Research Update on the Gut-Implant Microenvironment Axis

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

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.