Week 10 : Lecture 47: Nutrigenetics, Nutrigenomics, and Diet–Microbiome Interactions

Hello and welcome dear learners to the NPL course on nutritional epidemology a way towards a healthy life for the model 4 diet nutrient dietary patterns and disease epidemology for the chapter 47 we are discussing about the nutrienatics, nutrienomics and diet microbiome interactions. What does it follow for giving us the introduction to the precision nutrition, neutrogenetics and gen diet interactions, nutrienomics and personalized nutrition, gut microbiome and health outcomes, diet microbiome interactions and opportunities, limitations and ethical considerations. So for the precision nutrition we know that for early to a near century public health nutrition related a populationwide dietary guidelines standard recommended dietary allowances these baseline recommendations assume as an average human metabolism. However, uh the clinical reality demonstrates that substantial interindividual variability two individuals consuming the same caloric intake and macronutrient breakdown while exhibits the widely different postradinal glycemic lipmic and inflammatory responses. Now for the precision nutrition what we will try to see is that the shift of the paradigm from generalized public health targets to highly individualized predictive algorithms. It integrates the multivariant inputs including the host, genome, epigenome, metabome and deep phenotyping, lifestyle factors and the gut metabome to design a targeted nutritional interventions that maximizes the metabolic resilience which prevents the chronic non-communicable diseases that is called as NCD. So this gives us what is a precision nutrition which has a paradigm shift in itself. Now the nutrienetics and gene diet interactions carefully to understand over here the nutrienetics investigates how an individual's existing genetic variation inherited with DNA sequences. you know the DNA sequences which gives us the dictate of their physiological metabolic response to specific dietary components. For example, you may find the primary focus of neutrogenetic researches centers on single nucleotide polymorphins. Okay, that is N SNPS and the singlephase pair variation in DNA that alters the binding affinity structural stability and catalytic efficiency of metabolic enzymes and transport the proteins. Okay. And now the cycle how to go ahead with the neutrogenetic mechanistic matrix. We will see the dietary input and exposure that is the high saturated fat intake. the host genetic architecture that is APO A2 polymorphism that is CC versus TT genotypes and clinical phenotypes that is severe visceral obesity and metabolic syndrome risk. You will understand over here that uh we can find the visual workflow on the the slide which serves as an premier case study for neutrogenetics. This is the perfect illustration of how a populationwide advises fails. Imagine you have two different patients sitting in your clinic. [snorts] Both of them consume a diet that is high in saturated fats as usual and specifically which is exceeding 22 g per day. So under the old nutrition paradigm, we would assume both individual will face the same metabolic consequences. But do you really think that this will really have the same consequences? We'll see and understand over here. Neutrogenetics proves this assumption as a wrong. Why? Because introducing the host genetic architecture as the ultimate gatekeeper in this matrix. The gatekeeper is polymorphism in the APOA2 gene at the 265T versus C promoter site. and we can find the pathway for your first patient with the CC genotype. This highs saturated fat environment behaves like a biochemical match. It triggers a profound phenotype change and the high lipid exposure causes visceral fat accumulation bringing a severe risk of metabolic syndrome, insulin resistance and cardiovascular issues. This is for the first patient. For the second patient, what it is? It is with the TT genotype. Previous case it was CC genotype. Second case it was TT genotype and they are consuming the same amount of beon butter and red meat. Same like the previous one. Yes. Mathematically and clinically there is a zero statistical correlation between their fat intake and their body mask index. So this is very important to be understood. Their metabolic pathways safely process the intake without triggering the obesity. So you will not find obesity triggered over here and you can understand in many patients like this. So as a clinical researcher this metric teaches us the diet is the exposure but genome dictates the end point. Okay I again repeat the diet is the exposure but the genome is dictating the endpoint. So we cannot truly understand chronic disease risk without evaluating both variables simultaneously. So you need to understand the CC genotype as well as the TT genotype. Now the classical clinical uses case the APO A2 gene and saturated fat that is obesity risk which encodes the epo lipoprotein A 12 a structural component of high density lipoprotein that is HDL particles. individuals carrying the homozygous CC genotype exhibits a unique sensitivity to dietary lipids. So what it is when you use a saturated fat intakes that is high the CC genotype act as a genetic trigger that dramatically applies the risk of visceral obesity. So you find in the second case and the insulence resistance for individuals which are carrying the TT genotype the saturated fat intake shows no significant correlation with the body mask index. So you will find obesity at one place and no obesity at the other place. the MTHFR gene and the folate that is homocyine cleaning. The MTHFR gene regulates the synthesis of methyline trifolate deductase a foundational enzyme in the folate homocyine cycle. Okay. So the 677 C polymorphism causes a thermoliable structural alteration in the enzyme reducing its catalytic activity by up to 70% in the homozygous TT individuals. Okay. Carefully understand that when dietary folate index is low, the genetic impairment halts the remlin of homocyine to methylinine resulting in elevated circulating plasma homoyine levels. Okay. So a powerful direct metabolic risk factor for cardiovascular pathology and endothelial dysfunction. So here the gene is giving you a cardiovascular pathology. Now understanding the neutrigenomic and personalized nutrition. While neutrogenetic details how genes affect dietary response, neutrogenomics inverts the equation. It is ulta. So it explores how dietary components actively modulate the expression of the whole genome. Nutrients act as signaling the leans that directly interact with the transcription factors cascades alter the chromatin structure or regulate the epigenetic modification thus dictating the cellular protein. So in this the neutrogenomic cascade is like nutrient molecule. Okay. and then nuclear receptor activity and a epigenetic or we can say transcription in the nutrient molecule that is a longchain omega3 and in the nuclear receptor activation that is PP alpha transllocation to DNA promoter sites and the epigenetic transcription you will have a downregulate NFB halting the inflammatory cytoines okay so here you can understand How the neutrogenomic cascades is going on? The molecular pathway of dietary regulation in the nuclear receptor ligans. The polysaturated fatty acids acts as the natural signaling lians to proxogone and polifate activated receptors. Upon binding a longchain omega3 fatty acids, the PP alpha complex undergoes a nuclear transllocation and binds to a specific promoter regions on the DNA called as peroxim polyrate response elements. Okay, what it is called as peroxone polyrate response elements. So this interaction upregulates the transcription of genes responsible for mitrochondrial beta oxidation. that is called as fat burning while simultaneously when you are downregulating the nuclear factor kapa B the pathway effectively turning of the transcription of pro-inflammatory cycines okay then the epigenetic remodeling what is epigenetic remodeling that is a DNA methylene and bioactivate so dietary bioactivate serves as a major environmental regulators of the epiggenome you will find that this is acting as a natural histone uh deactylase inhibitor by shutting down the hyperactive HDAC enzymes. All sulforophane allows histones to retain their acetyl groups opening up tightly the packed chromatin structure and restoring the transcription of crucial tumor suppressor gene. Okay. So in this way you can see that there is a similarity that is dietary methyl donors directly feed into the S adino slimythamine pathway and driving the targeted DNA methylation that can silence the pro-inflammatory genetic regions without altering the underlying genetic code. So this molecular pathway of dietary regulation is cleared by stating over here to understand the section one which is with the nuclear receptor liance and the section two with the epigenetic remodeling where you may find in the first section as a PUFA binding the PPR binding and the genetic transcription actually which is giving over here versus two for the section two the HDAC inhibition DNA methylation and DNA methylation which gives us the outcome towards a macrosomium culumation. So this is an integrated division from the other pathway and visually detailed manner and balancing a retailing and graphic of the description which is seen over here where no text remains scrambled. Now what is gut microbiome and health outcomes. So as you have understood that in the gastrointestinal system of the human which harbors a trillions of microorganism you might have seen that there is lot of encoding a meta genome that drops the human host genome and what is the ratio it is 100 to1 okay so what is the complex microbial ecosystem that we encounter and which acts as a metabolic and imunological hub that directly regulates the host hemoasis and you need to maintain the hemoasis. Okay, this is where the main tragic comes where you find the metabolic pathway of dis uh disbiosis where you say the symbiotic metabolic zone and the disbiosis inflammatory zone. In the symbiotic metabolic zone you may find a dominated sacrolytic taska fermentation of complex fibers yielding with bate acetate and propinate and the disbiosis inflammatory zone that is dominated by pathobenotins. Okay. Degradation of mucosal barrier and yields with lipopolyacrates. Okay. So the gut microbome and health outcome also defines to state that how it is regulating the hemostasis the metagenomic health impact. If it finds to see that the SCFA cascade which is the sacrolytic bacteria fermentss the complex nondigestible dietary fibers to product what is that product short chain fatty acids the principally acetate proportionate and bureate which serves as a primary fuel source for colonocytes reinforcing tight junction proteins to maintain a gut barrier integrity and so where we find that they are more involved in hippatic uh glycogenis and induced static signaling which you come across to state that how the metagenomic health impact is being reflected to this the LPS endotoxmia matrix which is conversely a state of prolong microbial disbiosis which we have seen in the previous slide characterized by a loss of taxonomic diversity and a overgrowth of gram negative pathoburns resulting in excess shedding of lipopolyaccharides. When the protective gut barrier is compromised, LPS transllocates directly into the host circulatory system which triggers to give you the cells that is immune cells sparking chronic systemic lowgrade inflammation that drives you for the insulin resistance, vascular endollethal damage and hippatics stenosis. Now in diet microbomb interaction the gut microbome is highly dynamic with the taxonomic composition and functional output heavily shaped by the dietary substrate provides by the host. What it is? It is giving us the complexity that substrate driven transformation. What is this complexity? The FODMAPs and gas kinetics that is the fermentable oligosaccharides, disaccharides, monosaccharides and poly are shortchain carbohydrate and that escape small intestinal absorption. Upon entering the colon they undergo a rapid microbial fermentation by highly efficient methogenic and hydrogen producing taxa. While this pathway yields beneficial SCFAS, the rapid gas kinetics combined with osmotic water shift can induce [clears throat] visceral hypersensitivity and structural bowel distension. A key factor for IBS which you might encounter with the current diet that people are trying to take and we get the pathology of irritable bowel syndrome. The kite tao that is ether atherosclerotic vector which in a host consumes a diet rich in lcartinine found in the red meat choline found in eggs and specific gut taxa expressing the trimethylamine lias enzymes converts these substrates into gas called as volatile trimethylamine. The TMA is absorbed in the portal circulation and travels directly to liver where the host hippatic enzymes FMO3 oxidize its into TMOA. Eliminating the circulating TMOA alters the cholesterol metabolism inhibits the forward bile acid trapod and you may find there is lot of regurgitation which is being feed into this area which gives more scavenger receptors accelerating the development of ethoscalotic plagues into the human arteries. This can be seen into this picture where the food maps and the gas kinetics the substrate in digestion where the food maps is going more towards the absorption enter into the colon and the PPR binding which is the final outcome giving you the dimensions ordered and here on the other part which is being seen the gut conversions towards the volatile TMA gas and the liver conversions of TMA particularly which is more towards the circulatory and pathology of moving towards accelerating the eth sclerotic plague development opportunities, limitations and ethical considerations. You have to take in understanding that how the major clinical opportunities that translate from the bench to the bedside phases which is significant in the structural, scientific and ethical challenges. But there are some opportunities in clinical practices. Precise nutrition allows clinicians to move past generic advice and offer datadriven interventions that yield a higher patient compliance due to personalization. So it is very much acceptable by identifying the subclinical phenotypes through integrated multiomics clinicians can design targeted prevent diet before chronic disease manifest clinically. So you don't need to wait, you have to grab the opportunity. Analytical and technological limitations. This comes with a very productive gap. Very important where you may find that although the multiomic data sets that is metagenomics plus epigenetics and deep phenotyping generate a immense amount of data, current machine learning algorithms still struggle to explain the full variance in the individual metabolic responses. But human biology is highly dynamic. Okay. To a level where you can find environmental factors like sleep deprivation, physical activity, cardiac rhythms, acute psychological stress often overshadow the pure genetic and microbial predictions. And the data sparity and assembling issue of metagenomic sequencing provides relative abundance data rather than absolute quantification making cross cohort comparison challenging. Furthermore, it lacks the industry supports for standardized laboratory benchmark for sequencing the depths the bioinformatic pipelines leading to inconsistent results between commercial test providers. Okay. So limitations are there on the other sides of analytical and technological where versus there are even opportunities in the clinical practices. Now we have to go with the ethical legal and policy consideration where the direct to consumer that is DTC wild west the market is flooded with commercial DTC genetics and microbomb testing kits which is like offering a sweepy unelivated health claim based on weak epidemological correlation. Many of these algorithms rely on single NSP inputs ignoring the complex polygenomic architecture of human chronic diseases. This can use unnecessary patient anxiety where you may find that the nutrient deficiencies due to over restrictive diet recommendations are being coming over and the data privacy part and genetic discrimination where you may come across very highly sensitive inidentifiable biological signatures. If these massive multiomic databases are compromised or sold to commercial third parties, what will happen? It will create a serious risk regarding genetic discrimination in the health insurance underwriting. Corporate wellness on boarding and employment screening which will give that a clear national and international degra bodies must be establishing a safeguard a pattern of shield where the patients autonomy ensuring the equitable access to precision health innovation which is very very important. Then comes the final key takes away where the precision nutrition which we have studied over here gives a transition between public health away from one size fit all guidelines by in integrating to the host genome epigenome and multi- mettogenome to target individual metabolic profiles. The genomic biirectionality that is a nutrienetics details how in inherited genetic variations NSPS determine individual metabolic responses to food groups while multigenomics explores how dietary bioactive actively change the gene expression from epigenetic and transomic pathways and the metabolic cross talk. The gut microbiome functions as a key metabolic translator. It converts dietary substrates into protective signaling molecule like short chain fatty acids or inflammatory vectors like trimethylamine and oxide directly driving the chronic disuses. This is very keenly connected with the either part and the rigorous implementation what it is realizing the potential of precision nutrition requiring the addressing major data standardization limit and bridging the predictive gap in current machine learning models enforcing the strict regulatory protection around the consumer data privacy. So it is more on the part to make you clear about the precision nutrition transition with the references we find that precision nutrition through the diet gut microbe interactions and all this uh you can go in clarity and understand how neutrogenetics and neutrogenomics really works for. So with this we come in end to this chapter. Thank you very much. [music] >> [music] [music] [bell]