My long time friend Cort Johnson has done four posts on this promising new drug for CFS/ME (and possibly other autoimmune conditions).

• The Cortene Way: New Drug to Be Trialed in Chronic Fatigue Syndrome (ME/CFS) Soon – Pt. I
• Cortene II: A New Drug & A New Hypothesis For Chronic Fatigue Syndrome (ME/CFS)
• Cortene III – A New Drug for Chronic Fatigue Syndrome (ME/CFS): The Clinical Trial
• Cortene IV – The Co rtene Chronic Fatigue Syndrome (ME/CFS) Drug Trial Begins

My own focus is the microbiome – keeping to a merging of concepts from Occam’s razor and Osler’s Principles. For a new drug that is just starting clinical trials, this presents a challenge.

The model behind this application is the HPA axis, hypothalamic-pituitary-adrenal axis. And specifically three items are cites:

• Corticotropin-releasing factor
  • CRF1 – low stress,
  • CRF2 – high stress
• Urocortin 1 (UCN1) – a 40 amino acid peptide that normalizes the above

What related information is on PubMed

• Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress.[2018]
  • ” we studied the effects of the chronic stress-microbiota interaction on HPA axis activity and on the expression of colonic corticotropin-releasing hormone (CRH) system, cytokines and 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that determines locally produced glucocorticoids…  In the colon, the microbiota attenuated the expression of 11HSD1, CRH, urocortin UCN2 and its receptor, CRHR2, but potentiated the expression of cytokines TNFα, IFNγ, IL-4, IL-5, IL-6, IL-10, IL-13 and IL-17, with the exception of IL-1β….The data suggest that the presence of microbiota/intestinal commensals plays an important role in shaping the response of peripheral tissues to stress and indicates possible pathways by which the environment can interact with glucocorticoid signaling.”
  • Microbiota Modulate Anxiety-Like Behavior and Endocrine Abnormalities in Hypothalamic-Pituitary-Adrenal Axis. [2017]
• Involvement of Corticotropin-Releasing Factor and Receptors in Immune Cells in Irritable Bowel Syndrome [2018].
  • “Corticotropin-releasing factor (CRF), a major mediator in the stress response, is involved in altered function in GI, including inflammatory processes, colonic transit time, contractile activity, defecation pattern, pain threshold, mucosal secretory function, and barrier functions. This mini review focuses on the recently establish local GI-CRF system, its involvement in modulating the immune response in IBS, and summarizes current IBS animal models and mapping of CRF, CRFR1, and CRFR2 expression in colon tissues. CRF and receptors might be a key molecule involving the immune and movement function via brain-gut axis in IBS.”
  • Impaired emotional learning and involvement of the corticotropin-releasing factor signaling system in patients with irritable bowel syndrome. [2013]
    • “CRF-R1 ….appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.”
• Inhibition of corticotropin-releasing hormone receptor 1 and activation of receptor 2 protect against colonic injury and promote epithelium repair.[2017]
  • “Our results show that in response to MS, CRHR1 mediates gut injury by promoting intestinal inflammation, increasing gut permeability, altering intestinal morphology, and modulating the intestinal microbiota. In contrast, CRHR2 activates intestinal stem cells and is important for gut repair. “

Short Version

It appears to be established that CRF shifts are associated with issues associated with intestinal inflammation, gut permeability, and changes in the intestinal microbiota. There is a chicken-and-the-egg question. Did the microbiota change first and the others are consequences OR did things like gut permeability altered the microbiota. My working hypothesis is that the microbiota shift occurred first.

This may also explain why I seem to be able to recover from CFS/ME multiple times. My personality type has been evaluated as a Pollyanna, thus significantly less inclined to be stressed mentally, nor dwelling on the past and with a strong positive future perspective.

Bacteria links:

• “Both CRF and UCN1 were significantly augmented by Bacteroides vulgatus and Fusobacterium varium at both the mRNA and protein levels. In particular, B. vulgatus stimulated human MoDCs, resulting in extremely high levels of CRF and UCN1. Conclusion: Stimulation of MoDCs by B. vulgatus and F. varium may be associated with CRF/UCN1-related intestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease.” [2014]
• “. In conclusion, Lactobacillus rhamnosus GG (LGG)  stimulates IL-4, IL-10 and Ucn expression ”  [2010]

How does Cortene work is the question!

My first prediction is simple: it will alter the microbiome. If it’s main mechanism of action is the microbiome, then my second prediction is that will be effective for only a percentage of patients — why? Every patient have a unique, and frequently very different, microbiome.

“Cortene’s drug, CT38, is a CRF2 agonist, i.e., it stimulates CRF2. It is comprised only of amino acids that occur naturally in the human body.” [post]

Bottom Line

This drug is still in early stages and my gut feeling is that it will have limited success for a small number of people.  The CRF/UCN imbalance is very likely real — but my bet is on a microbiome shift being the maintainer and likely cause of this imbalance.