Gut Microflora Modulates Th17/Treg Cell Differentiation in Experimental Autoimmune Prostatitis via the Short-Chain Fatty Acid Propionate

Abstract

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a very common urological disorder and has been gradually regarded as an immune-mediated disease. Multiple studies have indicated that the gut microflora plays a pivotal part in immune homeostasis and autoimmune disorder development. However, whether the gut microflora affects the CP/CPPS, and the underlying mechanism behind them remain unclear. Here, we built an experimental autoimmune prostatitis (EAP) mouse model by subcutaneous immunity and identified that its Th17/Treg frequency was imbalanced. Using fecal 16s rRNA sequencing and untargeted/targeted metabolomics, we discovered that the diversity and relative abundance of gut microflora and their metabolites were obviously different between the control and the EAP group. Propionic acid, a kind of short-chain fatty acid (SCFA), was decreased in EAP mice compared to that in controls, and supplementation with propionic acid reduced susceptibility to EAP and corrected the imbalance of Th17/Treg cell differentiation in vivo and in vitro. Furthermore, SCFA receptor G-protein-coupled receptor 43 and intracellular histone deacetylase 6 regulated by propionic acid in Th17 and Treg cells were also evaluated. Lastly, we observed that fecal transplantation from EAP mice induced the decrease of Treg cell frequency in recipient mice. Our data showed that gut dysbiosis contributed to a Th17/Treg differentiation imbalance in EAP via the decrease of metabolite propionic acid and provided valuable immunological groundwork for further intervention in immunologic derangement of CP/CPPS by targeting propionic acid.

Molecular mechanism and promising treatments of chronic prostatitis/chronic pelvic pain syndrome: An exploratory bibliometric analysis and literature review of preclinical studies

“…And they found fecal bacteria transplants from EAP mice, but not from control mice, into the pseudo‐germ‐free mice, significantly exaggerated host depression‐like behaviors [ 67 ] . Additionally, Du et al found that gut dysbiosis contributed to a Th17/Treg differentiation imbalance in EAP mice via the decrease of metabolite propionic acid [ 68 ] . Recently, a novel diagnostic model for CP/CPPS based on different gut microbiome compositions was proposed, presenting the promising potential of gut microbiome for noninvasive diagnostic biomarkers and future therapeutic targets for CP/CPPS patients [ 69 ] .…”

Crosstalk between Gut Microbiota and Host Immunity: Impact on Inflammation and Immunotherapy

“…[81] and Akkermansia muciniphila (A. muciniphila) [82] can also induce RORγt + Treg cell-mediated immune responses. Comparatively, lowered levels of the gut-microbiota-derived metabolite propionate (a short chain fatty acid) can contribute to a pathological imbalance in the Th17/Treg cell differentiation [83,84].…”

Gut Microbial-Derived Metabolites as Immune Modulators of T Helper 17 and Regulatory T Cells

“…Finally, it has been reported that SCFA and gut microbiota populations, which are great producers of these fatty acids, such as Clostridium , Faecalibacterium , or Roseburia , among others, [ 40 ] present lower levels in patients with IBD [ 41 , 42 , 43 ] as well as in patients with MS [ 44 , 45 , 46 , 47 ] or colorectal cancer [ 48 , 49 , 50 ] compared to healthy individuals. Their beneficial effect has also been demonstrated in experimental models such as colitis [ 25 , 32 , 51 ], experimental autoimmune encephalomyelitis (EAE) [ 33 , 52 ], allergic asthma [ 53 ], arthritis [ 51 , 54 ], and prostatitis [ 55 ], among others. Thus, this positive effect that has been partly attributed to the induction of Treg cells could be translated into the clinic, and in fact, a few clinical trials have shown some preliminary but encouraging results [ 56 , 57 , 58 ].…”