Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis

Pernigoni, Nicolò; Zagato, Elena; Calcinotto, Arianna; Troiani, Martina; Mestre, Ricardo Pereira; Calì, Bianca; Attanasio, Giuseppe; Troisi, Jacopo; Minini, Mirko; Mosole, Simone; Revandkar, Ajinkya; Pasquini, Emiliano; Elia, Angela Rita; Bossi, Daniela; Rinaldi, Andrea; Rescigno, Pasquale; Flohr, Penny; Hunt, Joanne; Neeb, Antje; Buroni, Lorenzo; Guo, Christina; Welti, Jonathan; Ferrari, Matteo; Grioni, Matteo; Gauthier, Josée; Gharaibeh, Raad Z.; Palmisano, Anna; Lucchini, Gladys Martinetti; D’Antonio, Eugenia; Merler, Sara; Bolis, Marco; Grassi, Fabio; Esposito, Antonio; Bellone, Matteo; Briganti, Alberto; Rescigno, María; Theurillat, Jean-Philippe; Jobin, Christian; Gillessen, Silke; Bono, Johann S. de; Alimonti, Andrea

doi:10.1126/science.abf8403

Cited by 139 publications

(97 citation statements)

References 55 publications

(73 reference statements)

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“…Future studies that work to disentangle to what extent dysmotility drives dysbiosis and vice versa in androgen-deficient states will be informative. Recent work in rodent models of prostate cancer has shown that androgen deprivation positively selects for commensal gut microbes that synthesize androgens ( 36 ). Any such microbial compensation was apparently insufficient to rescue AR signaling to the ENS, however, because the dysmotility in ORCH mice persisted for several months without improvement.…”

Section: Discussionmentioning

confidence: 99%

Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice

Rastelli¹,

Robinson²,

Lagomarsino³

et al. 2022

Journal of Clinical Investigation

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Functional gastrointestinal disorders (FGIDs) have prominent sex differences in incidence, symptoms, and treatment response that are not well understood. Androgens are steroid hormones present at much higher levels in males than females and could be involved in these differences. In adults with irritable bowel syndrome (IBS), a FGID that affects 5-10% of the population worldwide, we found that free testosterone levels were lower than those in healthy controls and inversely correlated with symptom severity. To determine how this diminished androgen signaling could contribute to bowel dysfunction, we depleted gonadal androgens in adult mice and found that this caused a profound deficit in gastrointestinal transit. Restoring a single androgen hormone was sufficient to rescue this deficit, suggesting that circulating androgens are essential for normal bowel motility in vivo. To determine the site of action, we probed androgen receptor expression in the intestine and discovered, unexpectedly, that a large subset of enteric neurons became androgen-responsive upon puberty. Androgen signaling to these neurons was required for normal colonic motility in adult mice. Taken together, these observations establish a role for gonadal androgens in the neural regulation of bowel function and link altered androgen levels with a common digestive disorder.

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Section: Discussionmentioning

confidence: 99%

Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice

Rastelli¹,

Robinson²,

Lagomarsino³

et al. 2022

Journal of Clinical Investigation

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“…As mentioned, the components of GI microbiota could be affected by serum androgen levels and castration ( 14 – 16 ), and both Enz and Abi could alter the components of GI microbiota ( 17 ). Recently, Pernigoni et al indicated that the GI microbiota could also provide an alternative source of androgen in patients and mice with CRPC ( 38 ). Therefore, our results indirectly evidenced the hypothesis that we mentioned previously.…”

Section: Discussionmentioning

confidence: 99%

Association of Novel Androgen Receptor Axis-Targeted Therapies With Diarrhea in Patients With Prostate Cancer: A Bayesian Network Analysis

Xiong

Wang

et al. 2022

Front. Med.

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ObjectiveTo perform a systematic review and network meta-analysis to characterize the effect of novel androgen receptor axis-target (ARAT) agents on diarrhea and constipation.MethodsWe searched the Pubmed, Web of Science, and ClinicalTrials.gov up to September 2021 for phase 3 randomized controlled trials (RCTs) of patients receiving novel ARAT agents for prostate cancer (CaP). A Cochrane risk-of-bias tool was used to assess trial quality. The primary outcomes were risk ratio (RR) of any-grade diarrhea and constipation for patients receiving ARAT treatment. RRs of competing treatments were evaluated by pairwise and Bayesian network meta-analysis.ResultsIn this study, 13 trials with 15,117 participants comparing 5 treatments (abiraterone, enzalutamide, apalutamide, darolutamide, and placebo) were identified. Use of novel ARAT agents was associated with a significant increased risk of any-grade diarrhea (RR = 1.30, 95% CI [1.16, 1.44]). As for subgroup analysis, abiraterone, enzalutamide, and apalutamide were all associated with significant increased risk of any-grade diarrhea (abiraterone: RR = 1.40, 95% CI [1.09, 1.81]; enzalutamide: RR = 1.17, 95% CI [1.02, 1.35]; apalutamide: RR = 1.35, 95% CI [1.03, 1.76]). Based on Bayesian modeling, abiraterone and enzalutamide showed the highest and lowest probability to rank first in terms of increasing risk of any-grade diarrhea. There were no significant differences of risk in any-grade constipation, grade 3 or greater diarrhea, and constipation between ARAT and control group.ConclusionThe present study indicates that the use of novel ARAT agents is associated with a significantly higher risk of diarrhea. Across the four agents, abiraterone may relate to the highest risk of diarrhea among patients with metastatic hormone sensitive prostate cancer (mHSPC) and castration-resistant prostate cancer (CRPC).

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“…While mechanistic studies investigating microbial regulation of host metabolism in men with PCa are limited, a recent study [ 84 ] using PCa mouse models demonstrated that certain species of the intestinal microbiota can modulate the host hormone (e.g. androgen) metabolism and in turn promote cancer growth.…”

Section: Functional Role Of Specific Microbes In Pcamentioning

confidence: 99%

“…androgen) metabolism and in turn promote cancer growth. Conversely, the study also found that circulating host androgens can alter the composition of the gut microbiota [ 84 ]. Notably, the same study showed that Ruminococcus gnavus and Bacteroides acidifaciens were enriched in the fecal microbiota of castrated (as compared to non-castrated) male mice, and that these species can metabolise androgen precursors, pregnenolone and hydroxypregnenolone, into downstream metabolites of the androgen biosynthesis pathway, dehydroepiandrosterone and testosterone.…”

Section: Functional Role Of Specific Microbes In Pcamentioning

confidence: 99%

“…Notably, the same study showed that Ruminococcus gnavus and Bacteroides acidifaciens were enriched in the fecal microbiota of castrated (as compared to non-castrated) male mice, and that these species can metabolise androgen precursors, pregnenolone and hydroxypregnenolone, into downstream metabolites of the androgen biosynthesis pathway, dehydroepiandrosterone and testosterone. As prostate tumors are reliant on androgens for continued growth, such an alternate source of androgen could lead to endocrine resistance in PCa patients undergoing castration treatment as shown in PCa mouse models [ 84 ].…”

Section: Functional Role Of Specific Microbes In Pcamentioning

confidence: 99%

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Dysbiotic microbes and how to find them: a review of microbiome profiling in prostate cancer

Salachan

Sørensen

2022

J Exp Clin Cancer Res

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The role of the microbiota in human health and disease is well established, including its effects on several cancer types. However, the role of microbial dysbiosis in prostate cancer development, progression, and response to treatment is less well understood. This knowledge gap could perhaps be implicated in the lack of better risk stratification and prognostic tools that incorporate risk factors such as bacterial infections and inflammatory signatures. With over a decade’s research investigating associations between microbiome and prostate carcinogenesis, we are ever closer to finding the crucial biological link between the two. Yet, definitive answers remain elusive, calling for continued research into this field. In this review, we outline the three frequently used NGS based analysis methodologies that are used for microbiome profiling, thereby serving as a quick guide for future microbiome research. We next provide a detailed overview of the current knowledge of the role of the human microbiome in prostate cancer development, progression, and treatment response. Finally, we describe proposed mechanisms of host-microbe interactions that could lead to prostate cancer development, progression or treatment response.

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Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis

Cited by 139 publications

References 55 publications

Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice

Diminished androgen levels are linked to irritable bowel syndrome and cause bowel dysfunction in mice

Association of Novel Androgen Receptor Axis-Targeted Therapies With Diarrhea in Patients With Prostate Cancer: A Bayesian Network Analysis

Dysbiotic microbes and how to find them: a review of microbiome profiling in prostate cancer

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