Gut Microbiome, ADT & Doxycycline

[pca2004]

In recent years there has been increased awareness of the importance of the gut microbiome for good health.

I stopped Minocycline when I decided to give Akkermansia a try.  It's been a while since my Akkermansia supply ran out.  I have just begun using Doxycycline & pondering the implications.

One can break the general topic down as follows:

1.  What are the common biome issues that might affect PCa risk & progression?

2.  How does PCa itself change the biome?

3.  How does castration affect the biome?

4.  How does the 'scorched earth' attack on steroidogenesis via Abiraterone affect the biome?

5.  What is the effect of Doxycycline added to [3] or [4]?

***

What follows is somewhat fragmentary.

[1]  not covered

[2]  "In PC-bearing mice, 

... PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT."  [X]

"We report a significant difference in alpha diversity in GI microbiota among men with versus without a prostate cancer diagnosis."  [Y]

[3]  Hong Kong (2021) [3]:

"Androgen deprivation therapy (ADT), either by medical or surgical castration, is the backbone for standard treatment of locally advanced or metastatic prostate cancer, yet it is also associated with various metabolic and cardiovascular complications. Recent evidence have shown that obesity, insulin resistance, or metabolic disturbances can be associated with changes in the gut microbiome, while animal studies also show that castration is associated with changes in the gut microbiome. This study aims to investigate whether the fecal microbiota in prostate cancer patients who had undergone prostatectomy or ADT are different ..."

"The alpha-diversity was significantly lower in the ADT group. The beta-diversity was significantly different between the groups, in which Ruminococcus gnavus and Bacteroides spp were having higher relative abundance in the ADT group, whereas Lachnospira and Roseburia were reduced. The Firmicutes-to-Bacteroidetes ratio is noted to be lower in the ADT group as well. The functional pathway prediction showed that the biosynthesis of lipopolysaccharide (endotoxin) and propanoate was enriched in the ADT as well as the energy cycle pathways."

***

...

"as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs"  [X]

"While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so."  [X]

[4]  Canada (2020) [4]:

"Abiraterone acetate (AA) is an inhibitor of androgen biosynthesis, though this cannot fully explain its efficacy against androgen-independent prostate cancer. Here, we demonstrate that androgen deprivation therapy depletes androgen-utilizing Corynebacterium spp. in prostate cancer patients and that oral AA further enriches for the health-associated commensal, Akkermansia muciniphila. Functional inferencing elucidates a coinciding increase in bacterial biosynthesis of vitamin K2 (an inhibitor of androgen dependent and independent tumor growth). These results are highly reproducible in a host-free gut model, excluding the possibility of immune involvement. Further investigation reveals that AA is metabolized by bacteria in vitro and that breakdown components selectively impact growth. We conclude that A. muciniphila is a key regulator of AA-mediated restructuring of microbial communities, and that this species may affect treatment response in castrate-resistant cohorts. Ongoing initiatives aimed at modulating the colonic microbiota of cancer patients may consider targeted delivery of poorly absorbed selective bacterial growth agents."

***"

We hypothesized that oral androgen receptor axis-targeted therapies (ATT), including bicalutamide, enzalutamide, and abiraterone acetate, may be associated with compositional differences in the GI microbiota."  [Y]

"Further analysis identified significant compositional differences in the GI microbiota of men taking ATT, including a greater abundance of species previously linked to response to anti-PD-1 immunotherapy such as Akkermansia muciniphila and Ruminococcaceae spp. In functional analyses, we found an enriched representation of bacterial gene pathways involved in steroid biosynthesis and steroid hormone biosynthesis in the fecal microbiota of men taking oral ATT."  [Y]

[5]  "In PC-bearing mice, 

... depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. "  [X]  !!!

-Patrick

[3]  pubmed.ncbi.nlm.nih.gov/338...

[4]  ncbi.nlm.nih.gov/pmc/articl...

[X]  International (2022) 

ncbi.nlm.nih.gov/pmc/articl...

[Y]  Johns-Hopkins, USA (2018)

ncbi.nlm.nih.gov/pmc/articl...

[JohnInTheMiddle]

Thanks for sharing PCA. Seems pretty important. I do eat sauerkraut everyday for the gut biome and also everyday Jarlsberg cheese for the K2. But can you interpret what it all means?

[Lyubov in reply to JohnInTheMiddle]

How much sauerkraut? How much Jarlsberg cheese?

[JohnInTheMiddle in reply to Lyubov]

Of the live sauerkraut, for the gut biome, about two heaping tablespoons worth. I'd like to eat more but it's expensive. (Not sure about the measurement here 😃).

And of the aged Jarlsberg cheese for K2, from Costco in the square containers, two slices.

Also a good handful of walnuts, for the urolithins.

And to top it all off lycopene pills or stir-fried tomatoes .

So far so good. 8 months in w/bone mets to spine. Triplet therapy (ADT, ARAT, 6 X Docetaxel) response outstanding. Back in business now. A little tired. Really need to exercise more for the myokines.

[Lyubov in reply to JohnInTheMiddle]

By "live" sauerkraut do you mean "fermented"?

[JohnInTheMiddle in reply to Lyubov]

I guess so. Sauerkraut is fermented by definition. But the problem is that some sauerkraut, which is sold just for taste, is pasteurized. So all the bugs are dead. And you might as well not bother. So you need to find the brand that is unpasteurized and where the bugs are still alive. Better for the biome. Mmmmmmm bugs 😃

[Raymo69 in reply to JohnInTheMiddle]

you bring up a good point about the “bugs” in sour kraut. I assume if you cook it like I normally do it would kill the bugs? Similar to taking probiotics with a hot drink?

[Hidden in reply to Lyubov]

yes, it’s fermented in the brine that is made by the vegetable itself. There is no heat or vinegar added. It’s the process that makes it more nutrient dense. A living food, so to say. You can eat other vegetables that are made with this process. In fact, you can make them yourself. I have found Hex ferments , sauerkraut tastes awesome.

[Lyubov]

I think I've seen it in the grocery store & will buy some for hubby to try. He's having all the problems, poor dear darling!

[Hidden in reply to Lyubov]

if he doesn’t like sauerkraut you can purchase carrot sticks okra cucumbers, really everything. It’s all in the processing. Good luck. I hope your hubby is drinking lots of water. It will help if you squeeze lemon in it to make it more palatable… good luck to you and hubby❤️

[cujoe]

Super info from both you and Patrick, esp your gut biome profile . Very interesting, indeed!

My dietary message for the last two years or so has simply been "EAT MORE FIBER" - as dietary fiber is the main fuel that feeds the gut biome and produces the Short-Chain Fatty Acids (SCFAs) that are it's biochemical foundation.

en.wikipedia.org/wiki/Short...

Somewhere over 90% of the adult American population does not even get the minimum daily fiber intake. (+/- 35 g for men and +/- 28 g for women) (*) And since nearly all dietary fiber comes from plant sources, any increase in daily fiber will result in a reduction in animal food products and more whole plant foods - not at all a bad thing, IMO.

(*) Add up the fiber in what you eat tomorrow and you'll likely see how far short you are of these numbers, which came from here and are based on 2500 cal for men and 2000 for women.

ask.usda.gov/s/article/How-...

Eat Well to Be/Stay Well. Just do it! Ciao - K9 terror

[MateoBeach]

The anti-inflammatory effects of doxycycline are preserved at low doses, 20mg twice daily (as in Periostat) or 40 mg extended release formulation (as in Oracea for Rosacea associated acne). The inhibition of MMP is also present to some degree at these low non-antimicrobial doses. And appear to have less harm to gut microbiome than the standard antimicrobial dosing of 100mg/day.

So that may be an option for those wanting these two potentially beneficial mechanisms on PC. However, the inhibition of mitochondrial biogenesis in actively reproducing cancer stem cells would likely require the anti-microbial higher dosing with attendant greater harm to the microbiome.

Chemically modified tetracyclines (CMTs) that do not have antimicrobial activity is another potential solution. But none of these have emerged from early phase research into availability. Here is a good review. Personally, I am holding off on taking doxy as my cancer is currently dormant or stable. If it was aggressively growing (short PSADT), I would be more willing to give it a personal test.

ncbi.nlm.nih.gov/pmc/articl...

“In 1983, it was first reported that tetracyclines (TCs) can modulate the host response, including (but not limited to) inhibition of pathologic matrix metalloproteinase (MMP) activity, and by mechanisms unrelated to the antibacterial properties of these drugs. Soon thereafter, strategies were developed to generate non-antibacterial formulations (subantimicrobial-dose doxycycline; SDD) and compositions (chemically modified tetracyclines; CMTs) of TCs as host-modulating drugs to treat periodontal and other inflammatory diseases. This review focuses on the history and rationale for the development of: (a) SDD which led to two government-approved medications, one for periodontitis and the other for acne/rosacea and (b) CMTs, which led to the identification of the active site of the drugs responsible for MMP inhibition and to studies demonstrating evidence of efficacy of the most potent of these, CMT-3, as an anti-angiogenesis agent in patients with the cancer, Kaposi's sarcoma, and as a potential treatment for a fatal lung disease (acute respiratory distress syndrome; ARDS). In addition, this review discusses a number of clinical studies, some up to 2 years’ duration, demonstrating evidence of safety and efficacy of SDD formulations in humans with oral inflammatory diseases (periodontitis, pemphigoid) as well as medical diseases, including rheumatoid arthritis, post-menopausal osteopenia, type II diabetes, cardiovascular diseases . . .

[cujoe]

A model fiberist you are, feeding those friendly Akkermansia gut bugs. Unless cutting back to one meal a day, I'm at =>30 g day in and out, but =>45 g is probably on my best days. Since jdm3 is the resident SproutMaster 🥦, maybe we should anoint you as our resident FiberMaster 🥕🍄🍎🥜🥬 🍓ETC.

Another common recommendation is to eat 30 different plants every week. As with the fiber count, we tend to think we routinely do that, until we actually start counting.

[cujoe]

And a "regular" guy to boot. Toss in some condiments, herbs, and spices and you probably can hit 30 in stretch.