Kynurenine Pathway

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Slide 1

Hi my name is Wesley Hurell; Technical Support Specialist for Diagnostic Insight. I am excited to be able to provide you with a preview of the information to be covered in our upcoming Webinar. This webinar will focus on the critical role of the kynurenine pathway in inflammation and how the activity of the pathway can be measured using the OrganixTM Profile. As seen on the simplified diagram, the kynurenine pathway is made up of metabolites derived from tryptophan. Traditionally, most practitioners associate tryptophan with its vital role as a precursor of serotonin, however, only a minor percentage of total endogenous tryptophan is used for this purpose. In fact, over 95% of endogenous tryptophan is metabolized down the kynurenine pathway, with the remainder used for serotonin synthesis. This underscores the vital role that the kynurenine pathway plays in human physiology. Indeed, acute stimulation of the kynurenine pathway is one of the body’s key mechanism’s for fighting infection. The inflammatory cytokine, interferon-gamma, which is released during Th1 immune activation specifically stimulates the rate-limiting enzyme for the kynurenine pathway, namely, indole 2,3-dioxygenase (IDO).

Slide 2

Stimulation of this key regulatory enzyme, IDO by IFN-y acts to decrease endogenous tryptophan levels. This in turn leads to a reduction in protein synthesis, which helps arrest the growth of viral and malignant cells during infection. However, in situations of chronic inflammation, tryptophan depletion can be such that the proper functioning of T-cells is affected – eventually leading to immune deficiencies.

Slide 3

While Th1 immune activation is a normal response in acute situations such as viral infection, there are important conditions where chronic Th1 activation can be detrimental to the patient’s health. A classic example is in the case of autoimmune disease, such rheumatoid arthritis or SLE. Another important example is cancer. Chronic Th1 activation is a key mechanism by which malignant disease can escape immune surveillance by the body. In contrast Th1 activation serves as a protective mechanism for the susceptible developing fetus during pregnancy. Finally, Th1 activation can lead to allograft rejection in donor recipients

Slide 4

This example shows how Th1 activation in a patient with non-hodgkins lymphoma leads to tryptophan degradation with a resultant increase in the kynurenine pathway OrganixTM markers, picolinate and quinolinate.

Slide 5

Chronic up-regulation of the kynurenine pathway can also lead to a decrease in serotonin levels. This had led researchers to propose kynurenine pathway activation as a key mechanism by which psychosomatic and depressive symptoms are manifest in patients with inflammation. Some chronic conditions thought to be driven by inflammation include IBD, CFS, cardiovascular disease, dementia and obesity.

Slide 6

This slide shows a graphical explanation of how depletion in serotonin levels can explain a number of chronic diseases.

Slide 7

This slide is an example of a patient with SLE. Chronic Th1 activation has led to elevations for kynurenate, quinolinate and picolinate This in turn has led to a significant drop in the patient’s plasma tryptophan levels to the extent that it is the lowest of all the essential amino acids. This patient also complains of constipation, which is a symptom that can often be explained by low gastrointestinal motility secondary to low serotonin levels.

Slide 8

We hope this short presentation will entice you to register for our upcoming Webinar in July. During the webinar, we will go into more detail on the kynurenine pathway and its link with inflammation Further case studies will be presented highlighting the multiple types of conditions where Th1-immune activation can manifest as an abnormality in the kynurenine pathway Particular focus will be given to the recent research on botanical treatments shown to inhibit activation of the kynurenine pathway. Please check your email for the particular webinar dates and times in your state and city.

Slide 1

Kynurenine Pathway Measured by 4 Markers on OrganixTM Profile Metabolizes over 95% of endogenous tryptophan Body’s mechanism for fighting infection Th1 activation increases flux through pathway

Slide 2

Mechanism of Infection Response Activation of kynurenine pathway leads to tryptophan degradation Restricts protein synthesis Limits growth of intracellular pathogens or malignant cells Chronic depletion leads to immune deficiency Infected cells Malignant cells T-cells Clear infection Stop cancer Immune deficiency Tryptophan

Slide 3

Immune Regulation & Tryptophan Viral infection Autoimmune disease Malignant disease Pregnancy Allograft rejection Tryptophan IFN-g T-cell Target cell Schrocksnadel K et al. Monitoring tryptophan metabolism in chronic immune activation. Clinica Chimica Acta. 2006;364(1-2):82-90.

Slide 4

Example Patient with early stage non-hodgkins lymphoma Picolinate Quinolinate IFN-y Tryptophan Kynurenine IDO Activated T-cell

Slide 5

Tryptophan Degradation & Serotonin Any major change in kynurenine pathway activity can have significant affect on serotonin levels Chronic Th1-immune activation Key mechanism by which patients with chronic inflammation often present with psychosomatic and depressive symptoms Inflammatory Bowel Disease Chronic Fatigue Syndrome Cardiovascular Disease

Slide 6

Tryptophan Degradation & Serotonin Serotonin Melatonin Depression Schrocksnadel K, et al. Monitoring tryptophan metabolism in chronic immune activation. Clinica Chimica Acta. 2006;364: 82 – 90. Cognitive Impairment Dementia Bowel dysfunction IBS

Slide 7

Example Patient with SLE Autoimmune condition resulting in Th1 activation Stimulation of kynurenine pathway Resulting in depletion of tryptophan May explain symptoms of constipation

Slide 8

Be Sure To Tune In… Detailed overview of kynurenine pathway Significance of intermediates Significance of different patterns of the kynurenine pathway on the OrganixTM Profile Case studies of different conditions linked to activation of kynurenine pathway Botanical treatment options for correcting pathway Check email for times & dates…

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