More on the series of GAGs in particular hyaluronic acid. A bit of news and a bit of commentary on recent rabbit holes and why I refuse to further engage in current topics. Over, around, under or through has always been my response to hitting a wall in addition to returning to first things, in this case new positive developments post 2016 and in this article 2020 and 2021 in particular, in the field of oral natural immune therapy and SAM (severe acute malnutrition) syndromes that have major impacts on health, this includes GAG production and synthesis.

2020, 2021

Hyaluronic Acid For Inflammatory Conditions

Hyaluronic acid (HA) is a member of a large family of glycosaminoglycans (GAGs), which are the main components of the extracellular matrix (ECM). Unique features that distinguish HA from other GAGs are its simple structure and large molecular size. This simple molecular unit repeated thousands of times forms a structure of a very long linear polymer. Hyaluronic acid is synthesized by HA synthases on the inner surface of the cellular membrane and translocated into extracellular space along with the elongation of the polymeric chain. This is a unique method of synthesis, different from other GAGs. Hyaluronic acid is also the only GAG not linked to a core protein, and it does not undergo any post synthetic modifications.

Recently, it has been demonstrated that empty hyaluronic acid without bearing any therapeutic agent can be used therapeutically for the treatment of inflammatory diseases via modulating inflammatory responses.

In mammals, HA is found in heart valves, skin, skeletal tissues, vitreous of the eye, umbilical cord, and synovial fluid. In its native form, such as that in normal synovial fluid, HA presents as a high-molecular-weight (HMW) polymer as mentioned above. 

Hyaluronic acid can be obtained by extraction from animal tissues, microbial production, or enzymatic synthesis. In general, hyaluronic acid is commercially isolated from animal sources inside the synovial fluid, umbilical cord, skin, and rooster comb.

In tissue lesion and inflammation, high molecular weight hyaluronic acid is altered into monocyte-adhesive matrices that energize immune cells at the injured site to produce inflammatory cytokines through interactions with cell surface receptors. This results in the secretion of enzymes and free radicals, which break the long-chain high molecular weight (HMW) HA molecules into lower-molecular weight (LMW) forms that have extraordinarily wide-ranging and often adverse biological functions due to the activation of differential signal transduction pathways.

Previous studies have shown that low molecular weight hyaluronic acid fragments with pro-inflammatory, immuno-stimulatory, and pro-angiogenic features are essential as endogenous danger signals in initiating an inflammatory response. In contrast, high molecular weight HAs possesses protective anti-inflammatory effects by lowering gene expression and alteration of cytokine responses.  Initial studies showed that differential signaling pathways triggered by-products from the HA degradation process involve interactions between HAs and their HA receptors on cell surfaces. These opposing biological functions of HMW and LMW HAs were attributed to their ability to induce multivalent and various downstream signaling pathways that are different from that of LMW HA, which is why it is considered an anti-inflammatory agent. Self-assembled hyaluronic acid nano particles shielded by an hyaluronic acid outer shell, which presumably resembles high molecular weight hyaluronic acid containing multiple  binding sites that can induce clustering, have been shown to exhibit anti-inflammatory effects through the same mechanism as high molecular weight hyaluronic acid.

Active Targeting of Hyaluronic Acid Nano Particles to Macrophages

Macrophages play a crucial role in modulating a wide range of infectious and inflammatory diseases, such as tuberculosis, atherosclerosis, rheumatoid arthritis, type 2 diabetes (T2D), and multiple sclerosis. They are involved in triggering and stabilization of inflammation, resulting in tissue damage. For instance, a large number of macrophages are sensitized and can infiltrate the cholesterol-rich sites of an injured aorta, inducing damage to the fibrous tissue by capping the plaques that are common in atherosclerosis. An increase in the number of infiltrated macrophages in inflamed sites can be viewed as an indicator of the inflammation. Hence, practical approaches for observing macrophages and designing therapeutic delivery systems to mediate macrophage activities became more important in diagnosis and therapy.

Effects of Hyaluronic Acid Nano Particles in Macrophage Infiltration

Under pathological conditions such as inflammation, HA attached to vascular endothelia arbitrates the mobility and discharge of immune cells, and the HA-rich microenvironment at inflamed sites induces tissue penetration by immune cells. In conducted research infiltrated macrophages degraded the sub-endothelial matrix, whereas nanosized particles translocated to the atherosclerotic plaques through the transcellular migration pathway by exploiting intracellular vesicles. In this work, the potential effect of long-circulating hyaluronic acid nano particles on the vascular glycocalyx, which primarily consists of HA, was anticipated. Free HA is known to have a very short blood circulation half-life (3 to 5 min). However, hyaluronic acid nano particles might act as a circulating pool of HA owing to their favorable blood circulation kinetics and can be viewed as building constituents into the glycocalyx, limiting immune cell infiltration into injured sites. Hence, practical approaches for observing macrophages and designing therapeutic delivery systems to mediate macrophage activities became more important in diagnosis and therapy.

Cardiac Inflammation

Almost any anomaly at the heart level can initiate an inflammatory response and even systemic inflammation can trigger various inflammatory pathways within the heart tissue. Acute cardiac inflammation can result in a rapid decline in heart function, while chronic inflammation causes progressive structural damage, leading to the development of cardiac fibrosis. In the heart, HA is involved in physiological functions, such as cardiac development during embryogenesis, and in pathological conditions, including atherosclerosis and myocardial infarction.

Myocardial infarction (MI) appears when a coronary artery becomes blocked, leading to insufficient blood supply to the myocardium in the affected area. This leads to a reduction in oxygen distribution, nutrient and metabolic waste input and output. The repair mechanism of MI is a complex process, with different types of changes in cellular and extracellular components. Researchers synthesized HA oligosaccharides (o-HA) with 6–10 oligosaccharides through enzymatic degradation. Studies carried out on an MI model (subacute model of rat) show that oligosaccharide hyaluronic acid, o-HA can reduce the size of the infarction and the apoptosis of cardiomyocytes in the MI region, as well as promote myocardial angiogenesis and the reconstruction of myocardial function. It was also shown that o-HA improved the polarization of M2 macrophages and removed the inflammatory response caused by neutrophils to accelerate the reconstruction of myocardial function.

In a similar approach, other researchers developed an HA-based injectable hydrogel for MI regeneration and functional recovery of the heart. The hydrogel, when injected into the epicardium of the affected area (subacute model of rat, Sprague-Dawley male rats), showed, an increase in wall thickness after 4 weeks, as well as a decrease in the infarcted area. The number of arterioles and capillaries increased, and the apoptotic index decreased, when compared to the control group. The measurement of cardiac function indicated that hydrogel injection significantly facilitated functional recovery compared to the MI control. Due to the hygroscopic properties of HA, the hydrogel has a high expansion rate, which can lead to a change in the microenvironment in vivo. As this expansion occurs, fluids containing cytokines and other small molecules are absorbed, which in turn leads to decreased inflammation.

HA has an excellent potential for a wide range of applications, which comprise much more than the facial treatments with which it is typically associated. Its wide applicability is due to its distinctive biophysical properties, which give it enormous potential. The fact that HA is found in virtually all cell types is indicative of its biological advantages, ranging from its mechanical and swelling properties to lubrification, tissue regeneration and hydration.

A relevant aspect for all these biological properties is the cell surface receptors with which HA can interact, including those widely expressed in activated macrophages (which play a central role in the inflammatory process). It is the interaction with these receptors that enables the targeted delivery to target locations, resulting in greater cellular uptake and, therefore, beneficial results in reducing inflammation.

What is verified is that hyaluronic acid has been the subject of numerous studies in several pathologies. If the focus of HA applications is only inflammatory pathologies, especially OA and RA, it is clear that a great deal of effort has been devoted to the use of this molecule in the search for alternatives to conventional treatments.


The production of hyaluronic acid is related to nutrition and is naturally produced but can decline with age related malnutrition, this article highlights some of the important benefits of this glycosaminoglycan as an overview. No specific brands are recommended at this time but it is best to keep hyaluronic acid as a singular supplement rather than in combination supplements if you care to supplement. Vitamin C (sodium ascorbate form is best) is a necessary co-factor for production of collagen and carbohydrate digestion. Lactose can also increase benefit through enzymatic degradation. Hyaluronic acid can also help to activate macrophages in addition to changing polarity. In medicine, like other GAG’s it is also used as a transport molecule.



Collagen and GAG Types

Collagen is made up of proteins within a family of GAG’s, some are sulfated, chondroitin sulfate is one example. Hyaluronic acid is not a protein but a muco-polysaccharide. Both are considered GAG’s. The main difference between collagen and hyaluronic acid is that collagen is a polymer of protein while hyaluronic acid is the biopolymer of carbohydrates. Both are often found in the same bodily constituents (synovial fluid for example). Vitamin C, sodium ascorbate plays a critical role for both in bio synthesis and is required for the production of collagen.

I didn’t mean to confuse these categories in the video, collagen and GAG’s are often referred to as being the same substance within a matrix but having a type. Type I, Type II and so on…. but technically collagen is a protein. If I mention this again which I will in this series regarding all including the importance of Vitamin C for both I am referring to this matrix or family.

“Macrophage activation producing no side effects”…… I was referring to macrophage activation and GC protein statement by Nobuto Yamamoto. Autophagy is harmless cell turnover and recycling in biology. IBD is dysfunctional autophagy. Certain types of macrophage activation produce pro inflammatory effects in the normal healing process after which homeostasis is generally resumed

The immune state in mother and child are opposed during gestation, breast feeding and bifido colonization provide the immediate favorable condition to help both achieve a healthy immune state post birth. There is no pre immune state in the infant, that is the normal state during pregnancy, in the event that wasn’t clear; which it wasn’t. The effects on the non breast fed infant are explained. The effects on the mother can last months, years or in some mammals appear to be permanent if pregnancy was terminated. Sorry, my main focus was pointing out the importance of establishing and maintaining healthy microbiota before, during and after pregnancy and throughout life from a developmental and nutritional standpoint to prevent chronic conditions that are fundamental requirements of the immune system and good health (including repair, detox mechanisms and homeostasis, healthy immune response). Hyaluronic acid production is but another component for achieving that.

Whole foods vs. supplements:

Even though hyaluronic acid is quite effective as a singular component and there are very few ‘perfect’ foods containing nearly all that is required for nutrition (milk is but one) this is one more reason why I rarely support supplement use and that is in part due to the way scientific analysis is conducted. Most nutrition can’t be reduced to a singular component and remain as effective as the whole, until those necessary co-factors are considered and elucidated, the hypotheses appears ‘failed’ or not as effective as it could be. Also the end objective is creating a drug and profit, a near impossible goal as opposed to ‘natural’ whole substances. Cod liver oil vs. synthetic vitamin D is but one example, two very different outcomes dependent upon co-factors.

Alternavita: All you need to know (critical info in a nutshell)..... by focusing exclusively on these foundational health and immune development issues up to 90% of chronic conditions can be eliminated.

WHO STATEMENTS: 2017 Millennium Goal

  1. Breastfeeding,
  2. food (security)
  3. and water security (sanitation)

are major protective factors against malnutrition and critical factors in the maturation of healthy gut microbiota, characterized by a transient bifidobacterial bloom before a global rise in anaerobes. Early depletion in gut Bifidobacterium longum, a typical maternal probiotic, known to inhibit pathogens, represents the first step in gut microbiota alteration associated with severe acute malnutrition (SAM). Later, the absence of the Healthy Mature Anaerobic Gut Microbiota (HMAGM) leads to deficient energy harvest, vitamin biosynthesis and immune protection, and is associated with diarrhea, malabsorption and systemic invasion by microbial pathogens. A therapeutic diet and infection treatment may be unable to restore bifidobacteria and HMAGM.


Researchers found that malnourished children’s microbiota failed to follow the healthy pattern they identified in healthy children. The microbiota of malnourished children is immature, lagging in development behind that of their healthy peers. Supplementing these children’s meals with widely used therapeutic foods that increase calories and nutrient density reduces deaths from malnutrition, but it does not fix their persistent microbiota immaturity.

“Perhaps more insidious than slowing growth is malnutrition’s effect on less visible aspects of health, including impaired brain development and dysfunctional immunity, which follow these children throughout their lives”.

The Father of The Microbiome

Dr. Jeffrey Gordon


SIBO can cause severe malabsorption, serious malnutrition and immune deficiency syndromes in children (non breastfed) and adults. 

Prognosis is usually serious, determined mostly by the underlying disease that led to SIBO.



The WHO recommends that immunization or treatment be orally administered due to economic, logistical and security reasons. Furthermore, this route offers important advantages over systemic administration, such as reducing side effects, as the molecules are administered locally and have the ability to stimulate the GALT immune responses  (Levine and Dougan, 1998Neutra and Kozlowski, 2006Bermúdez-Humarán et al., 2011).



For ANY infectious or parasitic disease to start, it is ALWAYS a requisite that the host suffer IMMUNODEFICIENCY. At the same time, infectious and parasitic diseases themselves cause additional IMMUNE SUPPRESSION and more MALNUTRITION. This immune suppression is SECONDARY to the accumulation of free radicals, especially oxidizing species, that occurs during and after infectious and parasitic diseases.

Clinical Aspects of Immunology and Biochem J.


Current IBD Research 2016

Currently available treatments for IBD, which target the systemic immune system, induce immunosuppression, thereby exposing the patient to the risk of infections and malignancy. The interplay between the gut and the systemic immune system determines the final effect on target organs, including the bowel mucosa. Inflammatory bowel diseases (IBD) are associated with an altered systemic immune response leading to inflammation-mediated damage to the gut and other organs.

Clinical & Translational Immunology (2016)
Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

Most importantly, the immune modulatory agents used today for IBD do not achieve remission in many patients.

Not all IBD patients benefit from currently available drugs. Young people with IBD do not want to be on long-term drug therapy. Oral immune therapy, while not yet studied in large cohorts of patients, may provide an answer to this unmet need.

Clinical & Translational Immunology (2016)
Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel


Tolerance is the ability of the immune system to ‘see’ and respond appropriately. Without galactose (a necessary sugar) the immune system can not 'see'. Your immune system would not be able to function without galactose Your body wouldn’t know which cells are “good” and what cells are “bad.” Your body wouldn’t know who the invaders were and which ones should be attacked by antibodies. As you will learn the importance of these ‘sugars’ in gut microbiota health is a rapidly expanding field of research, only recently discovered, including HMO's (human milk oligosaccharides).

Why galactose? Milk sugar aka lactose has been shown to be very beneficial for the human body though unlike sucrose, lactose is made up of glucose and galactose. There is no fructose in lactose. It is a healthy disaccharide sugar. Galactose is known as the “brain sugar” and supports brain development of babies and children. Galactose helps triggers long-term memory formation. Galactose has been shown to inhibit tumor growth and stop its spread, particularly to the liver. This beneficial sugar can also enhance wound healing, decrease inflammation, enhances cellular communication, and increases calcium absorption.
What does immune ‘tolerance’ mean in simple language?
Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism. The Th1 cytokine profile is vital for clearance of certain organisms and ancillary immune activity, and a limiting effect on this cytokine profile may result in reduced chances for overcoming infections especially intra-cellular organisms residing within macrophages. Effective clearance will depend on appropriate macrophage activation (which occurs through IFN≥ release by Th1 and NK cells) and production of nitric oxide. If this pathway is disrupted IFN≥ secretion is blocked, impairing macrophage activation. Persistent blockade of these inhibitory receptors has lead to the breakdown in immune self tolerance, thereby increasing susceptibility to autoimmune or auto-inflammatory side effects, including rash, colitis, hepatitis and endocrinopathies. Many drugs may cause checkpoint blockade toxicity including pharmaceutical drugs termed ‘immuno therapy’ by pharmaceutical companies, these include Mab drugs and cancer treatments. Checkpoint Inhibitor–Induced Colitis: A New Type of Inflammatory Bowel Disease? Madeline Bertha, MD MS, corresponding author1 Emanuelle Bellaguara, MD, Timothy Kuzel, MD, and Stephen Hanauer, MD ACG Case Rep J. 2017; 4: e112. Published online 2017 Oct 11. doi: 10.14309/crj.2017.112 PMCID: PMC5636906 PMID: 29043290

The Elderly

Mammal milk is required for enhanced phagocytosis as shown by research, especially in the elderly. Whole fat mammal milk can actually restore phagocytosis in senescent cells in the elderly. Phagocytosis, by which immune cells ‘eat’ bacteria or infected cells, is one of the mechanisms that help to resist infections. Lactic acid bacteria strains like acidophilus also increases phagocytosis.