Normal Gut Flora, Inflammatory Markers, and Chronic Illness – Part 2

By: Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM

Read Part 1

Histamines and Inflammation

inflammatory markers and histamineHistamine is a messenger substance in the body that aids in cellular communication. In its role as a regulator in the body, histamine works in digestion in conditions of normal gut flora, lowers blood pressure, and regulates sleep patterns. Diamine oxidase (DAO) is an important enzyme that breaks down histamine. When histamine levels are high, levels of DAO are low. DAO is found in large quantities in the cellular membranes of cells lining the small intestine and colon. People with GI problems affecting normal gut flora are much more reactive to histamine rich foods. Some medications also can inhibit DAO production and function. Leading to an increase in inflammatory markers.

Because of an apparent relationship between histamine and estrogen, women are more frequently afflicted with problems related to histamine than men. With an increase in estrogen, mast cells containing histamine granulate more readily. This leads to an increase in circulating histamine and inflammation. Women who suffer from PMS or PMDD should avoid foods that are high in histamine. This is a condition that can result from AFS, as well.

Histamine in the body is produced in mast cells and basophils as a local immune response to foreign materials. It is also produced in the brain where it acts as a neurotransmitter. Another place where histamine can be stored and released is within the enterochromaffin-like cells in the stomach.

When histamine is released, it makes capillaries more permeable to white blood cells and proteins. This gives rise to the runny nose and watery eyes so familiar in allergies. When foreign antigens bind to IgE sensitized mast cells in mucous membranes, sneezing follows as a way to expel them from the body.

In the brain, the histamine neurons in the posterior hypothalamus affect wakefulness and prevent sleep. Histamines located in the stomach stimulate the parietal cells there to secrete the gastric fluids needed for digestion.

MPO and Inflammation

Myeloperoxidase (MPO) is an enzyme present when inflammation is present. It is released into the fluid around cells from polymorphonuclear neutrophils and macrophages. Because MPO is involved in oxidative stress and inflammation, it has been shown to be a significant marker when evaluating people with coronary heart disease.

Both oxidative stress and inflammation have been implicated in coronary problems. Macrophages and neutrophils infiltrate stable coronary artery plaques, making them unstable lesions. MPO is contained in these macrophages and neutrophils and can be measured in blood as an inflammatory marker. MPO aids in the conversion of chloride and hydrogen peroxide into hypochlorite and is secreted in inflammation. MPO reduces nitric oxide (NO) bioavailability inhibiting the ability of NO to decrease inflammation.

Along with IL-6, MPO is a good marker for the presence of inflammation.


HIF-1 Alpha and Inflammation

Hypoxia inducible factor (HIF) 1 alpha is a chief regulator of the homeostatic response to hypoxia on both cellular and systemic levels. It activates genes involved in energy metabolism, angiogenesis, and apoptosis. It also activates other genes that increase oxygen delivery or increase metabolic adaptation to hypoxia.

HIF functions can also be triggered by pathological stressors such as inflammation, infections, and cancer. HIF performs functions such as increasing phagocyte microbicidal, driving T cell differentiation, and cytotoxic activity. The immune control function of HIF plays a role in cellular metabolism that is a key regulator of immunity.

HIF transcription factors play a major role in immune cell metabolism and function.

inflammatory markers and Immune functionsIn its role of regulator of adaptation in low-oxygen environments, HIF also regulates gene expression involved in glycolysis, erythropoiesis, angiogenesis, and proliferation. In its regulatory role in inflammation, HIF aids in the optimization of innate immunity, acts to control pro-inflammatory gene expression, helps in controlling bacterial killing, and influences cell migration.

Hypoxia and inflammation are interrelated. Inflammation in the presence of hypoxic conditions appears to be the foundation of many chronic illness conditions. Metabolic supply and demand ratios for oxygen cause stabilization of HIF-1 alpha when intestinal inflammation is present, leading to inflammatory hypoxia. These same metabolic alterations that bring on stabilization of HIF-1 alpha are associated with lung inflammation, as well. Thus, HIF-1 can be seen as an inflammatory marker

TGF-beta and Inflammation

This cytokine affects growth and proliferation of many cells and has both pro- and anti-inflammatory effects. TGF-beta is produced in many cells. Some of these are macrophages, fibroblasts, microglial cells, and T and B lymphocytes.

TGF-beta 1 is the form of TGF-beta most involved in inflammation and a great inflammatory marker. People with biotoxin or mold problems will often have high levels of TGF-beta.

TGF functions as protection against autoimmune gut disorders through increasing serotonin transporters and uptake in the gut. This neurotransmitter is low in IBS and IBD.

TGF-beta also plays a role in killing T cells that invade tissue. One of the normal functions of TGF-beta is tumor suppression, although tumors can develop resistance to this substance late in their progression.

In infection conditions, TGF-beta protects against collateral damage by the immune system. Unfortunately, it also aids pathogens in evading the immune response, which leads to chronic infections.

While TGF-beta stimulates local immune and inflammatory responses, it suppresses the immune system at the systemic level. Research has shown mice who have a deficiency in TGF-beta tend to develop a significant inflammatory response that can lead to death. This suggests TGF-beta has a role in actively suppressing inflammation.

TGF can also increase inflammation. It produces pro-inflammatory Th17 and TH9 cells and inhibits TH22 in an inflammatory condition.

Another negative aspect of TGF is its ability to increase VEGF by increasing HIF, thus helping in the spread of tumors. In gastric cancer patients, a high level of TGF-beta can indicate lymph node metastasis and a poor prognosis.

TGF-beta will also make mast cells, fibroblasts, neutrophils, monocytes, and lymphocytes adhere to sites of tissue injury and inflammation. It will stimulate these cells to produce pro-inflammatory cytokines, such as IL-6, IL-1, and TNF.

It appears TGF-beta plays a role in several chronic inflammatory illness conditions.


Obesity, Lipotoxicity, and Inflammation

Finally, it is important to discuss inflammation in the setting of obesity and your metabolism.

In conditions of normal gut flora and normal metabolism, the body is supplied with the energy its cells need in order to function properly. With the disruption of metabolism, this process becomes imbalanced and inflammation results.

When immune responses are triggered, inflammatory markers are sent out and inflammation begins, the metabolic process is interrupted. These changes in metabolic activity are brought on by increased recruitment of neutrophils and monocytes, both types of inflammatory cells, and by dramatic increases in lymphocyte populations. This brings a significant shift in energy supply and demand, resulting in metabolic acidosis and lowered availability of oxygen to cells leading to hypoxia significant enough to bring on serious changes in tissue metabolism.

These shifts in tissue metabolism bring on a lack of local nutrients, increased demand for oxygen, and release of an abundance of reactive nitrogen and oxygen components.

inflammatory markers and insulin resistanceResearch into obesity and the insulin resistance that often accompanies it, along with inflammation showed obesity to be a major driving force behind immune cell infiltration which adds to metabolic inflammation. One of the major components of this metabolic inflammation is the presence of adipose tissue macrophages (ATM). The levels of these ATM increases in obese individuals anywhere from 10 to 60 percent. With increased saturated fatty acid intake, pro-inflammatory M1 genes are activated. These M1 genes contribute to insulin resistance. Typically, much of the standard American diet contains saturated fatty acids.

The infiltration of immune cells brings inflammatory markers within metabolic tissues. These inflammatory markers can disrupt insulin signaling. Obesity also increases oxidative stress, further adding to insulin resistance.

With this information, it’s easy to see the connection between the epidemic of obesity and the epidemic of inflammation in this country. It is important to get your inflammatory markers checked.

There is likewise some significant current research indicating the effects of “meta-inflammation” in organ systems involved in metabolism. For example, the liver is involved in metabolic homeostasis, lipogenesis, gluconeogenesis, and cholesterol metabolism.

Lipotoxicity can develop from metabolic inflammation that comes about when the liver goes over its ability to store and use fatty acids. This condition is the side effect of lipid accumulation on glucose and insulin metabolism.

Lipotoxicity sets the stage for the development of potentially dangerous lipid species, impaired insulin signaling, and non-alcoholic fatty liver disease. Insulin resistance in the liver can also be caused by steatosis, which interferes with the ability of insulin to lower production of hepatic glucose and increase the synthesis of glycogen.

Lipotoxicity is an important part of metabolic inflammation.

Meta-inflammation in muscle groups is also significant. Impaired insulin signaling, such as from obesity induced metabolic inflammation, also inhibits glucose metabolism in skeletal muscles. Since muscles take care of 80 percent of glucose uptake after insulin stimulation, this process is important. Increased free fatty acids lead to lipotoxicity and decrease skeletal muscle insulin sensitivity.

The pancreas is also negatively impacted by lipotoxicity and glucotoxicity brought on by obesity. The insulin resistance seen in obesity raises the metabolic demand on the pancreas with resulting hyperglycemia when these cells can no longer keep up with their compensatory load. This hyperglycemia produces glucotoxicity that brings on a decrease in insulin gene expression in the pancreas.

It appears the proinflammatory cytokine IL-1 beta plays a major role in these disorders. A part of the process appears to be an overproduction of metabolites such as uric acid and cholesterol crystals outside the cells are signals sensed by NLRB3, which then increases the production of IL-1 beta. This line of research shows the role of metabolism during host defense and inflammation.


Summary on Inflammatory Markers

inflammatory markers and gut floraWith normal gut flora and a fully-functioning metabolism, the body can perform its multitude of tasks and remain healthy. But when metabolism is disrupted, inflammatory markers are released and inflammation that can ultimately lead to several serious chronic illness conditions results.

The typical laboratory tests performed by conventionally trained healthcare professionals do not always give the type of comprehensive information needed to determine the presence of markers indicating chronic, low-level inflammation that can signal the onset or predict the likelihood of chronic illnesses. The inflammatory markers needed can be found, but are often not recognized as the markers they are.

To have a complete picture of a person’s health condition that will lead to successful remediation efforts, healthcare professionals must know about the inflammatory markers that can reveal the underlying inflammation that leads to chronic illnesses.

Read Part 1

© Copyright 2018 Michael Lam, M.D. All Rights Reserved.

inflammatory markers