Androgens may mediate protection through an effect on Retinoic acid production

General Discussion
#1

This could be an off target protein.

Lupus is much more prevalent in females. Depleting androgens via castration increases disease and mortality in male NZBxNZWF1 (BWF1) mice, suggesting androgens are protective. We have found that treatment of male BWF1 mice with CD103-neutralizing antibody induces disease and increases mortality suggesting CD103+ cells are important for disease protection in males. Mesenteric lymph node (MLN) CD103+ dendritic cells (CD103DC) from castrated male mice exhibit decreased ability to induce conversion of CD4+Foxp3+ cells (Tregs) in vitro and decreased expression of RALDH2, an enzyme involved in retinoic acid synthesis (hallmark of CD103DC function) vs control mice. Also, castrated BWF1 male mice have significantly decreased circulating and peripheral LN Tregs vs control mice, suggesting androgens may affect Tregs via an effect on CD103DC. We have found CD103DC express androgen receptor (AR) mRNA levels that are lower than splenic macrophages (positive controls), but higher than splenic myeloid DC (negative controls) suggesting that androgens could have a direct effect on CD103DC. To determine whether signaling through the AR is required for androgen-mediated protection and CD103DC function, male BWF1 mice were treated with flutamide (AR inhibitor). Male mice treated with flutamide exhibited increased disease incidence and severity, and decreased CD103DC function including a decreased ability to induce conversion of Tregs in vitro and decreased expression of RALDH2 mRNA. Taken together, these data suggest that androgens may influence immunoregulation via a direct effect on CD103DC function and may, at least in part, mediate protection from lupus through this mechanism.

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#2

Adding to this.
Retinoic acid synthesis a hallmark of CD103DC function

The Role of CD103+ Dendritic Cells in the Intestinal Mucosal Immune System

While dendritic cells (DC) are central to the induction and regulation of adaptive immunity, these cells are very heterogenous and specific subsets can be characterized based on the expression of cell surface markers and functional properties. Intestinal CD103+ DCs are the subject of particular interest due to their role in regulating mucosal immunity.

The epithelial surfaces of the body are constantly exposed to a wide variety of antigenic material, ranging from dietary proteins and commensals to pathogenic bacteria, viruses, and allergens. These antigens are separated from the delicate underlying body surfaces by a thin layer of cells, the epithelium. The cells and tissues comprising the mucosal immune system are located in the gastrointestinal tract (GIT), the upper and lower respiratory tracts and the urogenital tract. It also includes exocrine glands associated with these organs, such as the pancreas, the conjunctive and lacrimal glands of the eye, the salivary glands, and the lactating breast. The GIT and respiratory mucosa are the main portals of pathogen entry and therefore the generation of effective immune responses at these surfaces is vital to prevent infection. However, various regulatory mechanisms must also be in place to prevent damaging inflammatory reactions from occurring against benign antigens. There is increasing evidence that the dendritic cell (DC) populations located at these sites are vital in the maintenance of this immunological balancing act.

Strategically positioned within the lamina propria, CD103+ DCs play an important role in maintaining intestinal immune homeostasis.

#3

Adding another element to this, dysbiosis or disruption of the gut microbiome by anti-androgens.
So now you could maybe say anti-androgens cause dysbiosis that could center around the loss or suppression of retinoic acid production.
Btw those that have taken Fin, are you familiar with Vitamin A?
Its ironic everything that has been looked at on here over the years, Vitamin A really hasn’t been.

EF-05 Androgens regulate microbiota composition, function and protective properties in lupus-prone mice

Dysbiosis (alterations in microbiota composition) is associated with autoimmune diseases, including lupus. Factors that are thought to influence gut microbiota include diet, age and more recently, sex. Like humans, female NZBxNZWF1 (BWF1) mice spontaneously develop lupus-like disease, and exhibit much greater incidence of disease than males. Castration of male BWF1 mice increases disease onset/incidence and decreases survival suggesting that male sex steroids, androgens, play an important role in protection of males from disease.

We have found that the composition of gut microbiota and metabolomic/lipidomic profiles differ between mature female and male BWF1 mice. Transfer of male microbiota to female BWF1 mice suppresses disease and increases survival. Further, we found that male microbiota may protect, in part, via an effect on tolerogenic CD103+ dendritic cells (CD103DC) that induce peripheral Tregs (pTregs) through TGFβ and retinoic acid (RA) production. Female BWF1 CD103DC have a decreased ability to induce pTregs and express retinaldehyde dehydrogenase, (RALDH2), an enzyme involved in RA synthesis. Transfer of male microbiota to female BWF1 mice reconstitutes both RALDH2 expression and the ability of the CD103DC to induce pTregs. Interestingly, castration of male mice significantly alters gut microbiota composition and metabolomic/lipidomic profiles by comparison to males, diminishes CD103DC function and decreases the ability of the microbiota to protect female mice from disease. The mechanisms underlying male microbiota-mediated protection from disease are unknown, but may be mediated through the production of metabolites. We have identified several metabolites that are increased in male compared to both female and castrated male feces that function as retinoid X receptor agonists and enhance RALDH2 activity and increase pTregs in vivo .

Our data suggest that androgens alter the composition and function of the gut microbiota in males, and the metabolites produced by the male microbiota may have potential for development into therapeutic strategies for the treatment of disease.

#4

Manly bacteria, that could be a thing. What determines an alpha male or dominance?
Obviously genes, but bacteria may play a role as well.

Increased raldh2 expression or RA synthesis could be a desirable trait or characteristic of a male type microbiome.
Notice the impact of the bacteria itself (not the host), as they were able to reconstruct its effects in a female as well.

#5

There’s a study out there somewhere talks about the increased tissue and organ RA catabolism, so retinol might be ok , and p450 returns to normal , but at a organ , tissue level increased catabolism causing a deficiency.

#6

Let me piece this together one more time,

Anti-androgens may significantly alter gut microbiota composition.

Male mice treated with flutamide exhibited increased disease incidence and severity, and decreased CD103DC function including a decreased ability to induce conversion of Tregs in vitro and decreased expression of RALDH2 mRNA.

Retinoic acid synthesis is a hallmark of CD103DC function.

we found that male microbiota may protect, in part, via an effect on tolerogenic CD103+ dendritic cells (CD103DC) that induce peripheral Tregs (pTregs) through TGFβ and retinoic acid (RA) production.

#7

Seeing how this lines up,

Bifidobacterium longum subsp. infantis 35624 ( B. infantis ) was originally isolated from resected human healthy gastrointestinal tissue and human clinical studies have demonstrated its efficacy in Irritable Bowel Syndrome patients [15], [16]. In addition, murine studies have demonstrated that this microbe protects against inflammatory disorders across a range of inflammatory conditions including colitis, pathogen infection, arthritis and respiratory inflammation [17]–[20]. Previously, in vitro studies with human dendritic cells suggested that promotion of retinoic acid metabolism by B. infantis was a key regulatory feature of this bacterium [21]. In this report, we demonstrate that B. infantis feeding to mice results in increased CD103+RALDH+ dendritic cells within the mucosa, which are responsible for the suppression of TH1 and TH17 lymphocytes and amelioration of dextran sulfate sodium (DSS)-induced colitis.