Study suggests why circumcised men are less likely to become infected with HIV
Changes in bacteria within the penis microbiome documented for the first time
PHOENIX, Ariz. - Jan. 5, 2010 - Circumcision, which substantially lowers HIV risk in men,
also dramatically changes the bacterial communities of the penis, according to a study led by scientists at the Translational
Genomics Research Institute (TGen) and Johns Hopkins University and published Jan. 6 in the scientific journal PLoS ONE.
And these bacterial changes may also be associated with earlier observations that women whose male partners are
circumcised are less likely to develop bacterial vaginosis, an imbalance between good and harmful bacteria.
The study - The Effects of Circumcision on the Penis Microbiome - could lead to new non-surgical HIV preventative
strategies for the estimated 70 percent of men worldwide (more than 2 billion) who, because of religious or cultural beliefs, or logistic or financial
barriers, are not likely to become circumcised.
"It has important public-health ramifications," said Dr. Lance B. Price, Director of TGen's Center for
Metagenomics and Human Health and co-lead author of the scientific paper, which describes the world's first molecular assessment of the bacterial
diversity of the male reproductive organ.
This new study is part of a larger effort by the U.S. National Institutes of Health to study and describe the "human microbiome" - the microbes
that exist collectively on and in the human body. Other projects are focused on microbiomes involving the skin, nose, mouth, digestive and female genitourinary
tract. Jointly, the goal of these projects is to define the various roles of microbes in human health and disease.
In investigating the impact of male circumcision on the penis microbiome, a collaborative team from TGen and the Johns Hopkins Bloomberg School of Public
Health found for the first time that circumcision significantly changes the bacterial community of the penis.
Other epidemiological studies have shown that male circumcision is associated with significant reductions in HIV acquisition in men.
evidence for a cause-and-effect relationship between circumcision and HIV risk reduction came from three randomized-control trials in sub-Saharan Africa,
where the circumcision rate is relatively low and the HIV infection rate is relatively high. All three demonstrated a more than 40 percent reduction in
HIV acquisition among circumcised men.
The largest of these three studies - in Rakai, Uganda - was led by Dr. Ronald H. Gray, a renowned epidemiologist at Johns Hopkins and the
scientific paper's senior author. Dr. Gray's group collected penile swabs from all of the circumcision trial study participants, which provided the data for
the new TGen-Johns Hopkins study.
The new study found that circumcision - the removal of the foreskin, or prepuce, from the penis - eliminates an area of mucous membrane and
dramatically changes the penile bacterial ecosystem. Significantly, TGen's analysis of more than 40 types of bacteria, using a 16S rRNA gene-based pyrosequencing
approach, suggests that the introduction of more oxygen following circumcision decreases the presence of anaerobic (non-oxygen) bacteria and increases the amount
of aerobic (oxygen-required) bacteria.
"This study clearly shows that male circumcision markedly reduces genital colonization with anaerobic bacteria in men,'' said Dr. Gray,
the William G. Robertson Jr. Professor in Population and Family Planning at the Johns Hopkins Bloomberg School of Public Health.
"These bacteria, which cannot grow in the presence of oxygen, have been implicated in inflammation and a number of infections affecting both men
and women. Our randomized trials have shown that male circumcision prevents HIV infection in men and protects their female partners from vaginal infections,
especially bacterial vaginosis. It is possible that the virtual elimination of anaerobic bacteria by circumcision contributes to these benefits of the
procedure," Dr. Gray said.
Several mechanisms have been proposed for how circumcision reduces HIV acquisition in men:Circumcision reduces the amount of mucosal tissue exposed to vaginal secretions during heterosexual intercourse and thus may reduce the potential
interactions between the virus and its target immune cells.
Circumcision results in a process called keratinization, whereby the top layer of the inner foreskin becomes thicker, which may provide additional
protection for the underlying target immune cells.
Circumcision-associated physiological changes of the penis - including lower moisture and oxygen availability around the head of the penis - may
reduce the number of pro-inflammatory anaerobic bacteria that could make the target immune cells more vulnerable to HIV infection.
"These potential explanations are not mutually exclusive and may work in concert to reduce HIV risk," said Dr. Price, an Associate
Investigator in TGen's Pathogen Genomics Division.
The new study found that specific bacteria taxonomically defined as anaerobic dominated the microbiota of the penile coronal sulcus before
circumcision. However, after circumcision, these bacteria decreased dramatically.
"Thus, the reduction in the putative anaerobic bacteria after circumcision may play a role in protection from HIV and other sexually
transmitted diseases," the study concluded.
Bacteria that form in the absence of, or lower levels of, oxygen may be associated with inflammation and the activation of Langerhans cells.
These cells, which are part of the body's normal immune system, work to capture and degrade the virus when they are in an inactivated state. But once activated,
the Langerhans cells become re-directed to assisting HIV infection by presenting the virus to CD4+ cells.
Circumcision remains a controversial procedure that has ardent proponents and opponents. Those who favor circumcision point to many studies
demonstrating lower risk for sexually transmitted diseases associated with circumcision. Those who oppose circumcision point to the potential dangers of
the procedure itself as well as cultural concerns.
This new study shows that circumcision significantly changed the penile bacterial ecology.
"The concept that there are good and harmful bacteria is essential to studying the human microbiome. Our work showed that the profile
of the penile bacterial communities changed significantly after circumcision," said Dr. Cindy M. Liu, a medical doctor and researcher at both TGen
and Northern Arizona University. She is the paper's other co-lead author.
"With the decrease in putative anaerobic bacteria, we saw a correlated increase in the proportion of other specific facultative anaerobic
and aerobic bacteria. This suggests that eliminating harmful bacteria may be only half of the needed action. Ensuring that the niche left by pre-circumcision
anaerobic bacteria are filled with "good" bacteria will also be critical," Dr. Liu said.
TGen and Johns Hopkins researchers plan to conduct more studies to determine whether specific bacteria are associated with increased HIV risk
and if such bacteria can be eliminated using non-surgical strategies.
The Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research
with life changing results. Research at TGen is focused on helping patients with diseases such as cancer, neurological disorders and diabetes. TGen is on
the cutting edge of translational research where investigators are able to unravel the genetic components of common and complex diseases. Working with
collaborators in the scientific and medical communities, TGen believes it can make a substantial contribution to the efficiency and effectiveness of the
translational process. TGen is affiliated with the Van Andel Research Institute in Grand Rapids, Michigan. For more information, visit: www.tgen.org .
About Johns Hopkins
As a leading international authority on public health, the Johns Hopkins Bloomberg School of Public Health is dedicated to protecting health and saving
lives. Every day, the School works to keep millions safe from illness and injury by pioneering new research, deploying its knowledge and expertise in the
field, and educating tomorrow's scientists and practitioners in the global defense of human life. For more information, visit: www.jhsph.edu .
The Translational Genomics Research Institute