Hi HAPsters,

I am happy to be writing a follow-up on the work I presented to you at the HAPS meeting in Portland, OR in May 2019. To briefly recap, I use an in vivo rat model of osteolysis to understand the mechanisms driving implant loosening. After bilateral intramedullary implants are placed, weekly injections of particles are administered to each knee joint. These particles are either LPS-doped polyethylene (LPS-PE) or cobalt-chromium (CoCr); two materials common to orthopedic implants. I discovered that the particle challenge in this model is associated with pro-inflammatory alterations in the gut microbiome as shown at the phylum level.

Fecal Firmicutes / Bacteroidetes ratio at the phylum level (1-way ANOVA p = 0.0282).

I also confirmed histologically that macrophage presence in the synovium is dependent upon particle challenge. Liver histology, which was read blindly by a veterinary pathologist, showed differential presence/absence of inflammation with particle treatment (p = 0.013, chi-square). Thus, we know there is inflammation local to the knee joint and remote in the liver; however, it is not currently clear if the liver effects precede, were secondary to, or were simply coincident with changes in the gut microbiome.

In a recently completed probiotic treatment experiment, I aimed to induce osteolysis using CoCr particles and then prevent implant loosening with a probiotic treatment of Lactobacillus reuteri. L. reuteri has been shown to decrease gut inflammation and increase bone density, prevent bone loss following ovariectomy and prevent bone loss post-antibiotic treatment in mice[1-4]. Plus, this probiotic has been shown to reduce age-related bone loss in a placebo-controlled double-blind clinical trial in humans[5]. Therefore, from the literature, this probiotic seemed to be a good candidate to dampen implant loosening from peri-implant bone loss. However, I found that the probiotic treatment did not change the gut microbiome and did not affect the implant microenvironment in Sprague-Dawley rats. From the microbiome analysis, I now know that S-D rats have an already high abundance of L.reuteri in their colon. A few possible reasons for the lack of probiotic effect in my model are: 1) there was no ‘niche’ in the gut for MORE L. reuteri to settle into, 2) the dose I administered was too low and/or 3) my probiotic was not viable. On another note, I have also learned that when I do not induce a change in the peri-implant bone (because sometimes our model does not ‘behave’), then the gut microbiome is unaffected. Together, our data still support the interaction between alterations in the gut microbiome and peri-implant bone loss following particle challenge.

Bidirectional gut-implant microenvironment cycle.

Don’t give up on the probiotics! The above-cited literature tells us this bacteria increases bone! Just because I did not get it to work in my model on the first try does not mean all hope is lost. I plan to revisit L. reuteri treatment in an upcoming experiment (after I complete a dose-response study) that will also include a prebiotic (high fiber ‘food’ for the bacteria already in the gut) treatment. Currently, I’m pursuing local inflammatory gene expression in the synovium and peri-implant tissue to determine if there is local upregulation and I plan to expand this to remote gene expression in the colon.

References

1. Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, Parameswaran N, McCabe LR. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol 229(11): 1822, 2014
2. McCabe LR, Irwin R, Schaefer L, Britton RA. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice. J Cell Physiol 228(8): 1793, 2013
3. Schepper JD, Collins FL, Rios-Arce ND, Raehtz S, Schaefer L, Gardinier JD, Britton RA, Parameswaran N, McCabe LR. Probiotic Lactobacillus reuteri Prevents Postantibiotic Bone Loss by Reducing Intestinal Dysbiosis and Preventing Barrier Disruption. J Bone Miner Res 34(4): 681, 2019
4. Collins FL, Rios-Arce ND, Schepper JD, Jones AD, Schaefer L, Britton RA, McCabe LR, Parameswaran N. Beneficial effects of Lactobacillus reuteri 6475 on bone density in male mice is dependent on lymphocytes. Sci Rep 9(1): 14708, 2019
5. Nilsson AG, Sundh D, Backhed F, Lorentzon M. Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial. J Intern Med 284(3): 307, 2018

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Dr. Moran is an Assistant Professor at Rush University Medical Center (RUMC) in the Department of Cell & Molecular Medicine in Chicago, IL. She conducts basic and translational research to understand the connection between the gut and bone. She uses a pre-clinical model of aseptic peri-implant osteolysis, which is bone loss around an implant, which is triggered by inflammation. This model mimics the osteolytic condition in humans with failed implants. Her goal is to understand the connection between the gut and bone to ultimately identify novel, non-invasive means to delay or mitigate implant loosening and the resulting invasive implant revision surgery by targeting the gut. Dr. Moran also taught human gross anatomy for 10 years to first-year medical students and physical therapy students.

The first breath.

The downbeat.

Music surrounds me.

I am happy.

 

I smile at my memory of singing in a choir.

I grew up oscillating between playing the piano and taking apart human anatomical models, so I was thrilled when 2019 HAPS speaker Lawrence Sherman, from Oregon Health & Science University, brought together my two favorite worlds: science and music.

The MRI scans of active music-making were fascinating. Dr. Sherman showed how the same parts of the brain are activated when one is learning new music, regardless of ability. Another scan showed an improvising jazz pianist which displayed that several parts of the brain turn off during this intense activity. He went on to explain exciting research on how music can stimulate neurogenesis

As Dr. Sherman led us through this data, my thoughts drifted to my own experiences as a musical performer. As a young adult, I had the privilege of singing with The Canticum Novum Singers; a New York City based chorus under the direction of Harold Rosenbaum. In one particular performance when we sang  Arnold Schoenberg’s Friede auf Erden, I experienced my anatomy in a surreal way:

We were on the stage at Lincoln Center looking out to a full house. My black binder filled with music was held high and my eyes were focused on the Maestro. The first breath. The down beat. Music surrounded me; beautiful voices, harmonies, the breath of my fellow singers… then something changed.

As I continued to sing, I felt myself as a beating heart in a body like no other. I was connected by vibrational blood vessels to the singers around me and to my conductor, who was our new nervous system, his motions telling us how fast/slow/loud/soft to sing. A powerful and unique energy field united us in song. The music on the page, a series of dots and lines, were as a genetic code, expressed by each musician and understood as we transcribed and translated our individual parts into a phenotype of beauty surrounding us and extending out to the audience.

In those moments I was a living being greater than myself. A being connected through the power of musical vibration.

Thunderous applause brought me back to myself, but the experience has always remained with me. If a scientist had analyzed my brain during that experience, what would my MRI scan have looked like in those moments? 

When we create music with a group, perhaps vibrational waves sum together and create a force grander than our own.  For many cultures, group singing is a common practice. The vibrations, tones and rhythms strengthen community and embody the musical history and evolution of humans in a way that an MRI scan can only begin to image. 

HAPS gives us another way to connect. Like singing in a choir, working and helping each other solve problems through HAPS brings us together and reminds us that no matter where we are, we have a community of professors ready to help us and connect us so that we can grow in our field.

Dr. Sherman’s talk inspired me to learn new piano music when I returned home. But more importantly, he reminded us all how music can increase neuroplasticity and ignite feelings of camaraderie. He gave us something truly special when he had the audience of his lecture stand up and sing those lovely notes from The Beatles’ Hey Jude. He bonded us not only through being at the HAPS annual meeting, but through the power of music. We vibrated together beyond our anatomy. 

We can strengthen that bond through continuing to reach out to each other in the myriad ways HAPS has to support us. I hope we can all sing together again at HAPS in Ottawa, 2020. Until then, we can hum the Beatles tune we all sang together, “nah—nah—nah, nah nah nah…”

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Bridgit Goldman has been teaching college-level biology since 1998.  She has a Ph.D. in Cellular, Molecular, and Developmental Biology from The Graduate School and University Center of The City University of New York. Since 2007 she has designed, developed and taught all the lecture and laboratory classes in Human Anatomy and Physiology at Siena College in Loudonville, NY.