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Novel Therapies for Neurological Disorders by Gut Microbiome

Microbes in the gut may contribute to certain symptoms associated with complex neurological disorders.  According to  Baylor College of Medicine researchers, their findings indicate that microbe-inspired therapies could one day aid in neurological treatment.

This research was publish in Cell under title “Dissecting the contribution of host genetics and the microbiome in complex behaviors”.

Mauro Costa-Mattioli, PhD, director of the Memory and Brain Research Center at Baylor and professor and Cullen Foundation Endowed Chair in neuroscience, discovered with his team that the host's genes and microbiome are interdependently controlled by various abnormal behaviors. The researchers discovered that hyperactivity is dominated by the host's biology in mouse models of neuro-developmental disorders, while social behavior deficiencies are mediated by the gut microbiome.

Treatment with a particular microbe that encourages the development of compounds in the biopterin family in the gut or treatment with a metabolically active biopterin molecule improved social behavior but not motor function.

Many neurological disorders' central symptoms have long been thought to be caused by genetic variations that influence brain development and function. The gut microbiome, however, is another significant source of variation that can affect particular behaviors. As a result, the researchers write, “unraveling the contributions of host genetic variation, the microbiota, and their interactions to complex behaviors is critical.”

In the Cntnap2/model for neuro-developmental disorders, we discovered that various maladaptive behaviors are interdependently controlled by the microbiome and host genes. The hyperactivity phenotype of Cntnap2/ mice is regulated by the gut microbiome, while the social-behavior phenotype is induced by host genetics. Interestingly, upregulation of metabolites in the tetrahydrobiopterin synthesis pathway by unique microbial interference selectively rescued the social deficits in Cntnap2/ mice.

According to their  observations, behavioral abnormalities could have different causes (host genetic and microbial)that could alter how we think about neurological conditions and how we handle them.

Although host genes have received the majority of attention, the gut microbiome, or the population of microorganisms that live within us, is a significant source of genetic knowledge, according to Costa-Mattioli.

Costa Mattioli's team appears to provide a new perspective on neurological conditions in which both human and microbial genes interact and contribute to the disease. Their results also indicate that to adequately resolve all symptoms, successful therapies will need to target both the brain and the stomach.

They also raise the likelihood that other complex diseases, such as cancer, diabetes, viral infection or neurological disorders have a microbiome component.

Since studying these complex associations in humans is difficult, the Costa-Mattioli lab used a mouse model for neurodevelopmental disorders in which the animals lacked both copies of the Cntnap2 gene (Cntnap2-/- mice), according to first author Sean Dooling, a PhD candidate in molecular and human genetics. “These mice displayed social defects and hyperactivity, which are close to those seen in autism spectrum disorders,” says the researcher (ASD). Furthermore, these mice, like many people with ASD, had variations in the bacteria that make up their microbiota when opposed to mice that did not have the genetic change.”

Further studies revealed that altering the gut microbiome enhanced the mutant mice's social behavior while having little effect on their hyperactivity, suggesting that improvements in the microbiome lead to the animals' social behavior selectively.

“We were able to distinguish between the microbiome's contribution to behavioral changes and the animal's genetic mutation,” Dooling continues. “This demonstrates that the gut microbiome is a critical variable to consider when researching health and disease.”

Additional research was conducted to better understand the mechanism underlying the microbiome's impact on the social deficits of the animal. The researchers used the probiotic microbe L. reuteri to treat the mice based on their previous research.

“We discovered that L. reuteri can restore normal social behavior in Cntnap2-/- mice, but it cannot correct the hyperactivity,” said Shelly Buffington, PhD, a former postdoctoral fellow in the Costa-Mattioli lab who is now an assistant professor at the University of Texas Medical Branch in Galveston.

Furthermore, when the scientists gave the  mice a metabolite or compound, they discovered that L. reuteri increased the amount of it in the host's gut. They found that treating the animals with the metabolite rather than the bacteria enhanced their social deficits as well.

“This gives us at least two options for modulating the brain from the gut: bacteria or bacteria-induced metabolites,” Buffington says.

Although it is still too early to tell for sure, the researchers are especially enthusiastic about the implications of their results in terms of translation.

According to Buffington, "our work reinforces an evolving idea of a new frontier for the creation of safe and efficient therapeutics that target the gut microbiome with selective probiotic bacteria strains or bacteria-inspired pharmaceuticals."

“As we learn more about how these bacteria function, we will be able to more specifically and efficiently harness their ability to better treat the brain and probably other diseases,” Dooling continues.

Many disorders, especially those affecting the brain, remain difficult to treat, so this study appears to be a significant step forward in the field.

“Despite all of the scientific developments and the potential of gene manipulation, modulating human genes to treat diseases remains difficult, but modulating our microbiome could be an interesting, noninvasive alternative,” Costa-Mattioli says, noting that L. reuteri is currently being studied in an Italian clinical trial in children with autism, and Costa-Mattioli plans to begin his own trial soon.

Ending with a  hope “I could never have believed that microbes in the gut could affect actions and brain activity in my wildest dreams. It's still nuts, but very exciting to think that microbial-based strategies might be a feasible way to treat neurological dysfunction.”

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