Autoimmune Disease in the U.S.- Part 6 in 6-Part Series

What is the Functional Medicine approach to the treatment of AI disease?  The importance of supporting the glutathione and nitric oxide systems. The importance of addressing intestinal permeability and the GI tract. The role of vitamin D.

Main points of this issue:

  • The primary medications being used by conventional medicine to treat autoimmune disease are immune-suppressing medications
  • Functional medicine treatment of AI disease focuses on modulating the autoimmunity, dampening immune response, decreasing tissue destruction and enhancing patient’s ability to recover
  • There are two systems that regulate all of these aspects of the immune response: the Glutathione Recycling and Nitric Oxide Systems
  • Glutathione is one of the most critical immune-modulating substances that we know of
  • Glutathione prevents leaky gut
  • There are several natural compounds that ave been shown to support the glutathione recycling system
  • Nitic oxide plays both destructive and protective roles in autoimmunity, depending on which isomer is expressed
  • How these isomers are manipulated or modulated will determine how much destruction of tissue or ability to recover from autoimmune flare-ups a person has
  • Vitamin D and EPA-DHA help decrease inflammation and minimize tissue destruction
  • Zince carnosine and turmeric help repair the intestinal lining and decrease gastrointestinal inflammatory responses

How is AI disease treated?

Let’s first look at how autoimmune disease is treated by conventional medicine. We will then look at the goals of treatment in functional medicine and the systems that are targeted in the modulation of the autoimmune response.

Conventional medicine: steroids and other immune-suppressing medications

The primary medications still being used by conventional medicine to treat autoimmune disease are immune-suppressing medications, such as prednisone and immune-suppressing medications. However, there are many known side-effects of these medications. Some of the side effects of steroids include: immune suppression, bone loss, neurodegenerative impacts on the brain, insulin-related issues, epithelial thinning, and catabolic states so they cannot recover from flare-ups.

“Drugs developed by the pharmaceutical industry have thus far been associated with toxicity and side effects, which is why natural substances are of increasing interest”1

“Current Western therapies for inflammatory diseases are suboptimal; increasingly, patients are turning to complementary and alternative medicine for symptom relief and improved quality of life”2

“There is emerging evidence that many of these therapies have the ability to modulate the immune system and disrupt the proinflammatory cascade through a variety of mechanisms, including antioxidant effects, alterations in cell signaling (in particular the nuclear factor (NF)-B pathway), cytokines, proinflammatory mediators, and disruption of bacterial flora”3

“Finding therapeutic agents which can modulate the inflammatory reaction is the highest priority in medical research today”4

The Functional Medicine Approach to Treatment of AI Disease:

  • Modulate the autoimmunity
  • Dampen immune response
  • Decrease tissue destruction
  • Enhance patients ability to recover

To be successful at managing AI disease, you need to address the following:

  • Enhance integrity of mucosal membrane
  • Balance TH1 and TH2 systems
  • Enhance the TH3 regulatory system
  • Decrease the TH-17 response

The Role of Glutathione and Nitric Oxide Systems in Autoimmunity

There are two systems that regulate all of these aspects of the immune response:

  • Glutathione recycling system
  • Nitric oxide isomer system

The Role of Glutathione in Autoimmune Modulation

A study published in 2008 showed a significant correlation between the amount of available glutathione in the blood and the severity of the disease of SLE (systemic lupus erythematosus):

“A significant correlation between plasma glutathione and SLE severity exists that may aid evaluation of the disease severity and usefulness of the management of SLE”5

Here’s what they found:
The lower the glutathione status, the greater destruction of tissue they had. The ones that had the highest amount of glutathione activity had the least amount of tissue destruction. Glutathione helps recover tissue, helps support regulatory T cells, and helps stop hapten-induced immune responses. This system is absolutely critical for overall modulation of autoimmunity.

“These data indicate that glutathione peroxidase dependent control of intracellular reactive oxygen species accumulation is important not only for regulatiojn of Th-cell proliferation, but also for modulation of differentiation into TH1, TH2 and TH17 cells.”6

Glutathione is one of the most critical immune-modulating substances that we know of

“Accumulation of evidence suggests that intracellular GSH (glutathione) levels in antigen-presenting cells such as macrophages, influence the TH1/TH2 cytokine response pattern. The observations reported herein show that pro-GSH molecules represent new therapeutic agents to support immune modulation.”7

In other words, one of the ways we can modulate these TH1/TH2 shifts is through the glutathione system.

Glutathione prevents leaky gut

When a person loses their glutathione recycling system, they also cannot prevent intestinal lining inflammation which then leads to leaky gut. The glutathione recycling system is one of the main systems that prevents leaky gut onset.

“Glutathione is suggested to play an important role in gut barrier function and prevention of intestinal inflammation”8

This whole glutathione system does several things:

  • It prevents environmental compounds from triggering autoimmunity
  • When it is depleted, it causes TH1/TH2 flare-ups

When this glutathione recycling system fails:

  • We lose the ability to enhance regulatory T-cells which modulate the attacks and flare-ups in these systems
  • We cannot regenerate the intestinal lining properly

Clinical Strategies to Support Glutathione Recycling

If you look at the literature, there are several compounds that help raise intracellular glutathione, activate the glutathione peroxidase and reductase enzymes, and make this process work more efficiently:

  • Cordyceps: within minutes has been found to raise glutathione levels and has a powerful effect on the enzymes that increase glutathione (used in Chinese medicine for thousands of years)
  • Centella asiatica
  • Silybum marianum
  • N-acetyl-cysteine
  • Alpha lipoic acid
  • L-glutamine
  • Selenium

Strategy for Glutathione Recycling

  • Modulates TH-1 and TH-2 polarization which dampens AI tissue destruction
  • Activates TH-3 regulatory T-cells which dampens AI tissue destruction
  • Dampens TH-17 activity which dampens AI tissue destruction
  • Enhances tissue and intestinal regeneration which enhances AI tissue destruction recovery
  • Protects cell mitochondria which enhances AI tissue destruction recovery
  • Prevents activation of iNOS which dampens AI tissue destruction

The Role of Nitric Oxide in Autoimmune Modulation

The other system that is important in autoimmune modulation is the nitric oxide system. Nitric oxide (NO) can be a compound that helps with tissue recovery or a compound that causes tissue inflammation.  NO is an important messenger molecule involved in many physiological and pathological processes. It plays both destructive and protective roles in autoimmunity, depending on which isomer is expressed.

Nitric Oxide Synthase Isomers

  • nNOS
  • eNOS
  • iNOS

In AI disease, there is destruction of tissue due to:

  • Increased iNOS (increased tissue destruction)
  • Decreased eNOS (cold hands, feet, decreased blood flow
  • Decreased nNOS (decreased brain function)

How these isomers are manipulated or modulated will determine how much destruction of tissue or ability to recover from autoimmune flare-ups a person has.

“Based on these data, it appears that the isoforms of NOS contribute to pathophysiology, and that induced NOS and NO may function, in part, in a protective pathway.”9

“Collectively, these data implicate discrete roles for the NOS isoforms in the emergence of local tissue pathology and underscore the need to define the specific pathways that are being targeted.”10

“We conclude that NO (nitric oxide) plays a critical immunoregulatory role and NO modulation may prevent the onset of autoimmune reactions”11

“We propose IL-17 and NO modulation could be relevant forms of therapy for autoimmune disorders”12

Compounds Shown in Literature to Modulate Nitric Oxide Isomers:

  • Adenosine
  • Huperzine A
  • Vinpocetine
  • L-alpha-glycerylphosphosphorylcholine
  • Alpha-ketogluteric acid
  • Xanthinol niacinate
  • L-acetylcarnitine

Vitamin D

“Vitamin D down-regulates nuclear factor-kB (NF-kB) activity, increases IL-10 production and decreases IL-6, IL-12, IFN-c, and TNF-a production, leading to a cytokine profile which favors less inflammation”13

“VDR plays a critical role in mucosal barrier homeostasis by preserving the integrity of junction complexes and the healing capacity of the colonic epithelium”14

EPA-DHA Essential Fatty Acids (Fish Oils)

“EPA appears to exert much of its anti-inflammatory benefit by suppressing NF-kappaB activation via activation of PPAR-alpha and thus reducing elaboration of proinflammatory mediators”15

“When endoscopic endpoints were used to evaluate the role of fish oil in the treatment of ulcerative colitis, 3 of 3 studies showed statistically significant improvement in the study group that received fish oil supplementation”16

Other compounds that help regenerate and repair intestinal lining (and decrease risk of AI flare-ups and onset):

Zinc Carnosine

“Regarding intestinal permeability, Zinc Carnosine caused an approximate threefold increase in gut integrity and repair”17


“Curcumin, a component of turmeric, has been shown to be non-toxic, to have antioxidant activity, and to inhibit such mediators of inflammation as NFB, cyclooxygenase-2 (COX-2), lipooxygenase (LOX), and inducible nitric oxide synthase (iNOS)”18

“In a larger, randomized, double-blind, multicenter trial involving patients with quiescent ulcerative colitis, administration of 1 g of curcumin twice daily resulted in both clinical improvement and a statistically significant decrease in the rate of relapse”19

“In various chronic illnesses in which inflammation is known to play a major role, curcumin has been shown to exhibit therapeutic potential. These diseases include Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, epilepsy, cerebral injury, CVDs, cancer, allergy, asthma, bronchitis, colitis, rheumatoid arthritis, renal ischemia, psoriasis, diabetes, obesity, depression, fatigue, and AIDS”20

Content provided by Datis Kharrazian, D.C., Autoimmune Regulation of the Nitric Oxide and Glutathione Systems, 11/4/10

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