Secretory diarrhea, adenylyl cyclase, and molybdoenzymes

There are several types of diarrhea: osmotic diarrhea, secretory diarrhea, inflammatory diarrhea, and diarrhea resulting from intestinal motility problems. (See http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/diarrhea.html) Cholera, which kills via dehydration from awful diarrhea, has been extensively researched. Partly from the work done on it, we know the following about secretory diarrhea:

Secretory Diarrhea
Large volumes of water are normally secreted into the small intestinal lumen, but a large majority of this water is efficienty absorbed before reaching the large intestine. Diarrhea occurs when secretion of water into the intestinal lumen exceeds absorption.
Many millions of people have died of the secretory diarrhea associated with cholera. The responsible organism, Vibrio cholerae, produces cholera toxin, which strongly activates adenylyl cyclase, causing a prolonged increase in intracellular concentration of cyclic AMP within crypt enterocytes. This change results in prolonged opening of the chloride channels that are instrumental in secretion of water from the crypts, allowing uncontrolled secretion of water. Additionally, cholera toxin affects the enteric nervous system, resulting in an independent stimulus of secretion.
Exposure to toxins from several other types of bacteria (e.g. E. coli heat-labile toxin) induce the same series of steps and massive secretory diarrhea that is often lethal unless the person or animal is aggressively treated to maintain hydration.
In addition to bacterial toxins, a large number of other agents can induce secretory diarrhea by turning on the intestinal secretory machinery, including:

• some laxatives

• hormones secreted by certain types of tumors (e.g. vasoactive intestinal peptide)

• a broad range of drugs (e.g. some types of asthma medications, antidepressants, cardiac drugs)

• certain metals, organic toxins, and plant products (e.g. arsenic, insecticides, mushroom toxins, caffeine)

In most cases, secretory diarrheas will not resolve during a 2-3 day fast.

(Excerpted from http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/diarrhea.html)


Secretory diarrhea can be caused by many things. In fact, inflammatory diarrhea often ends up stimulating secretory diarrhea:

The immune response to inflammatory conditions in the bowel contributes substantively to development of diarrhea. Activation of white blood cells leads them to secrete inflammatory mediators and cytokines which can stimulate secretion, in effect imposing a secretory component on top of an inflammatory diarrhea. Reactive oxygen species from leukocytes can damage or kill intestinal epithelial cells, which are replaced with immature cells that typically are deficient in the brush border enyzmes and transporters necessary for absorption of nutrients and water. In this way, components of an osmotic (malabsorption) diarrhea are added to the problem.

(Excerpted from http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/diarrhea.html)

Contrary to its public image, cholera often does not cause any noticeable illness. In fact, around 75% of people with cholera are asymptomatic. (https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/vibrio-cholerae.html) Why the variation in cholera's effects on people? Why does the above chain of events involving adenylyl cyclase not result in diarrhea for so many people?

Based on the number of people who've told me that molybdenum glycinate (a supplement form of the trace micronutrient molybdenum) significantly lessens or ends diarrhea, I think dietary molybdenum helps explain why many people don't get diarrhea despite having cholera. How might it be doing so? Molybdenum is used as a cofactor by five known enzymes in the human body. All five of these enzymes have functions that tend to lessen the total activity of adenylyl cyclase:

• Sulfite oxidase--catalyzes the conversion of sulfite to sulfate. Sulfur dioxide (a sulfiting agent) and its derivatives have been shown to increase the activity of adenylyl cyclase. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047873/, https://www.ncbi.nlm.nih.gov/pubmed/17923104/) By decreasing sulfite in the small intestine, sulfite oxidase would thus apparently have the effect of decreasing sulfite-caused stimulation of adenylyl cyclase activity.
• Xanthine oxidase and aldehyde oxidase--catalyze the conversion of nitrite to nitric oxide (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797155/, https://www.ncbi.nlm.nih.gov/pubmed/9731211). Nitric oxide decreases activity of adenylyl cyclase. (https://www.ncbi.nlm.nih.gov/pubmed/12612912, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137135/) Further, nitrite is a substrate of sulfite oxidase, meaning that excess nitrite can contribute to an elevated sulfite level (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523048/). Moreover, in an aqueous aerobic environment, such as one would find in the upper small intestine, nitric oxide turns back into nitrite (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC47296/); hence, it is important to promote nitrite-to-nitric oxide activity if there is to be more nitric oxide available to decrease adenylyl cyclase activity in the small intestine.
• The two mitochondrial amidoxime reducing components, mARC-1 and mARC-2--can also catalyze the reduction of nitrite to nitric oxide. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036158/)

Getting enough molybdenum in the small intestine therefore appears to be very important to moderating activity of adenylyl cyclase and in that way alleviating secretory diarrhea.

I've been told of an acquaintance with part of his small intestine removed who was suffering chronic diarrhea, probably because less small intestine surface means less removal of the water secreted into it early on in the digestive process; taking a molybdenum supplement once a week has given him great relief from the chronic diarrhea. I've heard of another man whose medications were giving him diarrhea, so he likely had secretory diarrhea as a drug side effect; molybdenum supplementation ended his diarrhea. And, as posted on this blog several times already, I've observed and been told of many people in whom molybdenum supplements greatly reduced or even eliminated diarrhea from viral gastroenteritis, which is likely secretory diarrhea overlaying inflammatory diarrhea. In over two years of telling people about molybdenum, I have only heard of one person who experienced diarrhea as a result of taking molybdenum; I will write about her experience in my next blog post [Update 7/20/2018: here's a link to that post] and explain the mechanism by which I think molybdenum induced diarrhea for her.

(Disclaimer: I do not prescribe the use of pharmaceutical drugs in any way. I am not a physician, and I reject out of hand any attempt to hold me liable for what boils down to a discussion of food. Any use of a molybdenum supplement should be prudent and guided by the tested tolerable upper intake levels for its usage (see http://lpi.oregonstate.edu/mic/minerals/molybdenum for those limits). Any use of an isolated molybdenum supplement during pregnancy should be under the direction of a medical professional as such supplements have apparently not been tested during pregnancy.)