hand is a substrate that is selectively utilized by host microorganisms to confer a health benefit on the host. And these include tractor oligosaccharides, galacto oligosaccharides, inulin, fructans, and galectins. And a combination of both probiotics and prebiotics is what is known as synbiotic. And this exerts both a probiotic and a prebiotic effect.

Natalia: 06:19

Now that we are all on the same page on the meaning of probiotics, prebiotics and synbiotics, let’s look at clinical evidence.

Dr Neerja: 06:26

If you just do a quick PubMed search, you will find more than 8000 publications on probiotics and prebiotics. And this is a study that has been conducted in India, which was basically to evaluate the role of a probiotic in preventing acute diarrhea in children in a slum setting. It was a community based randomized, double blind, placebo controlled study. And it was conducted in the slum setting, which is what 66 in one city of Calcutta, which is quite compromised when it comes to hygiene and sanitation. So The number of children who were included in the study were 3758. And the age group was between one and five years. So this is a very, very crucial age group for children, especially in some settings, because about 300 million children die because of diarrhea just in this age group. So they were divided into two groups we had 1894 in the probiotic group, and about 1864 in the nutrient group, and they were given a probiotic fermented metric for a period of 12 weeks, and then followed up for another 12 weeks. And these are some of the pictures of the study where the children were actually consuming the probiotic fermented Maitri. And what was observed was that the group that got the probiotic there was a 14% reduction in incidence of diarrhea, imparting protective efficacy in the probiotic group for prevention of acute diarrhea in this group of children. That is enough and more data which suggests that the oral intake of probiotics during pregnancy, and postnatal helps the newborn acquiring a much healthy microbiome and a better immune system with increased IGA T regulatory cells, interleukin 22, and enhanced epithelial barrier integrity. And this is The world allergy organization, which has suggested the use of probiotics in pregnant women at high risk for having an allergic child choosing probiotics and women who breastfeed infants at high risk of developing allergy and probiotics in infants at higher risk of developing allergy. So this is just to give you the length and breadth of the areas where probiotics find benefit. And now there was a recent review in nature, which suggested the potential applications of probiotics and prebiotics for the prevention and treatment of COVID. Of course, this is hypothetical, these are very new evidence which are being generated. But there is a lot of scientific data, which suggests the efficacy of probiotics and prebiotics. And that is where, you know, scientific clinical trials become increasingly important when you have to make a health claim on these products.

Natalia: 06:43

In the topic of gut health and gastrointestinal GI health, clinical trial, we also learned more about the power of phytochemicals in digestive health from Dr Chin-Kun.

Dr Chin-Kun: 09:14

So, today I would like to introduce a very interesting combination, This is Burdock complex. We combined some nature materials. One very important one raises Burdock, this is a tropical vegetable. And the other one on this is Angelica. This is traditional Chinese medicine. And also the Gromwell, this is also one kind of medicine, and then be honest, the last portion that is sesame oil. Of course we screen our in vitro and then move into animal model and then to the clinical trial, but in the clinical trial, we use the carbon 13 UBT measurement to measure how is the infection of H. pylori, and we can see after the intervention of Burdock complex, UBT value actually was greatly suppressed and show time dependent. We can also record a gastrointestinal symptoms and we can see after the treatment of the burdock complex, actually, symptoms also greatly improved. And we also measured different kinds of inflammatory markers. For example, CRP, but CRP is very normal inflammatory marker, it doesn't work. But we can see the TNF alpha actually, after the intervention of Burdock in combination, actually is greatly suppressed. We can also see some antioxidant enzymes, for example, SOD (superoxide dismutase) and catalysts, actually after the intervention also increased. And this is clinical observation. We used endoscope and we can see before the intervention, some ulcers can be found here and after the treatment, all the ulcers disappear. We can also see what happened whether the phytochemicals here the H. pylori, is something that we find is very interesting because we can find that H. Pylori, adhesion to epithilian cells can be suppressed after the treatment or blood materials. And also the CagA and interleukin eight (IL-8) secretion and also the total amounts of interleukin eight also suppressed after the intervention of Burdock complex. This is the papers about the burdock And of course, in my laboratory, we also found as several nature materials, for example, the Noni (Morinda citrifolia) nali, I think, is maybe some people know much about it is also some kinds of tropical materials. Yeah, it really is, was well known mentor on the microbiome and even the anti inflammatory activities. Now, this is the other example. This is. Ixeris [chinensis] it is also show very similar results. And we also use different materials, for example, this one is prune essence is in clinical trial. And we can find it can modify the microbiome, and also regulate brown EPS at the same time. Yeah, so this is the other studies, also a clinical trial, we try to understand how is the efficacy of fermented plant extract? Actually, we know a lot of plant extract a lot is fermented materials, but in our study, we can find that it can modify the microbiome, and also metabolomics, and then promote some health benefits. So, because I work in Medical University and hospital, so our team usually combine different departments and work together. So basically, we have a lot of clinical trial.

Natalia: 12:27

Great insights shared by both Dr Neerja and Dr Chin-Kun about the digestive health market and clinical trials in Asia. Now to dive a little bit more into the topic, we will share some of the questions covered during the live panel discussion. To start with, one of the questions was asking whether formulators should look at a single function like protective or structure when selecting a probiotic ingredient, or should they seek synergy?

Dr Neerja: 13:00

I think they should seek synergy. A probiotic bacteria may have more than one function. Most probiotic bacteria are live bacteria. So they reach the target side life and they produce either lactic acid or acetic acid as an end product of fermentation and modulate the gut environment. Again, they have surface structure molecules, like peptidoglycan complex or a polysaccharide, which can actually interact with the immune system of the intestine and augment both immune response, both you know systemic as well as your natural immune response. So there are probiotics, which have more than one mechanisms by which they act and therefore assign energy would be a better option.

Dr Chin-Kun: 13:43

Yeah, according to on my personal experience, except for the probiotics, actually, any kinds of, you know, phytochemicals of materials, after eating, we are influenced the microbiome on the intestine. And we also find led metabolomics is also quite important. Maybe if we can have very good phytochemicals, and together with various spatial probiotics together, maybe they have some very good synergistic effect like that. So I don't think only the single formulation for single function. In the future, maybe we can have many more studies. So for example, in my laboratory, we also do the microbiome after any intervention of the phytochemicals. And actually, we can identify some very specific probiotics. And then we can combine very specific and also useful probiotics together with the phytochemicals and for Advanced Study. Now, basically, the results is very positive and very interesting. I don't think in the future only single formulation for single function, maybe is some kinds of multiple function.

Natalia: 14:56

Okay so the key message here seems to be that synergy is the way to go for formulators looking to develop digestive health products. But with bacteria strains often being associated with some health disbenefits, we had a question about whether a single microorganism can have both positive and negative effects on the host, or express differently in hosts with different physiology.

Dr Neerja: 15:19

Again, when you're looking at a probiotic, if it is a microorganism, it can have a positive and a negative effect. But if you're looking at a probiotic organism, then these organisms are tested for their safety, and most often they have a grasp status, which is generally recognized as safe. So, they have not only a positive effect, and in any case, they have to be validated. Like we said, clinical trials are very important. Scientific validation of the health benefits is very, very important. And therefore, you have a lot of scientific studies in animal models, as well as humans to determine the safety as well as the efficacy of the strain. So most often these organisms, which are probiotic, tested both in vitro as well as in vivo, for the safety and efficacy and have a positive effect.

Dr Chin-Kun: 16:08

Yeah but, you know, basically, many, many more findings show that some kinds of very good probiotics have found recently. And but one thing is very important, not only the one way before the probiotics are basically your host, is also very important. Yeah, actually we have a cooperative program together with many countries, and the results are actually are very amazing. Even the some well-known probiotics, are they show very specific health benefits. But after our studies, we can see some health benefits in some region, but in some region, it doesn't work. Yes, yeah. So maybe the lifestyle, dietary behaviour, and also maybe even older person, personnel, personal genetic problems, the performance is also different. Yeah, But I believe, maybe in the future soon, many, many more findings can help us to understand more.

Natalia: 17:06

Another thing for product developers to keep in mind is how probiotic effects and differences occur depending on the region, which draws into consumers’ lifestyles, diet habits, age, genetic information, among other factors. And speaking of consumers, we had a question about consumers asking if in Asia, do consumers tend to take probiotics as a cure for illness or to maintain their current health?

Dr Neerja: 17:31

Most often, probiotics in Asia are available in the form of foods. They are classified as functional foods, so not really for treatment of disease, because when it comes to foods, there are strict regulatory compliances, so we cannot use words like treat, prevent or mitigate. But yes, they basically used to improve your overall health and reduce the risk of diseases. So most often in Asia, people are understanding the importance of gut health. And you know that the gut plays a very important role in almost every aspect of health. And now that we know that we have over 100 trillion microbes and these microbes, the kinds of microbes we have, are so important not just for digestive disorders but also for metabolic disorders, so your metabolic syndrome, there is a lot of studies that it is your mood as well, as you know, symptoms of anxiety and depression are actually controlled by the kind of microbes that you have or and therefore, that, again, makes the gut so important. And it is largely for improvement of overall health and not so much for treating or curing a particular disease.

Natalia: 18:37

Another interesting question was about how consumers navigate the market, with so many probiotic options available, how can consumers know which probiotics are suitable for them and which are not, as well how can they know which probiotics are in excess in their gut?

Dr Chin-Kun: 18:52

In the market, so many kinds of commercial probiotics, how do you know, some of them in the amounts, it actually is a very good question. Some of them only very, very minor or medium, several median, but actually, you know, only several million colony, it doesn't work. At least every time maybe several billion. Yeah, it will go works well. So please don't worry about for your gut, usually human is very sensitive, if something wrong, you should understand or maybe too much. So because the probiotics, why we call them probiotics, because actually, they can bring positive health benefits to our human body. And also they produce some very special metabolomics. So usually no side effect. But I think our human body should be weakened. So we can sense how is the feeling? How is the feedback? Very specific.

Natalia: 19:45

We had lots of questions coming in during this panel discussion, but before we end the show, let’s hear some takeaway home messages around challenges of clinical trials and the potential of phytochemicals on the gut-brain axis.

Dr Neerja: 19:59

When you want to launch a product in the country or anywhere, it needs to be backed with science, it's very, very important to design a clinical trial and to get the funding for the clinical trial is not so easy. So a lot of funds are required for the clinical trial. Design of the study, the appropriate length or the period for that particular study is very, very important and also defining the outcomes, you know, for a particular study, when it's drugs it's very, very easy, because you know that it If you're taking a particular drug and you're designing a clinical trial around a drug, it has to treat that disease. But when it comes to functional foods, nutraceuticals, probiotics, prebiotics, and I think also phytochemicals, you know, the design of the study, the final outcome of the study, the period of that study, those are the key challenges, you know, which kind of can sometimes hamper, you know, initiating a clinical trial.

Dr Chin-Kun: 20:52

I say only very short words. There are a lot of treasures in nature. Yeah, especially, you know, fresh vegetable fruits, berries, according to our experience, they really bring very positive effect and improve the health benefits to our body.

Natalia: 21:07

Both Dr Neerja and Dr Chin-Kun shared very valuable insights to our Vitafoods Insights Virtual Expo Asia audience, who fully engaged into the discussion by asking questions. We are very pleased to be able to share some of that thought-leadership knowledge to our Vitafoods Insights podcast audience. Looking ahead for more insights and entry strategies into the Asian, APAC region, stay tuned for our Vitafoods Asia 2022 hybrid event later in the year. Vitafoods Asia will co-locate with Fi Asia at Queen Sirikit National Convention Center in Bangkok, Thailand, and online. The smart events will begin digitally on 26 September, and convene the in-person experience from 5 to 7 October. If you are an industry expert interested in speaking at Vitafoods Asia, we’re accepting speaker proposals through our online speaker portal which you can find a hyperlink into the show notes. Thank you for joining me and see you next time.