The Gut Microbiome and Men's Sexual Health

The Gut Microbiome and

Men's Sexual Health

Faysal A. Yafi, MD FRCSC

Assistant Professor of Urology

Chief, Division of Men’s Health and Reconstructive Urology

Director of UCI Urology Newport Beach

Disclosures

• Antares Pharma: Advisory board, speaker

• Coloplast: Advisory board, consultant

• Endo Pharmaceuticals: Consultant, speaker

• Viome: Research grant primary investigator

The Gut Microbiome (GM)

• The flora of microbes that make up the GI tract of their host organism

• Consists of trillions of microbes that contribute to vital functions in the host organism

• Our microbial census exceeds the total number of our own human cells by ~10 fold

• The aggregate genomes of these gut species (microbiome) may contain >100 fold more genes than our ‘own’ genome

Functions of the GM

Amon P. et al. Arch Dis Child Educ Pract Ed. 2017. doi: 10.1136/archdischild-2016-311643.

Modulators of the GM

Clarke G. et al. Pharmacol Rev. 2019. doi: 10.1124/pr.118.015768.

Gut Microbiome Dysbiosis

• Any alteration in the GM composition and function

• Linked to numerous diseases such as:

• Metabolic Syndrome (MetS)

• Cardiovascular disease (CVD)

• Inflammation

• Depression, other psychiatric issues

• Very hot topic today and research in most fields of medicine currently underway

GM Dysbiosis and Allergy/Asthma

Durack J. et al. J. Exp. Med. 2018 doi: 10.1084/jem.20180448.

GM Dysbiosis and Other Pathologies

Autism Parkinson’s Disease Alzheimer’s Disorder Type 2 Diabetes

Clostridia Prevotellaceae Clostridia Clostridia

Bacteriodes Enterobacteriaceae Bacteriodes Bacteriodes

Desulfovibrio Verrucomicrobia Parabacteriodes

Bacteriodes fragilis Prevetolla

Lactobacillus Firmicutes

Subdoligranulum BetaProteobacteria

Lactobacillus

Table 1: Bacterial Species Prevalent in These Diseases

Ghaisas S, et al. Pharmacol Ther. (2016) 158:52–62. 10.1016/j.pharmthera.2015.11.012

Causes of GM Dysbiosis

Nature Reviews Immunology Vol 9, May 2009| 313

Modulator type Example Duration/rate

Prebiotics β, 1-4 Galacto-oligosaccharide (GOS) Short-term/intermediate

Probiotics L. rhamnosus GG Short-term/intermediate

Antibiotics/drugs Chemotherapy Short-term/rapid

Host immune response Toll-like receptor mediated gene expression

Long-term/rapid

Diet High fat vs. low fat diets Long-term/slow

Transplantation Fecal Transplant Long-term/immediate

How We Can Alter the GM

Arnold, et al. Trends in Microbiology. 2016;24(11):887–901.

The Metabolic Syndrome

GM and Inflammation

• Lipopolysaccharide (LPS) is a bacterial endotoxin that is involved in the inflammatory cascade of the host immune response in the gut and has been shown to be linked to the development of inflammatory markers associated with MetS and osteoarthritis.

• Microbial products have been shown to trigger IL-23 and IL-17upregulation in mouse models of colorectal tumorigenesis.

• Dietary intervention can lead to a decrease in blood plasma IL-6 levels and CRP levels.

Huang ZY, et al. Osteoarthritis Cartilage 2016:24:1769–1775. Nicolucci AC, et al. Gastroenterology 2017:153:711-722. Grivennikov SI, et al. Nature 2012:491(7423):254-258 Morales P, et al. Clin Transl Gastroenterol 2016:7. Doi:10.1038/ctg.2016.20.Benjamin JL, et al. Gut 2011:60:923-9. Thomas S, et al. Cancer Res. 2017;77:1783–1812.

GM and Cardiovascular Disease• 218 subjects with CVD compared with 187 healthy controls:

• Significant increase in abundance of Enterobacteriaceae and Streptococcus species.

• 4,007 subjects:

• Trimethylamine-N-oxide (TMAO) is pro-atherosclerotic metabolite in the gut.

• Highest quartile of plasma TMAO levels associated with a 2.5x increased risk of MACE compared to lowest

• TMAO levels decreased significantly after the administration of antibiotics and reappeared after discontinuing antibiotics

Jie Z, et al. Nat Commun 2017:8:845. Wang Z, et al. Nature 2011:472:57–63. Tang WH, et al. N Engl J Med 2013:368:1575–84.

GM and the Metabolic Syndrome

• Metabolic Syndrome in Men (METSIM) study

• 10,197 Finnish men

• Methanobrevibacter and Peptococcaceae correlated with reduced triglyceride levels

• Tenericutes and Christensenellaceae shown to be strongly associated with lower BMI and triglyceride levels and higher HDL levels

• TMAO directly associated with abundance of Peptococcaceae/Prevotella and negatively associated with abundance of Faecalibacterium prausnitzii

Laakso M, et al. J Lipid Res 2017:58:481–93.

GM and Men’s Sexual Health

• To date ZERO studies looking for a correlation between the GM and men’s sexual health diseases

• BUT the GM is linked with many conditions that are also linked to men’s sexual health diseases, such as the metabolic syndrome, inflammation, and CVD.

We hypothesize that it is highly likely that there is a link between the GM and men’s sexual health diseases.

Men’s Sexual Health

• Erectile dysfunction

• Ejaculatory dysfunction

• Hypogonadism

• Peyronie’s disease

ED and Inflammation

• Men with ED shown to have increased blood serum levels of:

• Vascular cell adhesion molecule (VCAM)

• Intercellular adhesion molecule (ICAM)

• Fibrinogen

• CRP

• Tumour necrosis factor-alpha (TNF-α)

Bocchio M, et al. J Urol 2004:171:1601-4; Sullivan ME, et al. Int Angiol 2001:20:195-9Billups KL, et al. Int J Impot Res 2003:15:231-6; Chiurlia E, et al. J Am Coll Cardiol2005:46(8):1503-6; Long T, et al.. J Sex Med 2012:9:1801-14; Matos G, et al. Andrology 2013:1:872-8. Doi:10.1111/j.2047-2927.

Peyronie’s Disease and Inflammation

Nat Clin Pract Urol, 2005; 2:291.

ED and the Metabolic Syndrome

Bansal TC et al. J Sex Med. 2005;2(1):96-103.

ED and Cardiovascular Disease

• 9,457 patients with 7 year follow up:

• Significant increase in a CV event when comparing those with ED to control

• 1,136 men with CVD:

• Men with more severe CVD at an increased risk of ED

• 95,038 men:

• Men with ED at a significant increased risk of experiencing a cardiac event compared to those without ED

Thompson IM, et al. JAMA 2005:294:2996-3002. Doi:10.1001/jama.294.23.2996.Lane-Cordova AD, et al. Am J Hypertens 2017:30:815–821. Banks E, et al. PLoS Med 2013:10. Doi:10.1371/journal.pmed.1001372.

So…

What’s Next?

16S Sequencing Metagenomic Analysis Viome MetatranscriptomeSequencing

Identifies only a fraction of your gut bacteria; unable to identify nonbacterial microorganisms

Cannot identify any RNA viruses or RNA bacteriophages

Identifies all microorganisms living in your gut: bacteria, viruses, archaea, yeast, fungi, and eukaryotes

Sequences DNA, which can come from food and dead microorganisms

Sequences DNA, which can come from food and dead microorganisms

Sequences RNA, which comes from live microorganisms that have a great impact on our health

Low resolution (mostly genus and lower resolution)

High resolution (species and strain level), but does not include RNA viruses

High resolution (species and strain level) of all microorganisms

Unreliable; sequencing the same sample twice can yield very different results

Minimal variation in results, but partially biased analysis (no RNA viruses)

Minimal variation in results and unbiased analysis

Does not measure microbial gene functions Does not measure microbial gene functions Quantifies expression levels of activemicrobial gene functions

Does not assess what the microbes are doing

Low resolution and lack of gene expression data preclude actionable recommendations

Does not assess what the microbes are doing

Lack of gene expression data preclude actionable recommendations

Allows assessment of pathway activities that can lead to personalized health insights and recommendations with molecular-level precision based on what the microbes are doing

“The biochemicals that are produced are more

important than the microorganisms

themselves.”

GM and ED/PD

• Goal:

• Identify species and strains of all organisms (bacteria,

viruses, fungi, phages, yeast, parasites, etc.) in the gut

• Assess how active these organisms are, and analyze

whether they are producing nutrients or toxins

• Strategy:

• ED: 100 patients – 50 with ED and 50 matched controls

(through AI)

• PD: 100 patients – 50 with PD and 50 matched controls

(collected)

GM and PD

Preliminary data with 14 PD and 15 control

Conclusions

• To-date there have been ZERO studies that have looked for a correlation between the GM and men’s sexual health.

• Due to the common pathologies that are highly associated with both the GM and men’s sexual health, there is likely a link between the two.

• Our work and others will hopefully help shed more light on these associations and potentially serve as a new avenue for disease prevention and personalized targeted therapies.

Acknowledgements

Natalie R. Yafi, RDMomo Vuyisich, PhD M. Mahdi Osman, BS &

Farouk M. El-Khatib, MD