Does it All Begin W/ Vitamin K in the Gut? Vitamin K ⇆ Gut Interactions Link in Intestinal Dysbiosis, Prostate Health and an Emerging Cause of Severe Pregnancy Complications?

Is there a "bacterial link" between prostate issues and pregnancy complications? Are both promoted by a messed up microbiome?
You know what a hypothesis is, right? Well, in that case the title of the scientific journal "Medical Hypothesis" should tell you that the two studies the "results" of which I am about to present in the following brief write-up are hypothetical. This means, it will require further research efforts to prove that vitamin K is the missing link in prostate health and to confirm that instestinal dysbioses (=messed up gut microbiome) are at the heart of the an ever-increasing number of pregnancy complications.

As of now, both assumptions are based on scientific evidence, the "last" 100% convincing evidence, however, is still missing.
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As Micheal Donaldson points out in his 2015 paper in the aforementioned journal, age-related prostate enlargement is very common in Western societies, and the causes of benign prostate hyperplasia (BPH) have been diligently sought after, there is no biological, mechanistic explanation dealing with the root causes and progression of this very common disorder among men. Unfortunately, all currently available "treatments" don't actually deserve being referred to as "treatment", because they are at best achieving symptomatic relief.

The absence of a BPH and thus probably even a prostate cancer solution is, as Donaldson rightly points out, not the least due to our incomplete understanding of cause of the disease.
Varicoles are defined as a mass of varicose veins in the spermatic cord.
"However, recent advances have shown that even subclinical varicoceles, which are more common than generally realized, cause retrograde blood flow from the testes past the prostate gland causing over a 130-fold increase in free testosterone in the veins near the prostate.

By treating the varicoceles via embolization of the internal spermatic vein and its communicating and connected vessels the prostate enlargement can be reversed with corresponding symptomatic relief" (Donaldson. 2015).
So if those varicose veins in the pampiniform venous plexus, varicoceles, are the direct cause of BPH, what causes the cause? That means: Why do varicoceles develop in the first place?

Now this is where vitamin K comes into play

Recent research has uncovered the role of vitamin K in the calcification of varicose veins as well as a role in the proliferation of smooth muscle cells in the media layer of the vein wall. Vitamin K is intimately involved in the formation of varicose veins. The hypothesis Donaldson presents in his latest paper is thus
"[...] that poor prostate health is essentially a vitamin K insufficiency disorder. By providing vitamin K in the right form and quantity, along with other supporting nutrients and phytochemicals, it is likely that excellent prostate health can be extended much longer, and perhaps poor prostate health can be reversed" ().
A protective role for vitamin K with respect to advanced prostate cancer was already found in the Heidelberg cohort of the EPIC study.
Figure 1: In fact, studies indicate that there is an inverse association between the intake of menaquinones, but not that of phylloquinone, and prostate cancer. Further studies of dietary vitamin K and prostate cancer are warranted (Nimptsch. 2008).
In his paper Donaldson argues that this hypothesis must be further evaluated in studies examining the connection between vitamin K and varicoceles, and also by examining the connection between varicoceles and benign prostate hyperplasia. If it is then found to be true, management of prostate health will be radically altered.
"Rather than focusing on prostate health as a hormonal imbalance, prostate enlargement will be seen as a result of poor health of the veins in general and the internal spermatic veins in particular" (Donaldson. 2014). 
Factors which promote the health of the veins will become a greater focus of research, including the role of vitamin K. This leads Donaldson to conclude that "the emerging understanding of the cause of BPH will empower men to take care of their bodies" in order to "enjoy much better health through their entire lifespan" (Donaldson. 2015).

From vitamin K intakes to the gut microbiome

In contrast to the promises in the shiny ads for probiotics, we are still miles if not light years away from understanding the complexities of our own gut microbiome well enough to effectively prescribe the "right" supplemental gut bacteria at the "optimal" dosage for specific conditions. What we do know, though is that the gut microbiota is intimately involved in numerous aspects of normal human physiology, including nutrition and metabolism, immunomodulation and behavior and stress response.

Figure 2: Maternal physiological adaptation and maladaptation during pregnancy. (A) Upon pregnancy challenge, normal physiological adjustments occur in maternal body, including cardiovascular, neuroendocrine, metabolic and immunological adaptations. These physiological changes are essential for promoting pregnancy success; (B) If disturbance occurs in any key link of normal physiological changes, abnormalities in these physiological changes would describe maternal maladaptations, such as maternal-fetal immune rejection, cardiovascular maladaptation and metabolic syndromes (Zhang. 2015).
There is also significant evidence that intestinal dysbiosis can be a contributing cause of many diseases, altering the function of both near and far organ systems.

It would thus not be surprising if a messed up gut microbiome would affect the health of both mother and child during pregnancy. During the ~280days of pregnancy, the maternal body undergoes dramatic physiological changes to support the growth of fetus-placenta. During that time, any imbalances of the intestinal microbiome aka "intestinal dysbiosis" may directly or indirectly disturb the remodeling of physiological balance, leading to maternal maladaptation.

Thus, intestinal dysbiosis, i.e., altered composition or metabolism of microbiota may adversely affect pregnancy outcome and lead to pregnancy complications via disrupting maternal adaptation.

As Zhang et al. point out, there is indeed an established risk of developing pregnancy disorders for pregnant women with potential maladaptations; and the latter are increasingly observed in clinical cases with the most compelling evidence being observed in studies on overweight or obese mothers for whom Collado et al. report a distinct composition of gut microbiota during pregnancy in overweight vs. normal-weight women (Collado. 2008).
Figure 3: Ratio of bacteria counts (overweight / normal weight women | Collado. 2008).
As it is usually the case for "medical hypotheses", comprehensive studies about the complex interrelationship between intestinal dysbiosis and maternal maladaptations in the context of pregnancy are relative lacking. Still, based on the existing evidence it appears reasonable to speculate "that the dysbiosis caused by potential risk factors in pregnancy may induce these maternal maladaptations" (Zhang. 2015).
From "pregnancy complications" to autism: Did you know that there is a definite link between a messed up gut microbiome and autism? In their 2013 paper Mulle, Sharp, and Cubells investigate the established and putative effects of the human gut microbiome on the development of autism and conclude that the existing evidence clearly supports "associations between gut microbial population profiles and ASD, and the data from research on rodents demonstrating myriad ways in which the gut microbiome influences neurobehavioral development, combine to suggest that further research on the trajectory of microbiome development in children at risk for ASD will be fruitful" (Mulle. 2014).
In fact, physiological changes that occur during pregnancy first alter the gut microbial community, which, in turn, creates a positive-feedback loop sustaining maternal physiological adaptations seen in normal pregnancy.
Figure 4: A schematic diagram illustrating our proposed model (Zhang. 2015).
"Considering that there are no studies investigating the role of gut microbiota in pregnancy complications development, our proposal may provide novel insights into the roles of gut microecosystem in pregnancy-complicated conditions as well as shed new light on the management of pregnancy in situations of intestinal dysbiosis.

We hypothesize that pregnant women with dysbiosis are more prone to develop pregnancy disorders due to maternal maladaptations that have deleterious effects on the balance of maternal-fetal interactions. Maternal maladaptations could be associated with fetus-placenta restriction and maternal systemic damage, typical features presented in pregnancy complications " (Zhang. 2015). 
Accordingly, Zheng et al. believe that "imbalance in gut microbiota, intestinal dysbiosis, may contribute to maternal maladaptations in pregnant women, which are correlated to adverse pregnancy outcomes" (Zheng. 2015 | see Figure 4).
These are only hypotheses, but both are convincing enough to spark an interest in further scientific investigations into (a) the role of vitamin K and the microvasvulature in prostate health and, eventually, the development of prostate cancer, and (b) the importance of a healthy gut microbiome, as well as means to (re-)establish it during pregnancy.

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That's it? Well not exactly. I mean vitamin K and gut dysbiosis. Does this ring a bell? No? Well, Escherichia coli plays a significant role in the production of vitamin K2, i.e. the cancer protective menaquinones in the human gut (Rizkallah. 2010).

Thus, eventually, both of the previously presented hypotheses may thus eventually support what Hattori and Taylor pointed out in their 2009 paper in DNA Research: "The human intestinal microbiome [is the] new frontier of human biology" (Hattori. 2009) | Comment on Facebook.
  • Collado, Maria Carmen, et al. "Distinct composition of gut microbiota during pregnancy in overweight and normal-weight women." The American journal of clinical nutrition 88.4 (2008): 894-899.
  • Donaldson, Michael. "Vitamin K: The Missing Link to Prostate Health." Medical Hypotheses (2015): Ahead of print.
  • Hattori, Masahira, and Todd D. Taylor. "The human intestinal microbiome: a new frontier of human biology." DNA research 16.1 (2009): 1-12.
  • Mulle, Jennifer G., William G. Sharp, and Joseph F. Cubells. "The gut microbiome: a new frontier in autism research." Current psychiatry reports 15.2 (2013): 1-9.
  • Nimptsch, Katharina, Sabine Rohrmann, and Jakob Linseisen. "Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg)." The American journal of clinical nutrition 87.4 (2008): 985-992.
  • Rizkallah, Mariam R., Rama Saad, and Ramy Karam Aziz. "The human microbiome project, personalized medicine and the birth of pharmacomicrobiomics." Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) 8.3 (2010): 182-193. 
  • Zhang, Dongxin, Yinping Huang, Duyun Ye. "Intestinal dysbiosis: an emerging cause of pregnancy complications?" Medical Hypotheses (2015): Ahead of  print.
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