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MFGE8 : New Target related to Sepsis,Inflammation, Gut Lining

mariovitali

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This is a proposed new Research target for ME/CFS. MFGE8 is Milk Fat Globule-EGF factor 8 Protein also known as Lactadherin.

CC : @Hip @JaimeS

Here are some excerpts :

Milk fat globule membrane (MFGM) is a complex and unique structure composed primarily of lipids and proteins that surrounds milk fat globule secreted from the milk producing cells of humans and other mammals. It is a source of multiple bioactive compounds, including phospholipids, glycolipids, glycoproteins, and carbohydrates that have important functional roles within the brain and gut.
Intestinal Epithelium Integrity :

The intestinal epithelium is a continuous single layer of cells that lines the intestinal tract. It provides a physical barrier that separates internal body compartments and the harmful environment of the gut lumen. Defects in epithelial barrier and immune functions can lead to infections with opportunistic and pathogenic microbes and contribute to the pathogenesis of inflammatory bowel disease (IBD). Recent studies have shown that macrophages in the underlying intestinal tissue produce milk fat globule-EGF factor 8 (MFG-E8) which directly targets intestinal epithelial cells and regulates the integrity of intestinal epithelial barrier function.
Inflammatory Disease :

Some studies have demonstrated that MFG-E8 plays a role in inflammatory degenerative bone diseases such as RA and osteoarthritis (OA). The expression of MFG-E8 is downregulated in inflammatory conditions and has also been found to be downregulated in the sera of RA patients, while an in vitro study revealed that MFG-E8 suppresses inflammatory responses by suppressing the production of proinflammatory cytokines. Moreover, the expression of MFG-E8 is decreased in arthritic mice, and the loss of MFG-E8 exacerbated arthritis and led to more severe bone loss in mice by inducing the production of proinflammatory cytokines and the infiltration of pathogenic neutrophils in the inflamed joints
Sepsis:

Sepsis is a high lethal systemic inflammatory disease characterized by the increase in proinflammatory cytokines and the accumulation of apoptotic cells. It has been reported that MFG-E8 is correlated with sepsis. During sepsis, a large number of immune cells undergo apoptosis due to the impairment of apoptotic cell clearance, which then induces secondary necrotic cell development that dysregulates proper immune function and induces the production of proinflammatory cytokines. Therefore, studying the function of MFG-E8 could lead to promising therapeutic approaches that facilitate the clearance of apoptotic cells by MFG-E8 in sepsis.

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Original text :

http://algogenomics.blogspot.com/2018/05/milk-fat-globule-membrane-mfgm.html
 

mariovitali

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Here is a sample algorithmic run :


algorun.png






As you can see, Extracellular Vesicles (Prof. Maureen Hanson) are also being selected. The tool also suggests a connection between cholecystectomy and ME/CFS.

It appears that Milk Fat Globule Membrane is being added to Infant Formulas :


https://www.arlafoodsingredients.com/our-ingredients/health-food-ingredients/phospholipids-mfmg/

If i was living in US i would give it a go although the fact that the product is Whey Protein which may be problematic for many ME/CFS Patients.

So i started taking MFGM through another route which is to take Milk Fat from Milk Cream (2 tea spoons of it). The good thing is that i can stop my regimen (which slowly brings back symptoms) and evaluate something new.

I will report back in this Thread.


EDIT : Here is a patent on MFGM. mentions Sepsis, Inflammation, Lactate Levels :

[0053] The invention also provides a method of preparing a pharmaceutical composition for treating a subject having sepsis or a subject at risk for sepsis, the method comprising formulating a recombinant human milk fat globule epidermal growth factor-factor VIII (rhMFG-E8) in a pharmaceutical composition in an amount effective to reduce a physiologic effect of sepsis, wherein the rhMFG-E8 has an amino acid sequence that is at least 95% identical to human MFG-E8 (hMFG-E8) (SEQ ID NO: l) and wherein the rhMFG-E8 is non-glycosylated.
https://patents.google.com/patent/WO2012149254A2
 
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mariovitali

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So. are you saying that if we ingest milk fat it will help us?

What about patients who are allergic to all milk products?
I do not suggest any ingestion of Milk, just presenting some findings. Butyric acid increases activity of MFGE8 also but the potential relevance of MFGE8 and Butyric acid to ME/CFS Pathology is proposed to be further investigated.
 

mariovitali

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In my stool test, it showed a lot of butyrate making bacteria. Have you considered this angle?
This is an interesting finding, however i would rather leave this to the experts. All i can say at this point is that Butyric acid (instead of Butyrate) appears to be of interest. I do not know why this is so.

If you also look at the algorithmic run above you will find the entry 'iga' which is actually IgA, Immunoglobulin A.

I had no idea why the algorithm was choosing this but then i found this :


The liver is not only a passive recipient and effector site of gut-derived agents, it also feeds back to the intestine through the secretion of bile, including BAs, as well as other mediators, such as IgA, affecting the gut-liver-axis.11 Secretory IgAs (sIgA) play a central role in regulating host-microbiota home- ostasis.12 sIgA regulates the composition of the intestinal microflora and protects mucosal surfaces by ensuring immune exclusion. In fact, IgA agglutinates bacteria and participates in biofilm formation, preventing bacterial translocation
In other words, i wish there were experts along the way, driving this process instead of us who have no idea.
 

Learner1

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I am utterly mystified by whatever process you are using that pulls together seemingly random information.

But, my doctors and I are familiar with a lot of the research that has been done around many of the topics you bring up and my doctors are using this knowledge to treat me, which seems to be working.

A few thoughts:
  • Having a healthy gut, with appropriate amounts of SIgA, butyric acid producing bacteria, as well as those that can process and help us assimilate nutrients from food we ingest is critical to getting well
  • Having a liver that is not overburdened with toxins and that has adequate cofactors to perform Phase I and Phase II detoxification is also critical
  • Having a gall bladder that works properly with adequate bile acids is critical for the above
  • Being able to ingest and assimilate lipids necessary for cell and mitochondrial membrane health as well as lipid rafts for moving things around is essential to getting well.
The metabolomics and microbiome ME/CFS researchers are touching on some of the above. Bringing in other research on the above topics and connecting it to the ME/CFS research would definitely be useful. Perhaps it's already being done?
 

mariovitali

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A few thoughts:
  • Having a healthy gut, with appropriate amounts of SIgA, butyric acid producing bacteria, as well as those that can process and help us assimilate nutrients from food we ingest is critical to getting well
  • Having a liver that is not overburdened with toxins and that has adequate cofactors to perform Phase I and Phase II detoxification is also critical
  • Having a gall bladder that works properly with adequate bile acids is critical for the above
  • Being able to ingest and assimilate lipids necessary for cell and mitochondrial membrane health as well as lipid rafts for moving things around is essential to getting well.
The metabolomics and microbiome ME/CFS researchers are touching on some of the above. Bringing in other research on the above topics and connecting it to the ME/CFS research would definitely be useful. Perhaps it's already being done?
I couldn't agree more with everything you say.

Right from the beginning these algorithmic methods were showing the Liver. As it appears the system did not have the necessary information (?) to identify Gut Dysbiosis.

Even though i wouldn't pay too much attention to the Gut, i have to do it now because many "signals" are pointing towards it.

In your thoughts you have exactly what exists also in my mind. The thing is that we must focus at both the Liver and the Gut. Any "Liver Stressor" (such as certain medications) may affect Liver function which in turn affect Bile Acid metabolism which in turn affects Gut Microbiome (?).

This is one potential route, i am sure there are others. We therefore have to look at all causes that may be affecting enterohepatic functioning. Not just Liver, not just Gut but both need to be evaluated and screened.

I feel that we are getting very close... after quite some time i can definitely feel this is so.
 

Learner1

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You might look into functional medicine, which looks at the body as a system of systems. There is a lot of focus on ensuring the digestive system is properly functioning as it controls the biochemicals that get to all the other systems in the body.

So, of course, having these organs work properly is needed to help us get well. Its an underpinning of health, no matter what the disease.

There have been findings by ME/CFS researchers of disturbed microbiomes, SIBO, disturbed methylation, and so on.

But it still doesn't tell us why we are sick or what switch to flip to get well. Many people without ME/CFS have poor liver and gall bladder function and disturbed microbiomes. What makes us different from them?
 

mariovitali

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But it still doesn't tell us why we are sick or what switch to flip to get well. Many people without ME/CFS have poor liver and gall bladder function and disturbed microbiomes. What makes us different from them?
Good question.

I hypothesize that it is a combination of issues on ER Stress Control, Inflammatory response, Phagocytosis and Autoimmunity (among others) that creates a vicious cycle that needs to be stopped.

All of these topics are included on the 32-page document i circulated to Prof. Davis / Hanson / Unutmaz and others