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EXTRACELLULAR MATRIX

The extracellular matrix is a network of proteins and other molecules in the space between cells. It helps cells attach to one another and move around. You can think about this like scaffolding for building a house: it provides support and structure for all kinds of activities inside the cell without getting too involved in how those things happen. When there’s damage or injury, it also sends signals to help repair or replace damaged parts of tissue by recruiting stem cells from elsewhere in the body. In this blog post, we will explore how extracellular matrix regulation works to maintain homeostasis from birth to death so you can better understand your body’s natural aging process!

WHAT IS THE EXTRACELLULAR MATRIX?

The extracellular matrix (ECM) is a dynamic structure that provides a structural framework for cellular organization and movement. It is a three-dimensional space, extending between cells that are defined by components produced by the cells themselves as well as cells that they neighbor.

The ECM consists of a dynamic mixture of structural proteins which are typically secreted from the cell into the extracellular environment. The extracellular matrix is made up of many components, including molecules like collagen and elastin, macromolecules like glycoproteins or proteoglycans, proteins like adhesion proteins that allow cells to bind to each other, growth factors that signal new tissue formation, and others.

Collagen is one of the most prominent components of the extracellular matrix. It provides strength and stability to tissues and is primarily responsible for wound healing and tissue repair.

There are many types of glycoproteins, or proteoglycans, which give the matrix its winding appearance, similar to DNA’s iconic double helix. These macromolecules allow cells to recognize and bind to the matrix components.

Several types of adhesive proteins promote cell-to-cell contact, which can be found on either side of a plasma membrane where they’ll spread out from the cell’s surface towards the extracellular matrix. These proteins will crosslink, or bond together with other adhesive proteins to form a mesh that reinforces the adhesive bond between cells.

4 Major Purposes of the Extracellular Matrix:

Containment of cell growth: This refers to how the matrix can “wrap” around cells while still allowing them to grow in size while confined by the surrounding ECM.

Cell signaling and communication: Cell signaling and communication refer to how cells can send signals through the matrix so that growth and development happen in the right place at the right time.

Binding cells together to form tissues or organs:  The adhesion proteins that hold cells together can also link them to the extracellular matrix.

Removal of dead or damaged cells from the body:  Cells are constantly dying and being replaced, so the ECM will send signals to attract stem cells that can migrate towards their location within tissue in order to repair or replace damaged cells.

HOW DOES THE EXTRACELLULAR MATRIX REGULATE CELL BEHAVIOR?

The extracellular matrix is a critical mediator of cell behavior. In fact, cells respond to their environment by changing shape and altering gene expression in order to perform their job properly. 

Cell adhesion: This refers to how cells bind together very tightly with adhesive proteins that can crosslink with other adhesive proteins across the plasma membrane so they strengthen the bond between cells.

In order for cells to join together correctly at the right times and places, they need to be able to sense their environment and respond by sending signals through a network of proteins that bind together in a very specific way. So if a developing embryo is going to form into multiple layers that will eventually become distinct tissues or organs, cells in each layer will need to bind to the ECM and pass signals through it to be able to change shape and function into whatever they’re supposed to become.

3 Types of Cell Adhesion:

Integrin: These proteins anchor cells to the extracellular matrix, primarily binding between adhesive proteins on one side of a plasma membrane and “integrin-binding sites” on the other side of the plasma membrane.

Cell-matrix adhesion: This refers to how cells can bind directly to ECM components, which involves integrins as well as other types of adhesion proteins.

Compartmentalization/Segregation: This refers to how cells can create closed boundaries that will separate different tissues from each other.

In order for cells to be able to create compartments, they need to regulate the way substances enter and exit the local environment. In fact, many types of tissue have a limited list of molecules that can diffuse across their borders in one direction or another – this is called “selective permeability”, and it’s a feature of many cell types.

2 Main Features of Selective Permeability:

1) Pores in the plasma membrane allow solutes to move through them but prevent water from moving freely through those pores, due to the presence of lipid bilayers. This allows cells to selectively control which molecules can enter or exit their local environment.

2) Cells can have a different level of permeability in different directions, so some proteins will move freely across the cell membrane while others cannot – this is called “anisotropy”.

HOW DOES SELECTIVE PERMEABILITY WORK?

Different types of cells can adjust how permeable their plasma membranes are to help create local boundaries and also take in the right molecular nutrients for their job. In regards to the extracellular matrix, the ECM can bind to integrins on the plasma membrane of cells, which helps create a boundary that separates tissues from each other. Integrins are the major cell adhesion proteins, which means they bind cells to the ECM. Cells will be able to pass molecules through the border into neighboring tissues, but if the molecule is too large it won’t fit through the pores of the membranes and therefore cannot go across. All cells have distinct levels of permeability in different directions to help create a very specific environment for each cell type.

EXTRACELLULAR MATRIX & LONGEVITY

Part of what allows cells to remain differentiated is the extracellular matrix. It provides cells with the appropriate molecular signals to maintain their state, and when they move to a different tissue it also helps ensure that they will behave correctly in their new local environment – which is why this system breaks down when there is damage or disease. Abnormalities in the extracellular matrix are linked with age-related diseases. When ECM is broken down, it releases many different molecules that can cause inflammation. Inflammation is an immune response meant to eliminate threats to the body, but chronic inflammation can be very harmful and eventually result in death. When this happens over time the extracellular matrix will degrade and build up in ways that are detrimental to our health. When this happens, it causes “inflamm-aging” which is when inflammation builds up over time due to wear and tear on the body.

As we age, the extracellular matrix continues to degrade in many ways. The aging process involves many deleterious changes in the cells and tissues of an organism, which can affect how it functions. Lifestyle factors may accelerate the degradation of the extracellular matrix. Since ECM is responsible for cellular differentiation, preventing this degradation could lead to greater longevity because it would allow cells to maintain their state and continue functioning properly.  

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Before taking any medications, over-the-counter drugs, supplements or herbs, consult a physician for a thorough evaluation. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

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CELL DANGER RESPONSE: What it is and why its important

The body’s immune system is a complicated, elegant machine that protects us from the outside world. It does this by recognizing invaders through amazing sensing mechanisms and responding to them with incredible precision. In the case of cell danger response (CDR), our cells do their best to protect themselves as they are being attacked by viruses or bacteria. Yet CDR can be dangerous if it overreacts and causes inflammation – which can lead to chronic diseases such as diabetes or even cancer. In this week’s blog post we will not only explain what CDR is but also how we minimize its risks so we may live a healthy life.

WHAT IS THE CELL DANGER RESPONSE?

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. 

How it works is by the cell senses that it is being attacked, then using specialized proteins to monitor our metabolism. When CDR is activated, the body will use available energy sources and switch its focus to self-defense rather than growth and reproduction. CDR is a mechanism that allows cells to sense ‘danger’ that may be caused by viruses or bacteria. This danger can also come in the form of molecules such as DNA, RNA, and proteins – all of which are components found inside our cells.  When these substances get leaked into the extracellular environment, CDR kicks into gear.

The activated CDR will then enter into a cascade – this is where it gets its name, the danger response cascade (DRC). The danger response cascade can be broken up into five steps that occur in succession: 

1. Detection: Detection of PAMPs (e.g., pathogen-associated molecular patterns like lipopolysaccharides) or damage-associated molecular patterns (DAMPs). PAMPs are substances that can be recognized by specialized receptors, such as Toll-like receptor (TLR), NOD-like receptor (NLR), and RIG-I like helicases (RLH). DAMPs refer to the cellular debris or damage that results from being attacked. 

2. Activation of MAPKs, IKKɛ, TBK1, PKA, and PKR. Next these activated enzymes activate transcription factors (which refers to a biochemical process by which a particular gene’s instructions are copied into RNA) that then activate or suppress inflammation-promoting genes while suppressing other essential genes involved in repair pathways. When we discuss activated enzymes, this refers to enzymes that have been phosphorylated, which means a phosphate group has been added to the enzyme.  

3. Activation of transcription factors such as NF-kB, FOXO3a, and HIF1α. These transcription factors then go on to stimulate or suppress the transcription of genes that regulate inflammation and also cell survival. 

4. Activation of MDA5 & RIG-I: MDA5 and RIG-I are critical to the CDR response because they activate an antiviral pathway known as type I interferon production. Type I interferon production is a pathway that allows our body’s immune system to help fight infections. 

5. Secretion of inflammatory cytokines to induce downstream immune cells to take action against the infection. Inflammatory cytokines are a group of signaling proteins that trigger inflammation at sites of infection. The cells which release these cytokines are called antigen-presenting cells (APCs) and include monocytes, macrophages, dendritic cells, and B lymphocytes. This cascade is what allows CDR to induce inflammation – yet it can have negative consequences if activated over and over again.

In addition, CDR can also occur in response to non-infectious stresses such as heat, UV irradiation, and oxidative stress. These stresses have been shown to activate IKKɛ (which is one of the last components in the cascade) and cause it to activate NF-κB (Nuclear factor-kappa B). When activated, this protein moves into the nucleus where it works with other transcription factors to promote the expression of genes that trigger inflammation. It is important to note that these events happen within minutes of your body detecting CDR triggers. 

WHAT IS THE DANGER RESPONSE CAUSED IN THE BODY?

Inflammation is a vital part of the CDR cascade. It’s what helps cells fight off disease, but there are consequences if it goes on for too long or isn’t properly regulated.  Left unchecked, inflammation can lead to several chronic conditions. 

 Inflammation has been linked to cardiovascular disease, arthritis, atherosclerosis, type 2 diabetes, Alzheimer’s disease, and even depression. One of the most well-known links between inflammation and chronic illness comes from the research of Dr. Robert Ader. In 1974 he conducted a study in which two groups were given an antitoxin to protect against poison. 

 Group A only received the treatment, while group B also had their spleens removed beforehand to prevent their immune systems from mounting an inflammatory response. After receiving the antitoxin both groups were then injected with the poison. However, unbeknownst to them this second injection was not actually poisonous but just saline solution therefore they should not have gotten sick. 

To the surprise of the researchers, group B got just as sick as group A even though they did not have an immune system. Basically, because their bodies had already mounted an inflammatory response when injected with the saline solution it was interpreted by their brains to be a poison so they could become ill. This example is just one of many that illustrate how chronic inflammation can lead to the development of disease.

HOW CAN WE AVOID THE DANGER RESPONSE?

The answer to this question is multifactorial. First, it’s important to avoid or control infections with your immune system because that is what triggers the response in the first place.  

Second, it’s also best to take care of your body. This means eating a healthy diet, exercising regularly, practicing stress management, and more. 

Third, optimizing your immune system is important.  The better it functions the less likely you are to succumb to disease and the more effective it will be at fighting off infections.

Fourth, protect your cells from damage and stress by limiting exposure to toxins and sources of oxidative stress such as UV radiation and environmental pollutants. This includes using antioxidants that can directly neutralize free radicals before they do damage: vitamin C, vitamin E, manganese, selenium, copper, zinc, and more.

Finally, genetic variation also determines how many times your immune system can mount a CDR response before producing dysfunctional cells. This means that although the danger responses in everyone are the same there is a big difference in their potential scope because of individual genetics. Different SNPs have also been linked to an impaired danger response.

Although the danger response is an important part of fighting infections, it can also be responsible for chronic inflammation which has been linked to many health problems. Fortunately, there are things you can do to prevent this from happening. By implementing lifestyle changes you can help your body fight off disease while simultaneously protecting your cells from damage. 

How can the Institute for Human Optimization help you? At IfHO, we utilize a personalized, precision-based approach to medicine. Precision Medicine acknowledges individual differences in genes.  By having a better understanding of the individual’s genes and making therapeutic decisions based on their genetics, we can work together to drive CDR in a desirable direction.   

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Before taking any medications, over-the-counter drugs, supplements or herbs, consult a physician for a thorough evaluation. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

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Advanced Glycation End Products: What they are and how they influence our health and aging

Advanced glycation end products, or AGEs for short, can influence our health and attribute to the acceleration of aging. When sugar reacts with protein molecules in food and drinks, it can lead to the production of AGEs which accumulate over time within the body. This process is also known as glycation–the reaction between sugars and proteins that creates damaging compounds called advanced glycated end products (AGEs). These end products have been linked to many age-related diseases including diabetes complications such as kidney disease and eye disease. There are things you can do to reduce your exposure to these harmful compounds which we will be exploring on this week’s blog.

Advanced glycation end products are products of chemical reactions between sugar molecules and protein or fat molecules. This process is called the Maillard Reaction, named after French chemist Louis Camille Maillard who discovered it in 1910 while working on food chemistry. Maillard’s work shows how sugar can brown and add flavor to cookies and bread, but it can also produce some very harmful compounds that studies show contribute to age-related diseases. AGEs are a general term that describes a number of compounds that result from this reaction. The Maillard Reaction showed how amino acids react with reducing sugars at elevated temperatures. AGEs are formed when these sugars become covalently bonded to proteins or lipid compounds without the controlling action of an enzyme. AGEs are found in all organisms and foods, but their concentration increases with cooking time and temperature. AGEs work in the human body by reacting with DNA and RNA, AGEs form a complex series of reactions that result in cross-linking AGEs to proteins. This reaction is not optimal as it increases AGEs ability to bind with AGE receptors in tissues. AGE additively increases the concentration of AGE receptor sites, resulting in an increase in AGE-mediated signal transduction between cells. This process is exacerbated by the fact that glucose also enhances AGE formation. Thus, it is believed that AGE stimulation of AGE receptors results in the human body moving from a homeostatic AGE receptor activity to AGE-mediated AGE receptor dysregulation. Homeostatic AGE receptor activity refers to a state in which a certain concentration of AGE receptor sites is present and a certain level of glucose is present, resulting in a specific amount of signal transduction between cells. AGE-mediated AGE receptor dysregulation refers to a situation where an increased concentration of AGE receptors results in an increased number of signals being transmitted between cells within the. Maintaining homeostatic AGE receptor activity is essential for cellular regulation (the process in which cells replicate, proliferate, and grow) and homeostatic function in healthy adults. 

HOW ARE WE EXPOSED TO AGEs?

Now that we know what AGEs are, let’s go over how we are exposed to them. Modern diets are largely heat-processed and as a result contain high levels of advanced glycation end products (AGEs). AGEs can be found in everyday consumables such as food products, but the main source of these products is from cooking and processing methods.

Cooking at high temperatures changes some of the sugars to AGEs. 

AGEs occur when sugars and proteins (in the case of food) come together in a process called glycation. These two substances can also interact with environmental factors such as UV radiation, oxidative stress, pollution, and smoking to form AGEs. AGEs are created through AGE-receptor interactions with AGEs found within foods, resulting in AGE-receptor dysregulation. AGE-receptor dysregulation refers to the processes by which AGEs affect AGE-receptor activity.

This interaction occurs by the body’s normal metabolic process, which is different than the glycation process. However, when excessively high levels of AGEs are reached in tissues this becomes harmful to the body.  

Thousands of AGEs have been identified from the glycation of proteins and lipids on y-positioned amino groups of lysine residues or oxygen-containing groups such as the following: aldehydes, ketones, and reducing sugars.  

  • Aldehyde is a compound containing a functional group with a carbon atom double-bonded to an oxygen atom and single bonded to -CHO. This carbon and oxygen is called a carbonyl group. 
  • A ketone contains a carbonyl group bonded to two other atoms such as the following: R-COCH= O (R= alkyl, aryl, etc.). 
  • Reducing sugars is a term used for monosaccharides and some disaccharides that can be oxidized to form aldehydes or ketones.

Some of the AGEs that can be found in our bodies are N ε -(carboxymethyl)lysine (CML), pentosidine, and others. CML and pentosidine are considered reliable biomarkers for oxidative stress and damage to DNA, RNA, and protein. Additionally, Pentosidine and CML is a biomarker for type 2 diabetic retinopathy. Oxidative stress refers to the damage produced in cells and tissues by non-neutralized free radicals. Oxidation is a process in which the structure of an organic compound is altered by the addition or removal of electrons to its molecules or atoms, causing it to become oxidized. Oxidation is dangerous to the body because it creates a chain reaction of oxidative stress.

Impact of AGEs on inflammation, oxidative stress, and insulin resistance

AGEs can disrupt cellular communication. Cellular communication refers to the internal biochemical messengers that carry information from cell to cell. Cellular communication makes up an important part of normal body function, allowing cells to ‘talk’ to one another and coordinate various functions necessary for the body as a whole (like growth, tissue repair, and organ function). AGEs interfere with cellular communication by binding to the surface molecules on cells. Examples of this include altering cell surface receptor function (such as the insulin and/or IGF-1 receptor), increasing cellular inflammation (via NFκB), and increasing oxidative stress.

AGEs have a direct impact on proteins and the extracellular matrix. The extracellular matrix is our body’s natural scaffolding that supports our cells (cells are attached to the extracellular matrix, AGEs accumulate in this area) AGEs cause damage to cellular proteins and the extracellular matrix by oxidative stress. AGE crosslinks have been documented to contribute to retinal capillary cell death, diabetic nephropathy, atherogenesis, etc. Additionally, AGEs can alter cell intracellular signaling by AGE-RAGE ( AGE receptor AGE ). AGEs have been suggested to be the cause of oxidative stress, inflammation, and insulin resistance. AGEs are linked to inflammatory markers like C-reactive protein (CRP) present in the blood, which is an indicator of systemic inflammation. 

MOBILITY AND AGING

Mobility is one of the most common problems that elderly people face. Mobility refers to the ability to perform the basic activities of daily living that are necessary for independence and is a core indicator of health and quality of life in aging. In older adults, the decline in physical function is a major determinant of frailty and loss of independence. The age-related decline in physical function results from a number of changes that occur at the cellular, organ system, and whole-body levels. AGEs are linked with the degradation of skeletal muscle function in older adults. AGEs are also known to play a role in the pathogenesis of arterial stiffness and hypertension, both strong predictors of cardiovascular disease which is one of the leading causes of death among elderly people.

REVERSE AGEs

Reversing AGEs requires reversing AGE modifications at the molecular level.  Since AGEs are modified by sugars, avoiding foods high in sugar and avoiding processed sugar are generally recommended. In addition to reducing or eliminating sugar intake, antioxidant-rich foods should be consumed to reduce oxidative stress. Additionally, supplements that promote healthy blood circulation may reduce the body’s exposure to AGEs. Some supplements that can support reverse AGE modification include carnosine, aminoguanidine known as Pimagidine, and benfotiamine. Unfortunately, there has been a challenge in reverse AGE at the molecular level but this challenge has led to the development of AGE inhibitors. Such inhibitors are now being developed for therapeutic use in order to manage diabetic complications and other diseases that result from AGE modifications at the molecular level. Examples include therapies targeting collagen cross-linking, glyoxalase I inhibition or amadoriase gene expression.

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Before taking any medications, over-the-counter drugs, supplements or herbs, consult a physician for a thorough evaluation. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

References

https://pubmed.ncbi.nlm.nih.gov/20544678/

https://pubmed.ncbi.nlm.nih.gov/24624331/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949097/

https://pubmed.ncbi.nlm.nih.gov/23525877/

https://www.sciencedirect.com/science/article/abs/pii/S0024320504009233

https://pubmed.ncbi.nlm.nih.gov/16280650/

https://pubmed.ncbi.nlm.nih.gov/8949973/

https://pubmed.ncbi.nlm.nih.gov/25786107/

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METABOLIC ENDOTOXEMIA

Metabolic endotoxemia is a condition that affects many people in America. In fact, recent studies estimate that over one-third of adults in the United States have this health issue. It’s been estimated that it may soon be indirectly a leading cause of death. Follow us on this week’s blog to learn what it is and how to prevent metabolic endotoxemia.

Metabolic Endotoxemia

Metabolic endotoxemia is the presence of too much LPS (lipopolysaccharides) in the blood. LPS are toxins that reside on the outer membrane of bacteria that would otherwise not be allowed into our bloodstream. The American Diabetes Association identified bacterial lipopolysaccharide (LPS) as the inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes.  LPS triggers a cascade of immune responses. For example, after binding to its receptor TLR4 (TLR4 is a receptor found on the surface of cells that can detect LPS) or CD 14, there is an elevated level of tumor necrosis factor-alpha (TNFα). TNFα is a protein signaling molecule that is an inflammatory mediator that triggers the innate immune response. The innate immune system, as its name implies, is a primitive type of immunity that all living organisms have. In contrast to the adaptive immune system (which is found in humans and other higher-order species), there are no actual distinguishing features between cells belonging to the innate system or adaptive immune system – they simply look different. TNFα activates more TLR4 which results in more TNFα. As you can see, it becomes a vicious cycle leading to chronic inflammation.

LPS also induces cytokine production by activating inflammatory transcription factors known as nuclear factor kappa B (NF-κB). NF-κB is a protein complex that controls the expression of genes involved in immunity and inflammation. Inducing cytokine production helps our bodies fight off infections. However, it also activates the immune response to clear away cells that are injured or damaged by short-term inflammation. If this clearing of dead cells occurs chronically, it can lead to tissue damage and autoimmune diseases where the body starts attacking its own healthy tissues.

DIET & METABOLIC ENDOTOXEMIA

Paracelsus, a Renaissance physician said: “All things are poison; everything is poisonous; there is nothing without poisonous qualities. Only the dose permits something not to be poisonous.” 

The severity of this disorder depends on how much LPS enters circulation and how sensitive an individual’s body is to these inflammatory agents. As expected, diet and lifestyle are critical when it comes to metabolic endotoxemia and other diseases. 

Inflammatory transcription factors are also activated in response to a high-fat diet rich in saturated fats and low in fruits and vegetables. Inflammatory transcription factors are transcription factors that contribute to the initiation, regulation, and mediation of inflammation.

Saturated fatty acids trigger macrophages to create a cascade of inflammatory signals. Saturated fats refer to a type of dietary fat with no double bonds between the carbon atoms. They are typically solid at room temperature and found in foods such as beef, pork, poultry, butterfat (in dairy products), palm kernel oil, lard (in meat products), and cocoa butter. Inflammatory foods have been linked to causing an inflammatory immune response that results in endotoxemia, which is the presence of bacterial endotoxin (LPS) in the bloodstream.

METABOLIC ENDOTOXEMIA AND DISEASE

The relationship between metabolic endotoxemia and the onset of diabetes, obesity, and heart disease is well established. Metabolic endotoxemia causes the body to have increased cortisol levels. This causes increased insulin resistance, which can contribute to type 2 diabetes. Metabolic endotoxemia causes the body to have increased cortisol levels. This causes increased insulin resistance, which can contribute to type 2 diabetes. In a healthy body, insulin resistance may be caused by high cortisol levels in response to stress. This insulin resistance is typically temporary as a protective mechanism for the body, but in most people who are insulin resistant, a high carbohydrate diet makes them even more insulin resistant. So, these individuals will typically crave carbohydrates when their blood sugar is low from the stress cortisol is causing on their bodies with elevated insulin resistance.

Metabolic endotoxemia causes an increase in persistent free radicals, which contributes to chronic inflammation and aging of the cells. An increase in persistent free radicals is not optimal as this can result in the accelerated development of chronic disease. Chronic inflammation is cause for concern because it is associated with elevated risks of cardiovascular disease, Alzheimer’s disease, cancer, and many other chronic diseases. Metabolic endotoxemia also causes oxidative stress. Oxidative stress refers to the process whereby free radicals in cells cause damage to molecules leading to tissue and organ dysfunction. The human body has both antioxidant and anti-inflammatory mechanisms in place that operate in a feedback loop, such as red blood cells, white blood cells, vitamins C and E, uric acid, nitric oxide synthase (NOS), and more. This feedback loop works by protecting the cells from oxidative damage and removing damaged cells. However, there are many variables that can break the loop using mechanisms called hormesis. Hormesis refers to acute stress that leads to a beneficial effect. For example, exercise causes the body to emit oxidizing free radicals because it requires large amounts of ATP (energy) for muscle contraction. Metabolic endotoxemia however is not a beneficial mechanism. It is the result of an overload of free fatty acids (FFAs), cytokines, and NOS-derived NO which cause circulating endotoxins to disrupt the host’s metabolism. 

Additionally, oxidative stress decreases cellular DNA repair. Cellular DNA repair is critical to our overall health and well-being. As we have discussed in recent blogs, DNA repair is critical for maintaining metabolic homeostasis. Failure to maintain metabolic homeostasis due to DNA damage from oxidative stress can lead to obesity, insulin resistance, and even type 2 diabetes.

In addition to causing insulin resistance and oxidative stress, metabolic endotoxemia has been linked to dysfunction of the hypothalamic-pituitary-adrenal axis. Our HPA Axis is critical for maintaining metabolic homeostasis. Our HPA Axis is responsible for the release of cortisol, our main stress hormone. We often think of the HPA Axis as being involved in stress but it involves every organ system in the body and is critical for maintaining normal body functions, including inflammation. Recent studies have established that in vivo administration of bacterial lipopolysaccharide (LPS) enhances hypothalamic-pituitary-adrenal (HPA) axis function by a mechanism involving endotoxin-stimulated cytokine release.  

IMPORTANCE OF DECREASING INFLAMMATORY ALLOSTATIC LOAD

Deceasing our allostatic load is a component of reaching our optimal health.  Allostatic load refers to the wear and tear on the body through stress. Metabolic endotoxemia contributes to the reduction in our allostatic load. Meeting one’s optimal health includes having a healthy weight, healthy blood sugar levels, and low inflammation among many things. The decreasing allostatic load can be done by increasing physical activity and mindfulness, improving nutrition, reducing stress, maintaining social connections, and getting enough sleep. Decreasing the number of factors involved in the allostatic load will help decrease the overall inflammatory response. 

Don’t know where to start? At the Institute for Human Optimization, we will work with you directly to optimize your well-being. No two patients are the same, so we work with you and create a personalized and individual approach to your health concerns. Contact us today to get started.

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References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695328/

https://diabetes.diabetesjournals.org/content/56/7/1761

https://pubmed.ncbi.nlm.nih.gov/14965237/

https://pubmed.ncbi.nlm.nih.gov/8892362/

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GUT-BRAIN AXIS

The gut-brain axis is a term that refers to the two-way communication system between the gastrointestinal tract and the central nervous system. The gut-brain axis can be disrupted by many different factors, including stress. With an unhealthy gut microbiome (bacteria) in your digestive tract, you are more susceptible to many health conditions. These include inflammation, metabolic syndrome, obesity, type 2 diabetes, depression or anxiety disorders, and neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease.

The purpose of this blog post is to share information on how a healthy diet can help heal your gut microbiome by providing proper nourishment for good bacteria while helping remove bad bacteria from your body through natural detoxification pathways.

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WHAT IS THE GUT-BRAIN AXIS?

The Gut-Brain Axis has recently been coined as the new “Central Nervous System”, which is a complex system of communication between the enteric nervous system in the gut and the central nervous system (CNS) in your brain. The Gut-Brain Axis is responsible for maintaining homeostasis between the autonomic nervous system and the immune system, regulating substances that may act as neurotransmitters. When the Gut-Brain Axis is not functioning optimally, this can lead to a range of problems including depression, anxiety, and stress-related disorders. Gut bacteria are responsible for maintaining the Gut-Brain Axis by producing neurotransmitters that can stimulate specific cells in the gut which can then send signals back to the brain through various neurological pathways.

Strong evidence suggests that gut microbiota has an important role in bidirectional interactions between the gut and the nervous system. It interacts with CNS by regulating brain chemistry and influencing neuro-endocrine systems associated with stress response, anxiety, and memory function. Gut microbiota can also influence brain function through the hypothalamic-pituitary-adrenal axis and autonomic nervous system. The hypothalamic-pituitary-adrenal axis is the major neuroendocrine system that mediates the stress response. Our autonomic nervous system is made up of the sympathetic nervous system (SNS) which is activated by stress and can stimulate colonic relaxation, vasoconstriction, and ileocaecal transit. Gut microbiota also interacts with immune cells in the gut, and these interactions have been shown to affect brain function. This has implications for mood disorders such as anxiety and depression that we will discuss later in this blog. Gut microbiota can also influence brain function through the autonomic nervous system, which regulates all of our unconscious actions (our heart rate, breathing pattern, etc).

Another factor worth mentioning is neurotransmitters. Neurotransmitters are essentially electrical signals in the brain that help us communicate and regulate many bodily functions including mood, emotions, ability to handle stress, and more. When our gut-health axis is off, our neurotransmitter signals can be disrupted which causes a cascade of brain issues. To make this simple, we are going to focus on serotonin as an example of what our gut-health axis can do for us. Serotonin is a neurotransmitter that regulates mood and behavior. When serotonin levels get messed up, it not only causes anxiety but also disrupts sleep patterns and more.

GUT HEALTH AND MENTAL HEALTH

Gut health is essential to mental health because it affects our mood, emotions, ability to handle stress, and symptoms of conditions such as Autism Spectrum Disorder (ASD). The Gut-Brain Axis is a two-way street, and both of these ‘roads’ are connected. When one road is in bad condition it affects the other road as well. This can cause inflammation, stress, and disease. As we learned in our inflammation series, inflammation can cause an increase in the release of cortisol from the adrenal glands. This is not good for us because too much cortisol disrupts our body and brain functions.

Stress also plays a large role in our gut-brain axis. Not only does stress cause our adrenal glands to release cortisol, but it can also lead to poor diet decisions that throw off your gut bacteria. Anxiety and depression are associated with changes in microbiome composition, as well as with increased gut permeability allowing lipopolysaccharides.  (LPS) refers to metabolic endotoxemia. LPS are not only harmful to your gut, but they are also a primary cell wall component of gram-negative bacteria. So as stress and anxiety increase your gut permeability and release lipopolysaccharides into the bloodstream these can cause inflammation in the brain leading to more cortisol production and an overall increase in inflammation throughout the body.

IMPORTANCE OF OPTIMAL GUT HEALTH

Maintaining good gut health is important as the gut microbiome may help with stress responses by influencing the synthesis of neurotransmitters and neuropeptides that have an impact on homeostasis, neuroinflammation, and neuronal plasticity. Recent research shows that the gut microbiome may also have an impact on neurogenesis. Neurogenesis is a vital process to maintaining mental health and is the generation of neurons from neural stem cells. Gut microbiota close to the enteric nervous system (ENS) exerts substantial influence over it. The gut microbiome can stimulate vagal afferent neurons by releasing transmitters such as 5-HT, acetylcholine, and norepinephrine. The gut microbiome can also stimulate afferent neurons in the submucosal and myenteric plexus of the ENS to release a range of chemicals including neuropeptides (e.g., substance P, cholecystokinin)

HOW IS THE GUT-BRAIN AXIS BEING USED IN MEDICINE TODAY?

Research is still underway on how to improve the balance of gut microbiota or modulate the gut-brain axis. Gut microbiome therapy may be used in some future medical therapies for psychiatric disorders, autism, and neurodegenerative disease.

Biological psychiatry is currently studying the Gut-Brain Axis by focusing on how metabolites from the microbiome can impact neurotransmitter function, synaptic plasticity, and neuroinflammation. The Gut-brain axis is being studied in clinical psychiatry for treating conditions like depression, anxiety disorders, and autism spectrum disorder (ASD). Although research is still underway on how to improve the balance of gut microbiota or modulate the gut-brain axis, some recent studies have been completed for Gut microbiome therapy.

WHAT CAN YOU DO AT HOME TO IMPROVE OUR GUT-BRAIN AXIS

Diet is one of the most important modifying factors of the microbiota-gut-brain axis. If you are experiencing any gastrointestinal symptoms (gas, bloating, stomach pain) as well as mental health issues such as anxiety or depression then a Gut-Brain Axis evaluation is recommended to determine if there is an imbalance in neurotransmitters due to the Gut-Brain Axis not functioning efficiently. The most important thing that you can do if you’re not feeling like yourself is to visit your Provider and get these tests done!

In the meantime, it is important to improve your Gut-Brain Axis by trying the following tips to get back on track:

  • Get enough fiber in your diet from fruits and vegetables
  • Get rid of the bad bacteria’s and yeast with beneficial bacteria
  • Reduce stress as much as possible and practice self-care!
  • Exercise regularly
  • Practice mindfulness

 The Gut-Brain Axis is the intersection of your gut and brain that affect each other. When your Gut-Brain Axis isn’t set up correctly it can be harmful to your overall well-being. This new discovery has been coined as the “central nerve” for all three major organ systems–the CNS, endocrine, and immune systems. It’s not just about digestion anymore! If you want to learn more about how this process works or if you’re looking to improve health with an integrative approach to optimal gut health – check out our most recent blogs.  Follow us next week as we take on: Metabolic Endotoxemia.

At the Institute for Human Optimization, we understand that what starts in the gut impacts the entire body. No two patients are the same, so we work with you and create a personalized and individual approach to your gut health issues. What can that look like? Would you plant grass seed or kill the weeds first? Weeds should be killed first. Similarly, we will work directly with you to reduce or remove the weeds, aka factors that are driving dysbiosis. After that, we can work together to restore balance in your gut microbiome.

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

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LEAKY GUT & MORE: THE IMPACT OF DYSBIOSIS

We recently discussed the importance of nurturing a healthy gut. Gut health has been linked to many health issues including autoimmune disease, heart disease, mood, obesity, endocrine disorders, cancer, and more. When dysbiosis in the gut occurs, it can lead to further gut problems. This week we will be discussing in more depth gut health issues such as leaky gut, SIBO, and what you can do at home to optimize your gut microbiome.

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Leaky Gut Syndrome

The term “leaky gut” has been a buzz term on social media lately. In fact, leaky gut is a more recently known term within the conventional medical community. Leaky gut, also known as increased intestinal permeability, refers to when food particles and other things such as bacteria and toxins, “leak” through the intestinal wall that otherwise shouldn’t. Your gut is lined by the intestinal wall, think of it as a patio screen door. Ideally, the screen door in your home is free of damage providing a barrier from the outdoor elements from coming inside the house. The screen acts as a filter and allows only certain things of certain sizes to enter your home. However, if your screen door is damaged and/or has holes, over time it is easier for large bugs, debris, and other critters to enter your home. With time, the screen door is no longer functioning as a barrier. Similarly, in our gut when our intestinal wall is damaged, the small holes become larger which now allows for harmful substances to enter our system. Naturally, we all have some level of leaky gut as the barrier is a screen and therefore not completely impermeable.

What causes Leaky Gut Syndrome?

Your bio-individuality may make you more sensitive to changes in the digestive system, but your DNA does not determine your gut health destiny. Let’s look at a few common causes of leaky gut:

  • Dysbiosis
  • Diet
  • Alcohol use
  • Stress
  • Food Allergies and Sensitivities

Dysbiosis

Dysbiosis occurs when pathogenic microbes (viruses, bacteria, mycobacteria) and symbiotic microbes that are beneficial to the microbiota by regulating our immune system, can no longer coexist in the gut in harmony. This is the leading cause of leaky gut syndrome.

Diet

Diet can determine the composition of gut microbiota, favoring the growth of organisms that are best suited for metabolizing commonly consumed food groups. Western diets are rich in a complex mixture of fats and are high in simple sugars, which significantly impacts the gut microbiome composition, and often leads to the development of gut inflammation and other related diseases, including intestinal disease [12].  

A diet rich in processed foods or foods you are highly sensitive to (we will discuss this later) can lead to leaky gut. Unfortunately, I see more times than not how the American diet impacts patient health outcomes. Studies continuously show how ultra-processed foods adversely affect our gut microbiome which in turn, drives inflammation. The rationale is that the nutritional composition of ultra-processed foodstuffs can induce gut dysbiosis, promoting a pro-inflammatory response and consequently, a “leaky gut”. 

Alcohol Use

Alcohol and its metabolites specifically promote intestinal inflammation through its influence on intestinal microbiota, immune function, and more. In large amounts, alcohol and its metabolites can overwhelm the gastrointestinal tract (GI) and liver and lead to damage both within the GI and in other organs.  Alcohol disrupts the epithelial cells, cells that line the surfaces of your body, and disrupts the space between the cells which allows increased gut leakage.

Stress

Stress is a health disruptor on your body, mood, and behavior. In the case of leaky gut, it can increase gut barrier permeability which can result in “leaky gut”. There are many stress management strategies that you can try to incorporate from the comfort of your home such as physical activity, meditation, relaxing music, and yoga. If you are unsure where to start and/or have taken steps to manage your stress with no results, your healthcare provider can work with you to create a stress management care plan.  

Food Allergies & Sensitivities

There is a difference between food allergies and food sensitivities. Food allergies are typically an acute hypersensitivity reaction that typically takes place within 2 hours of consuming the allergenic food. The symptomatic presentation can vary ranging from anaphylaxis, hives to respiratory or gastrointestinal distress. Food allergies are mediated by IgE immunoglobulin activity and cause a profound histamine release. Treatment can range from needing an epinephrine pen, steroids, and antihistamines. In contrast to Food Sensitivities, or intolerances which is typically more of a delayed hypersensitivity reaction which can take place upwards of 72 hours post-consumption which a varying symptomatic presentation which includes postprandial fatigue, migraines or body aches to common GI symptoms of gas, bloating, diarrhea or constipation. Food sensitivities are typically mediated by IgG and trigger inflammation. The problem is that foods that we are intolerant can present themselves very mildly compared to an allergy and cause chronic gut inflammation thereby increasing gut permeability. Additionally, it is important to keep in mind that 80% of our immune system resides in the digestive tract in the form of Gut Associated Lymphatic Tissue (GALT), and chronic exposure to larger food particles can ultimately lead to immunological programming and intolerances to foods that we commonly consume. Ultimately, this can trigger immunological dysregulation and autoimmunity.

SIBO

Another unassuming condition that often goes underdiagnosed and undetected is, Small Intestinal Bacterial Overgrowth (SIBO) occurs when excess bacteria are growing in the small intestine, disrupting the balance, and causing dysbiosis in your gut microbiome. Clinically, SIBO is an often-neglected mechanism for have patients presenting with weakened nutrition. Normally, you would find very little bacteria in the small intestine compared to the large intestine. SIBO has negative consequences on the structure and function of the small intestine and can cause mounting issues, including:

  • Osteoporosis
  • Kidney Stones
  • Incomplete Digestion
  • Vitamin Deficiency

Osteoporosis

Our bones are constantly undergoing continuous recycling throughout our lives. This process is known as bone remodelingand involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized. In other words, old bone is broken down and new bone is formed. For this to occur, our bones need a steady supply of protein, vitamins, minerals, and healthy fats to be properly absorbed. Healthy digestion is needed for optimal bone health. Over time, SIBO can cause poor calcium absorption which in turn drives bone loss.  

Kidney Stones

If you know anyone who has had kidney stones, you’ve heard enough to hope you never have one. Kidney stones are a multifactorial complex disorder between the gut, liver, bone, and kidney. If you have SIBO, you have an increased risk of kidney stones because of the absorption issues that are a result of bacterial overgrowth.

Incomplete Digestion

Our small intestine continues the process of digestion that begins in the stomach and runs to your large intestine. But unlike the stomach, which has minor absorptive properties, 90% of food absorption occurs in the small intestine. Whatever is not absorbed is then passed on to the large intestine. Bacterial overgrowth disrupts conjugated bacterial cells, and dihydroxylation of bile salts, which are needed to digest fats, resulting in incomplete digestion of fats and diarrhea. 

Vitamin Deficiency

The adverse effects of SIBO on nutrition involve several factors but one of the most common clinical manifestations is malabsorption. Vitamin B12 deficiency occurs in SIBO as the bacteria take up the vitamin. Vitamin A, D, and E are also commonly seen in SIBO due to the malabsorption of fat-soluble vitamins. 

How can you optimize your Gut Health? 

The health of our gut determines the health of the rest of our bodies. What are simple steps you can do at home to optimize your gut health?

At the Institute for Human Optimization, we understand that what starts in the gut impacts the entire body. No two patients are the same, so we work with you and create a personalized and individual approach to your gut health issues. What can that look like? Would you plant grass seed or kill the weeds first? Weeds should be killed first. Similarly, we will work directly with you to reduce or remove the weeds, aka factors that are driving dysbiosis. After that, we can work together to restore balance in your gut microbiome.

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

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