Microbiome for clinicians : Recommendations to correct dysbiosis

The human microbiome refers to the aggregate of all microbiota that reside on or within human tissues and biofluids, including the skin, mammary glands, seminal fluid, uterus, ovarian follicles, lung, saliva, oral mucosa, conjunctiva, biliary tract, and gastrointestinal tract. It consists of bacteria, archaea, fungi, protists, and viruses. The human microbiota consists of 10-100 trillion symbiotic microbial cells harbored by each person, primarily bacteria in the gut, while the human microbiome consists of the genes these cells harbor.

The terms?microbiota?and?microbiome?are often used interchangeably, but they have slightly different meanings, microbiota refers to the collection of microorganisms that live in a particular environment, such as the human gut. On the other hand, microbiome refers to the genetic material of these microorganisms. In other words, microbiota is the community, while microbiome is the genetic content of that community. The genes in our microbiome outnumber the genes in our genome by about?100 to 1, though recent publications indicate that the microbes maynot be that numerous.

These microorganisms impact human physiology, both in health and in disease, contributing to the enhancement or impairment of metabolic and immune functions.?The human microbiome is a diverse collection of microbial genomes that includes bacteria, archaea, fungi, and viruses, and it may consist of a total of 900 or 1,000 different species of microorganisms. The microbiome is the community of microorganisms, such as fungi, bacteria, and viruses, that exists in a particular environment, and in humans, it refers to the collection of all microorganisms, bacteria, fungi, and viruses. The gut microbiota and associated metabolites have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. The systemic effects of the gut microbiota are partly mediated through its by-products.?

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The microbiome is essential for human development, immunity, and nutrition, and its dysfunction has been associated with autoimmune diseases, infectious diseases, and chronic illnesses of the gastrointestinal system. Evidence is accumulating that the human microbiome plays a pivotal role in maintaining health and is involved in various biological processes and disease development

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The human microbiome significantly impacts health by contributing to the enhancement or impairment of metabolic and immune functions. The microbiome can influence the body's response to medical treatment, shape metabolism, susceptibility to diseases, and even responses to medical treatments. Microbiota dysbiosis can lead to dysregulation of bodily functions and diseases, including cardiovascular diseases, cancers, and respiratory diseases.?Imbalance of the normal gut microbiota has been linked with gastrointestinal conditions such as inflammatory bowel disease and irritable bowel syndrome, as well as wider systemic manifestations of disease such as obesity, type 2 diabetes, and atopy.

Molecules and metabolites produced by the gut microbiota according to the nutrients or metabolic source and their derived compounds. BSCFA, branched SCFA; LPS, lipopolysaccharides; PAMPs, pathogen-associated molecular patterns; SCFA, short chain fatty acids. The gut bacterial community plays an important role in the regulation of multiple aspects of metabolic disorders. This regulation depends, among other things, on the production of a wide variety of metabolites by the microbiota and on their interactions with receptors on host cells that can activate or inhibit signalling pathways, and either be beneficial and detrimental to the host’s health. The bacterial metabolites involved in these interactions are very diverse and range from small molecules to large macromolecules. They include by-products of bacterial metabolism, such as SCFAs, and complex macromolecules necessary for bacterial integrity, such as peptidoglycan and lipopolysaccharides (LPS).

The abundance and availability of these metabolites are dependent on the microbial composition and are therefore subject to modulation by diet and environmental factors.

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In healthy situation, colonocytes use butyrate as energy substrate via the beta-oxidation in the mitochondria, thereby consuming oxygen and directly contributing to maintain anaerobic condition in the lumen. Butyrate also binds to peroxisome proliferator-activated receptor gamma (PPARγ) which in turn repress inducible nitric oxide synthase (iNOS), decreases nitric oxide production (NO) and eventually nitrate production. Conversely, in pathological situations low butyrate content in the lumen is associated with lower PPARγ activity, increased glycolysis and lower oxygen consumption. This is associated with a higher expression of iNOS which in turn produces more NO and eventually increases nitrates availability for specific pathogens. Butyrate can also stimulate immune cells such as regulatory T cells (Treg) to reduce inflammation. The nuclear transcription factor aryl hydrocarbon receptor (AhR) is highly expressed and activated in healthy colonocytes, whereas agonists of AhR are lower or reduced AhR activity can lead to altered gut barrier function. Enteroendocrine cells (L-cells) are expressing several key receptors activated by short chain fatty acids (SCFAs), specific endocannabinoids (eCBs) and bile acids (BAs). Activating these receptors increase the secretion of key gut peptides such as glucagon-like peptide (GLP)-1, GLP-2 and peptide YY (PYY). Altogether, the interaction between the gut microbes and these molecular actors contributes to reduce intestinal permeability, to improve insulin secretion and insulin sensitivity, to reduce food intake, to lower plasma lipids and to avoid hepatic steatosis and metabolic endotoxaemia. All these effects are associated with lower inflammation. Conversely, opposite effects have been observed in pathological situations.

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Dysbiosis is a term used to describe an imbalance in the gut microbiota, which can lead to changes in bacterial composition, metabolic activities, or distribution within the gut. Dysbiosis can be categorized into three types: loss of beneficial organisms, excessive growth of potentially harmful organisms, and loss of overall microbial diversity. Dysbiosis has been implicated in a wide range of diseases, including inflammatory bowel disease (IBD), obesity, allergic disorders, type 1 diabetes mellitus, autism, and colorectal cancer in both human and animal models. The main factors influencing the composition of the microbiota include medications, dietary changes, as well as psychological and physical stress.

The diagnosis of dysbiosis involves an assessment of the individual medical history, followed by a through physical examination and a series of tests to confirm the diagnosis. The treatment of dysbiosis involves the restoration of a healthy balance of the gut microbiota, which can be achieved through various methods, including use of probiotics, prebiotics, dietary fiber , and polyphenols, among others.

Common symptoms include digestive problems such as cramps, diarrhea, constipation, gas, and bloating, as well as acid reflux, heartburn, and trouble urinating. Other symptoms may include chronic fatigue, inflammation, aching joints, skin issues like acne and rashes, and mental health issues such as anxiety, depression, and trouble with focus or concentration. Additionally, dysbiosis can be associated with a range of chronic illnesses and conditions, including allergic disorders, obesity, type 1 diabetes mellitus, autism, colorectal cancer, Crohn’s disease, and ulcerative colitis.

The triggers of dysbiosis can include dietary changes, chemical consumption, medications like antibiotics, poor dental hygiene, high stress levels, and unprotected sex.

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To support gut health and potentially address dysbiosis, it's generally recommended to avoid certain foods and focus on others. Foods to avoid often include:

• Processed and Ultra-Processed Foods: These can rapidly alter the microbiota and contribute to dysbiosis
• Refined Fats and Sugars: A diet high in these can also impact microbiota composition and diversity negatively
• Red Meat and Processed Meats: Consumption of these meats is associated with dysbiosis
• Carbohydrates in Corn, Oats, or Bread: Some carbohydrates may need to be limited
• Some Fruits: Bananas, apples, and grapes are mentioned as fruits that may need to be avoided
• Dairy: Certain dairy products, such as yogurt, milk, and cheese, may be restricted
• Foods High in Sugar: These include corn syrup, maple syrup, and raw cane sugar
• Meat: Some sources suggest avoiding certain types of meat

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On the other hand, foods that may be beneficial for dysbiosis include:

• Fresh and Seasonal Fruit and Vegetables: These are generally recommended for gut health
• Whole Grains: These can be part of a healthy diet to support gut health
• Fermented Foods: Kefir, sauerkraut, and tempeh are mentioned as beneficial for maintaining a healthy microbiota
• Foods Providing Resistant Starch: Pulses and sweet potatoes are cited as beneficial for the body
• Dark, Leafy Greens: Such as spinach and kale are mentioned as beneficial for gut health
• Fish: Including salmon and mackerel are recommended
• Prebiotics and Probiotics: These can support gut health, such as goat's yogurt, coconut yogurt, and soft cheeses.

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Metabolic changes encountered in dysbiosis primarily involve disturbances in microbial synthesis of short-chain fatty acids (SCFAs) such as butyrate and propionate, as well as increased bacterial production of hydrogen sulfide, ammonia, and secondary bile acids, particularly deoxycholic acid. These metabolic dysbioses can eventually lead to inflammatory bowel disease (IBD) or colorectal cancer.

Metabolic modeling has revealed reduced metabolic diversity in IBD, particularly in sulfur metabolism, and a wide variety of metabolic fluxes that are distinct in dysbiotic microbiomes. Dysbiosis has also been linked to non-communicable diseases (NCDs) including type 2 diabetes, fatty liver disease, and obesity. Additionally, dysbiosis can cause significant shifts in the gut microbiota, leading to metabolic changes. Therefore, dysbiosis can have far-reaching effects on metabolic pathways, potentially contributing to the development of various diseases.

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?Metabolic changes in dysbiosis can be detected through various methods, including the assessment of metabolites in different bodily fluids and tissues. Metabolic dysbiosis is primarily characterized by metabolic abnormalities, which can be detected through metabolomics, such as metabolic fingerprinting, profiling, and meta-metabolomics. Metabolites concentrations in colon (feces, biopsy samples), blood (serum, plasma), urine, or exhaled air, as well as metabolic profiles of examined substrates, can serve as biomarkers for metabolic dysbiosis. Additionally, deep-sequencing analyses of the microbiota have been instrumental in characterizing the association between dysbiosis and the development of diseases such as inflammatory bowel disease (IBD), obesity, and allergic disorders. ?Furthermore, dysbiosis has been demonstrated to affect the immunological and inflammatory status of the host, favor oxidative stress, and increase intestinal permeability, all of which can be indicative of metabolic changes. A ?study demonstrated a striking metabolic shift in the gut environment in prion disease, detecting a total of 145 significant metabolites, highlighting the potential of metabolite analysis to detect metabolic changes associated with dysbiosis.

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To diagnose dysbiosis, several tests can be used. A brief summary of the steps used by one company are as follows.

Sample can be stool or saliva, it is collected in a container provided by the company and transported to their laboratory.

The Nucleic acids (both DNA and RNA) are extracted and sequenced by Next Generation Sequencing. The DNA, RNA as well as gene expression data are measured to create multiple molecular data sets. Artificial Intelligence is used to implement in house algorithms to map and analyze 50 or so metabolic pathways involved and their interaction with food substrates and molecules (nutrition and precision supplements) to predict, identify and predict mechanism involved in various chronic diseases. ?This information is then translated into nutrition and supplement interventions. An interactive report is generated and the patient guided and symptoms monitored for the next few months and modifications suggested. It usually takes a few months for the changes to show effects and benefits become clear.

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Recommendations are aimed at

? Inhibit the growth of bacteria that secretes pro-inflammatory molecules

? Promote optimal microbial functions that promotes anti-inflammatory activities.

? Prevent inflammatory metabolites from passing into blood Stream

? Empower your cells to perform their functions optimally.

? Promote healthy gut brain communication to reduce instances of stress, anxiety & depression

? Optimize your glycemic response to food to improve your insulin sensitivity & reduce risk of type 2 diabetes.

? Overcome food & sugar cravings through improved secretion of GLP-1 & PYY

? Optimize your cholesterol metabolism & stimulate production of beneficial secondary metabolites to promote cardiovascular healthMicrobiota modulation through the use of prebiotics, postbiotics, dietary fiber, and polyphenols has shown promise in correcting dysbiosis and restoring a healthy balance of the gut microbiota. Further research is needed to fully understand the efficacy and safety of these compounds in addressing dysbiosis.

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Restoration of the dysbiotic gut microbiome, which refers to an imbalance in the microbial community structure, has emerged as a promising therapeutic approach. Several strategies have been investigated to achieve this.?These approaches aim to restore the balance of the intestinal ecosystem, counteract dysbiosis, and promote homeostasis. Research has shown that restoration of the gut microbiome can have a significant impact on reducing the risk of colitis and other intestinal and extra-intestinal illnesses.?Studies have also demonstrated that restoring a single microbe can be enough to correct lifelong dysbiosis, highlighting the potential for relatively small changes to have a dramatic impact on the microbiome.?Therefore, the restoration of the dysbiotic gut microbiome is considered clinically significant and essential.

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