Researchers from the University of Vermont (UVM) have found that a species of gut microbiome bacteria called Lactobacillus reuteri—which is commonly used in probiotics— can increase disease severity in a mouse model of multiple sclerosis (MS), but only in genetically susceptible animals.
The findings, published in Proceedings of the National Academy of Sciences (PNAS) indicate that complex interactions between host genetics and environmental factors may drive susceptibility to multiple sclerosis. The results also suggest that antibiotic or probiotic strategies that may be developed to help prevent or treat multiple sclerosis should take into account host genetics, the pre-existing gut microbiome, and the timing or mode of the intervention.
“Our gut bacteria are part of a complex ecosystem that holds great potential for the prevention, treatment, and/or diagnosis of chronic diseases,” said Dimitry Krementsov, PhD, who led the study. “However, many scientists have been going at it with a one-size-fits-all approach, and our research suggests that this is unlikely to work. Instead, a more personalized approach is needed.”
Krementsov and colleagues report on their findings in a paper titled, “Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity.”
MS affects about 2.3 million people worldwide, and is the leading cause of nontraumatic neurological disability in young adults, the authors wrote. But while recent evidence suggests that the gut microbiome may modulate the risk of MS, the specific bacterial species, and the role of host genetics, are not clear. “An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome,” they commented. “Many of the environmental risk factors for MS, including diet, vitamin D intake, smoking, stress, and previous infection can contribute to gut microbiome imbalance, suggesting that the gut microbiome may serve as an integration point for multiple risk factors … However, the identity of gut microbes associated with disease risk, their mechanisms of action, and the interactions with host genetics remain obscure.”
In many chronic diseases, scientists have found that the state of the gut microbiome is altered, which raised the possibility that restoring balance in the gut microbiome could treat or even prevent disease. This has spurred the popularity of probiotic products, typically consisting of live bacteria.
For their reported study, Krementsov, who is assistant professor in the Department of Biomedical and Health Sciences at UVM, and colleagues, modulated the gut microbiomes of genetically diverse mice with high or low susceptibility to experimental autoimmune encephalomyelitis (EAE), a common animal model for multiple sclerosis. In order to determine which features of these microbiomes conferred higher susceptibility to MS-like disease, the researchers isolated different bacterial species from the complex mix and transferred them to new mice, one at a time. “ … we utilized the principal autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), together with a genetically diverse mouse model representing 29 unique host genotypes, interrogated by microbiome sequencing and targeted microbiome manipulation,” the authors noted.
The findings were surprising: one of the culprits identified was Lactobacillus reuteri, a normal commensal resident of the human and mouse gut that is also a widely used probiotic. While this may have seemed to pinpoint the bacterium as the “bad guy,” the researchers also noted that this bacterium originally came from a genetically distinct mouse host that was normally resistant to MS-like disease. This suggested that the genetics of the host may also determine whether a particular microbiome state is “good” or “bad.” As the team pointed out, “Our results demonstrate a complex interplay between host genotype and gut microbiota in autoimmune disease, and identify a single commensal species capable of modifying disease susceptibility in a genetically susceptible host.”
The findings also raise a critical question: are probiotics generally good or bad? The reported results suggest that the answer is most likely dependent on the context, particularly on the individual who is receiving the probiotic. “Our model addresses the role of commensal microbiota as a risk factor for MS, rather than a therapeutic probiotic intervention,” they further pointed out. “Moreover, given L. reuteri’s widely accepted role as a probiotic species, our findings sound a cautionary note and highlight the need to consider both host genetics and baseline gut microbiome composition in probiotic or similar therapeutic strategies, especially given that such efforts are already underway in MS.”
The study authors also pointed out caveats to their work. The study was not designed to investigate probiotics per se, but rather study how normal commensal bacteria interact with the host. Probiotic bacteria are typically grown in a lab or food production facility and taken orally in massive daily doses. These probiotic bacteria are also genetically very distinct from their commensal counterparts, and the authors are currently exploring this possibility.
Additionally, what is “bad” for an autoimmune disease like MS may actually be “good” in other contexts, like stronger immune response against infection. There are numerous examples of genes that promote “good” immune responses against infection or vaccination, but which in turn also result in a higher risk of autoimmune disease. Finally, other scientists have used high dose daily treatment with probiotic strains of Lactobacillus to reduce MS-like disease in mice, although recent studies show that the probiotic bacteria do not even need to be alive for this to work. Thus, the answer is, probiotics may be good or bad, depending on the context. The next step is figuring out what this “context” actually is.
“With clinical trials involving direct fecal microbiome transplantation, as well as antibiotic and probiotic supplementation currently underway, our findings highlight the need to consider timing of exposure, host genetics, and baseline gut microbiome composition in interpreting these outcomes, and designing better personalized prophylactic and therapeutic interventions,” the authors concluded.