Narrator: 

Introducing Professor Berni Canani, internationally recognized as one of the leading researchers in the fields of pediatric gastroenterology, food induced diseases, and nutrition. Since 2019, he has been included in the PLoS list of the most influential scientists in the world, with more than 300 widely cited publications, currently serving as the chief of the Pediatric Allergy Program and founder of the Immuno Nutrition Lab at Ceinge Advanced Biotechnology Research Institute in Naples, Italy. Please welcome Professor Berni Canani.

Professor Berni Canani:

 Hello, hello, hello. so many friends and colleagues around them from many parts of the globe. This is, my conflict of interest disclosure. And let's start to talk about problems that we have every day in our clinical practice. We learn a lot of important things from the basic science. And let's start to translate the what is provided by the basic science literature for our clinical practice.

One of the most important problem for our clinical practice are the allergic disorders, and in particular, food allergy. When we are talking the first period of life, everybody knows the importance of an allergic match. What does it mean? Allergic march? I have an infant six months of age today in my office. This baby could present an increased risk.

Develop other allergic condition. Later in the life, this detrimental progression from the first period of life to the later ages is considered an allergic march. Atopic dermatitis, for example, is one of the most the sign of this kind of condition. We know that dermatitis is affecting up to 20-30% of children worldwide level, but it's important to underline that if I have a child affected by atopic dermatitis in the first months of life, this baby has, an increase risk to develop food allergy six times higher.

At the same time, if I have an infant affected by food allergy today in my office, this baby will present an increased risk to develop other atopic manifestation. A five times higher risk to develop allergic rhinitis or asthma. This is what's happening in our clinical practice every day. We have children, we have infants. A better to say that around the age of two three months, six months developing non-IgE mediated allergy, food allergy, blood in the stool, chronic diarrhea, vomiting, abdominal pain, constipation, then atopic dermatitis. Then many patients from known IgE mediated condition could shift to IgE mediated illness this, for example. This is a typical example. Then a later in their life is a case ulcerative colitis This one of the most prevalent chronic inflammatory condition of our GI tract in the 2023.

And asthma and rhinitis. This is the problem. And to counteract this problem, as a doctor or physician, as a pediatrician, we need to understand which are the mechanisms. And if you look at the literature, the explanation is same is exactly the same. All right. This is a combination between genetic background and environmental factors. Yes. My time a physician.

I'm a doctor. Roberto Canani and I would like to do my best for this family, for decide what is important. The genes are important. We know now around the one hundred genes that could be associated with the atopic march, with the development of food allergy later in the life, asthma and rhinitis. And interestingly, these genes are related to two the important aspect for our clinical practice gut barrier modification of intestinal permeability, abnormal passage of the genic peptide from the diet of the baby to the immune system, and of course, the immune system.

Another important aspect is epistatic. What does it mean? epistatic. I'm not super lucky because I have a polymorphism filaggrin. Filaggrin is a very important in modulating the intestinal permeability as well as the skin permeability. If you have a polymorphism in this filaggrin, you have also on overexpression of the receptor for IL4, IL4 is one of the most important gene factor of modulating the inflammatory state in a child affected by allergy.

So thinking about also epistatic. So having a well-modulated well developed well-structured gut barrier or skin barrier is extremely important to protect our babies against the occurrence of allergy to not only food allergy atopic dermatitis later in the life asthma and allergic rhinitis. So in other words this is the situation I need to have as as as Maria Carmen said I need healthy gut microbiome because if I have healthy gut microbiome, I have the perfect production of short chain fatty acid.

I have a beautiful modulation of the gut, microbiome of the intestinal permeability. I can advocate to the immune system because they can activate the Tregs. Tregs are the most important cells involved in immune tolerance. And if the Tregs are activated, there is the production of IL-10TGF-beta. And there is a downregulation of these cells that are responsible for the disease.

Fantastic. Beautiful. Simple. On the contrary, if I have a receiving too many antibiotic course, if I'm receiving junk food starting from the first period of life, I have an alteration of the gut microbiome. This leads to a breakdown of the barrier integrity. Look at this abnormal transport of antigenic peptides from the diet of them, of the child to the immune system.

Abnormal activation of the immune system, activation of TH2 Phenotype response. Cytokines IL4, IL5 and IL9 IL15 the engine force. of the allergic response at the end of the day, after few seconds. After a few minutes, the baby will present the signs and symptoms that you know very well in allergy.

So preserving the gut barrier is very important for our clinical practice. Let's push the importance of breastmilk. Let's consider a to to push the concept a healthy diet to starting from the weaning period. Let's use fermented foods prebiotics such as fiber fibers, fibers, positive biotics in this case I can modulate. They got the microbiome composition, I can produce a butyrate. I can modulate the mucosal layer. The external mucosal layer is the hormone. They got the microbiome without the mucus I cannot perform  for my gut micro microbes modulation of intestinal permeability activation the immune system against allergy, against inflammation, against autoimmunity. Remember this important point. On the contrary too many infections in the first people life at the weaning unhealthy diet. The junk foods, junk foods, junk foods or antibiotic decks or proton pump inhibitors, or in adolescence, alcohol abuse, sleep deprivation, stress, too many Playstation high up on a disruption of the got the microbiota barrier. I have an abnormal, intestinal permeability activation of the immune system toward allergy auotoimmunity, inflammation. This is the key is simple. We can counteract the aspect day by day in our clinical practice as pediatrician. Other important the powerful point is epigenetics. What does it mean? However this beautiful girl I can influence the dietary habits of this beautiful girl. For example, I can say let's eat more and more and more vegetable. Why? This could be important because as Maria said, I can shape the gut microbiome of this girl.

I can increase the number. The abundance of the healthy bugs. And these bugs are very important because these bugs are responsible for the production of metabolites propionate, acetate in particular, butyrate, among many other compounds could be reduced. It could be relevant, including lipopolysaccharide from the membrane of the of this bacteria. At the end of the day, these metabolites this post biotics are recognized by ourselves and I can activate the immune system against allergic immunity. Okay is interesting. The problem is I'm targeting, six months, 1 year of age. Baby, I would like to modulate the life of this baby and this metabolites in particular. Butyrate are very important because they are beautiful epigenetic modulators. Butyrate could influence through epigenetic mechanisms, more than 400 genes in our body. Modulation of DNA methylation. What does it mean? Methylation? I can block the expression a particular gene. I have a lot of family member in the Berni Canani family affected by allergy, but I can protect my son because through the epigenetic mechanism I can block the expression of this gene. So at the end of the day, my son is protected against allergy or micro remains or is still limited data deletion at this term.

At this point, I can influence a not totally one generation on cells, but also the next generation of cells I can exert a long-lasting modulation of the immune system against allergy, against autoimmunity against obesity is super powerful. It's super cool. We can do this from this very stupid education of the dietary habits. But you can do this also in non-breastfed infants with the formula choice, we be back on this point later in during my in my lecture. So gut microbiome alteration is very important. As Maria said even though dysbiosis could occur also months before the occurrence of or some day symptom of allergy. At this point they gut  microbiome alterations lead to an alteration of  the gut barrier increased permeability. At this point there is occurrence of a food allergy.

Food allergy is mediated by an alteration of the immune system. And this could lead to an increased risk of develop other allergic disorders. Allergic march is EoE but immune system dysregulation means that this baby is also present and increase the risk to develop other immune mediated condition, including IBD or celiac disease, and the immune system is able to talk with the the neurons modulating visceral pain perception, modulating the motility of the GI tract, and this leads to a dysregulation of the GI tract function increases the risk to develop functional gastrointestinal disorders. You know that the baby affected by cow’s milk protein allergy in the first year of life. More about 40% of this baby will present the functional gastrointestinal disorders within the life. It's an important problem we need to do. We need to consider this kind of stuff. The neurons that are living, that are acting in my gut are able also to talk with the neurons living and work in my brain, the so-called gut brain axis. And this is also important because we know now that the baby is affected by cow milk allergy. In the first months of life, present an increase the risk to develop other neuropsychiatric disorders in their life and such as autism. So this is the parameter we this is the progression of their condition. This is very important for my clinical practice.

And I need to know how to target how to block this evolution. And we need I need to know the environmental factor that could influence positively or negatively this type of evolution. And we know now which are the environmental factors. We know now that these environmental factors could act on the genetic background, the family members in the Berni Canani family, and through epigenetics, I can modify the phenotype or my son or my daughters, and they can inhibit the occurrence of allergic condition. So we have genetic predisposition, for example alteration in filaggrin alteration in testing of ability. We have at the same times the exposure to detrimental environmental factors. This could lead to an increased risk to develop atopic dermatitis. The effective in the barrier function of the skin as well as the gut, level abnormal antigen exposure to the skin or to the gut occurrence of food allergy if I can if i am able to to to modify to cure this baby, there is a persistent activation of tissue response and the sensitization or the inflammation goes to the lung to the nose at the baby will present asthma in the allergic rhinitis. But in 2023 there are also some good news we know, which could be possible to do in clinical practice, we know which are the environmental modifiers over the allergic march. Breast feeding. Early introduction of food antigen. by the age of four six months. Dietary factors. Let's start the weaning from the 4 to 6 months of age. But adding material diet fibers olive oil fish diet see probiotics. Stop smoking exposure at or later in the life. If the situation is not super good, let's use some drugs to modulate the occurrence of other allergic condition. I'm just back from the committee. In the United States, they are using so many biologics now also to to work in this direction to block the allergic march. And one of the most important environmental factor now in eliciting these problems are ultra processed foods. And one of the most important aspect, one of the most important compound within the ultra processed foods umbrella are the advancing glycation end products. Babies in Naples in my country loves this kind of stuff. They ask every time this kind of foods the problem within these foods there are these and advancing official name products is derived from the combination of sugars with proteins and fat. The problem is that these compounds are recognized by our cells to the receptor rates. rates means activation of the allergens. Allergens is that is a is a danger signals activation of TH2 response. Activation of the production of the other cytokines, such as either IL-33, or IL-25 or TSLP that are modulator intensity and ability, alteration, test ability, negative impact on got the microbiome increase the risk to develop many chronic non transmissible diseases. We investigated the possible influence of this kind of stuff in in food allergy. And we found an incredible higher consumption ultra processed food in children developing a food allergies compared with the control we have now a beautiful machine, noninvasive machine to measure the accumulation in the skin of this ultra processed food. And also the concentration was completely higher. And in vitro we observed an alteration in type junction structure, increase intensity variability, abnormal transport of allergenic peptide from the gut lumen to the lamina propria, activation of inflammation, activation of the pro-inflammatory cytokines involved in allergic response. Occurrence of food allergy. Exactly the same data. We are obtaining exactly the same data in in in in the esophagus of our child’s, this are completely new disorders. When I study medicine this was not a chapter dedicated to EoE. Now EoE is what is one of the most important inflammatory condition. If I'm collecting a bioptical sample from the esophagus autonomic control.

And they put in vitro in my lab and they can add the ultra processed food, I can induce a disease in vitro in one day. One day. Consider the fact now we are measuring again the consumption ultra processed food in our country enables the caloric intake is is mediated at up to 60% by ultra processed foods. If I'm asking it to A 2-3 years of age. Baby, what is this, a kiwi? What is this pear? I don't know, they live two three years at home because of the Covid 19 they are completely unaware of. Does it mean a fresh kiwi, a fresh pear? They are consuming ultra processed foods and this is the situation. So let's start early in their life as Maria say let's start at the beginning of the first trimester of pregnancy. Let’s explain to the mother. The potential importance of the healthy diet during pregnancy because the during pregnancy. I remember my my wife during pregnancy. She was like a doctor. I would like to understand them. So many fact the vitamins that the drugs this market blah blah blah blah blah blah. After after the delivery, Nothing more. Roberta ciao ciao I don't I don't care about this kind of son. But during pregnancy is important. We can teach the mother, we can explain to the mother. We can work with the obstetrician gynecologist to explain this kind of stuff. We are promoting so many activity in this field that the results are very, very interesting. Protection against obesity, protection against allergic protection against out immunity influencing and educating only the mothers. Because if I can educate the mother, by definition, I will educate to the child. No money. Super cheap, no drugs, no biologics, nothing. Simple words. But we need the nutritionist. We need dietitians because I cannot do everything by myself. And literature is full of data like this. If I can influence the diet of the mother during pregnancy, this diet could influence their gut microbiome the mother to pregnancy.. This is a normal production of short chain fatty acid. And in the fetus there is an epigenetic modulation. The protection of starting early life, starting pregnancy. So let's work on the maternal diet. Let's work during pregnancy. Let's work during lactation. We learned today that if the mother is receiving unhealthy diet. There is the perfect level in the breastmilk of HMOs or bacterial DNA secretory IgE, miRNAs, sIgAs, lactozyme, lactoferrin. This compound could be modulated by the diet of the mother and there is a beautiful effect on the infant gut microbiome on the infant immune system, metabolic pathways, long lasting production against infectious diseases and allergy and autoimmunity and obesity. Covid 19 was an important experience for us because we learned the importance gut barrier babies, adults with the defective gut barrier with the fact that gut microbiome were more prone, to be hospitalized in intensive unit.

And the diet of the mother is very important. Modulating butyrate. If the mother is receiving an healthy diet, she is able to produce the butyrate. Butyrate goes to the bloodstream to the to the breast milk, and the baby is receiving the right amount of butyrate. If you read the literature regarding butyrate against cancer, against obesity, against allergy, against immunity in all paper, the best concentration, the best effective concentration is 1 millimolar of butyrate.

Do you know which is the best concentration that we can find out in breast milk in a mother receiving a healthy diet 1 millimolar beautiful and one millimolar exerts a beneficial effect on the gut barrier a beneficial effect on the Tregs and on the cytokines. So this is the point we can modulate. We can modulate the gut microbiome.

We can increase butyrate. We can have a positive effect in the long term. And this is the mother. is the baby. Receiving this type of diet is protected against asthma and against obesity. The contrary is receiving this kind of diet asthma and obesity. So let's promote this kind of stuff. And let's promote as protection for food allergy. But also to stimulate something in baby affected by allergy.

When for the first time EHCF supplemented LGG based formula became available in my country. We started this kind of a clinical trial for the first time. We demonstrate a huge advantage in stimulating immune tolerance. These are a baby receiving from one year the new strategy or the other strategy. Look at the number of children who acquired immune tolerance after one year. Non IgE mediated subjects. IgE mediated subjects later. So many other patients receive exactly the same treatment. In all cases they observed exactly the same effect a stimulation of immune tolerance. Now we know that the mechanism are mediated by protein’s action and by LGG. These are experiments that we are able to perform at our lab collection of different formulas. Purification of the protein fraction, digestion using the artificial gut system, and incubation of cells collected from children affected by allergy or incubation of human enterocytes. Only peptides from casein were able to stimulate a TH-1 immune response. IL-10 interferon gamma protection against allergy. Only peptides from casein hydrolysis are able to stimulate Tregs activation andvTtregs activation to an epigenetic mechanism, a long lasting effect, I'm stipulating in not just one generation. And that's about the next generation in cells and only peptide from casein were able to stimulate got the barrier mucus thickness, the oral- gut microbiome occuldin, and Z0-1 intestinal permeability, no abnormal transport of antigenic tides from the gut to woman to the lamina propria. And if I try treat a baby with this kind of formula. All in this case. After six months of intervention, I can increase the number of bacteria that are biomarker of unhealthy gut microbiome. Why these? Because these are responsible for butyrate production. I can increase I can restore the production of butyrate in the gut to lumen in six months. In a child affected by food allergy by in this cow’s milk protein allergy. And  increasing butyrate production like thanks to this kind of stuff we can modulate epigenetics. And these are the data comparing children are treated with the EPICMA EHCF+LGG or with the soy formula. Baseline six months 12 months only in children receiving this strategy only these babies. We observe an epigenetic modulation of Tregs an epigenetic activation of Tregs. So all together this data strongly suggests that it's possible to counteract the atopic march in children affected by cow milk allergy.

Because in children affected by cow’s milk allergy I can I can select the formula in starting from this kind of evidence we design this study children affected by IgE mediated cow’s milk protein allergy visiting our centers because the necessity to perform a diagnostic of a food allergy, the formula shows, was performed by the family pediatrician asking from the other food challenge. So we obtain five different course as the EHCF supplemented with LGG rice, soy, whey or amino acids. We continue to follow up for one year and after one year, the first year, the second year, the three years of follow up, we observe this kind of data. Children are receiving a EHCF a supplement LGG presented a decrease risk to develop atopic march 20 percent 50% with the other formula.

The worst case scenario was amino acids. This formula because amino acids are unable to modulate the immune system, and these are the results for the asthma, eczema, rhinoconjunctivitis and urticaria. In all cases, we observed on a beneficial effect in protection against atopic march and of course, in a study like this is mandatory to perform an analysis, putting together all the variables that could influence the study outcome and the formula choice. The formula choice was the most important variable able to influence the occurrence of atopic march. So we are facing a changing scenario. We are observing a huge increase in the incidence and prevalence of food allergy, as well as many other allergic disorders in the pediatric age. But now we know which are the which are the problem, which are the target.

And with the diet strategy, we can counteract step by step all these points. I can counteract the I can modulate the dietary factor, the microbiome activity, the epigenetic mechanism. At the end of the day the immune system. And this strategy could have a positive impact on the natural course of food allergy, as well as the other preventing strategies against the occurrence of other allergic conditions later in the life.

I would like to thank you, but. Let me thank all the groups that are working hard on these topics. The giants of Naples. We like to walk together from the bedside to the bench, at bench to the bedside clinic unit to nutrition unit and research unit. Thank you very much for your attention.

Okay, we worked out today, but now we are not to know what we are learning. So we have we have now three different question. Please be concentrated. Pay attention. Because the questions are quite simple, but I need you to understand if this type of activities could be helpful for your clinical practice. The first question is which are the following sentences correct?

The allergic march. Of course, in all children affected by cow milk allergy, the second point is the allergic march. Of course, only initiated by atopic dermatitis, the allergic march occurs only in 20-50% of children with the food allergy. The allergic march occurs only in children with the IgEe mediated food allergy. Please vote.

The screen. Sorry, beautiful because the screen is completely different to your screen. Okay. Thank you so much. The question is, the answer to the right question is C. So perfect. We we are we are able to understand what's the important what's important, what’s allergic march much risk in children affected by cow’s milk allergy. So let's move to the second question.

All right. Which of the following sentences is incorrect. The progression from atopic dermatitis to later developing and food allergies, allergic rhinitis and asthma is called the allergic march. About 50% of children with atopic dermatitis will develop asthma. About 80% of children with atopic dermatitis is affected the by food allergy. Food allergies in childhood are a risk factor for allergic rhinitis and asthma.

This is very important question for our clinical practice for to avoid a misdiagnosis and overdiagnosis of food allergy in our children.

Perfect okay okay okay okay okay. This is very important. Only 20-30% of babies affected by atopic dermatitis in the first period of life, in the first months of life are really affected by food allergy in general. They present a more severe form of atopic dermatitis. In this case, we need you could can consider the occurrence of a food allergy but let's in this case adopt a, very, effective diagnostic workup to rule out the presence of a food allergy. The last question is which of the following sentence is incorrect? Allergic March results from complex and not fully known interactions between genetic, environmental, epigenetic factors. Atopic dermatitis often the first manifestation of the allergic march. There is a strong need for studies investigating a multifaceted preventive approach targeting but the gut barrier and environment early in life. The allergic march could not be prevented. Come on. Please.

Thank you very much. Thank you very much. Yeah. I will continue my discussion with the 10% of your that are not, in favor of the possibility that to prevent atopic march. Thank you very much again for your attention.