Expression of the MEF2C protein (green) in the nuclei of neuronal cells (stained with a neuronal marker protein in red) in the inner ear of a young adult mouse. Nuclei were stained with Dapi (blue). Image courtesy of Dr. Hainan Lang of the Medical University of South Carolina.

A cross-disciplinary team of researchers in the College of Medicine at the Medical University of South Carolina (MUSC) has discovered hearing impairment in a preclinical model of autism . More specifically, the researchers report in the Journal of Neuroscience that they observed mild hearing loss and defects in auditory nerve function. Closer examination of the nerve tissue revealed abnormal supportive cells called glia, aging-like degeneration and inflammation. The findings from this study highlight the importance of considering sensory organs and their interactions with the brain in understanding autism.

Many autistic people show increased sensitivity to sound. While many scientists in the past have looked to the brain for an underlying cause, the MUSC team took a different approach by studying the peripheral hearing system.

“Hearing impairment may have an impact on the higher-level auditory system and, eventually, cognitive function,” said Hainan Lang, M.D., Ph.D., professor in the Department of Pathology and Laboratory Medicine at MUSC and one of two senior authors of the study. Jeffrey Rumschlag, Ph.D., a postdoctoral researcher in the MUSC Hearing Research Program, is a co-first author of the manuscript.

Previous studies of aging-related hearing loss showed that the brain can increase its response to make up for reduced auditory signals from the inner ear. Lang wanted to find out if this increase, called central gain, could contribute to abnormal brain response to sound in autism. However, a significant obstacle lay in her path.

“We didn’t have a clinically relevant model to directly test this important fundamental question,” she said.

The preclinical model that would allow Lang to test her hypothesis was developed in the lab of Christopher Cowan, Ph.D., chair of Neuroscience at MUSC. Mice in this model have only one working copy of a gene called MEF2C. Cowan’s group had studied MEF2C in the past for its role in brain development and found that it was important for regulating circuit formation in the brain. They became especially interested in creating a preclinical model when a group of autistic patients tswere identified with MEF2C mutations. Cowan’s models also show autistic-like behaviors, including increased activity, repetitive behavior and communication deficits.

Lang and Cowan’s collaboration began as they presented posters side by side at an orientation for the College of Graduate Studies at MUSC. Lang’s lab had identified molecular regulators, including MEF2C, crucial for inner ear development, and she saw Cowan’s model as something she could use to test her hypothesis about hearing loss in neurodevelopmental diseases. Cowan enthusiastically agreed, and the research team began to assess the ability of the MEF2C-deficient mice to hear.

They first measured the response of the brain to auditory signals, using a modified version of a test that is commonly used to screen newborn infants for hearing loss. Mild hearing loss was observed in the mice with only one working copy of MEF2C while hearing remained normal in those with two working copies. To investigate this loss further, the researchers measured the activity of the auditory nerve, which carries signals from the inner ear to the brain. They found reduced activity in this nerve in mice with only one copy of MEF2C.

With their sights set on the auditory nerve, the researchers used advanced microscopes and staining techniques to determine what was going wrong. Although the overall hearing sensitivity loss was mild, the researchers were excited to see a big difference in auditory nerve response. Nerves from mice with a single copy of MEF2C showed cellular degeneration much like that seen in age-related hearing loss. The researchers also saw signs of increased inflammation, with disrupted blood vessels and activated immune cells called glia and macrophages. This finding was especially surprising to the researchers.

“Glial cells were not my first thought; I thought it was a neuronal change,” said Lang. “Now we understand that auditory nerve activity can also involve the immune system, and that’s the beautiful new direction we want to continue to study.”

Cowan also believes that the finding opens the way for a new area of neuroscience research.

“We have more appreciation now that there is an important interaction between the immune system in your body and the immune system in your brain,” he said. “The two systems play critical roles in shaping how nervous system cells communicate with each other, in part, by pruning excess or inappropriate connections that have formed, and this is an essential aspect of healthy brain development and function.”

The findings from this study could be important not only for patients who are MEF2C deficient but also for autistic people or hearing loss as a whole.

“Understanding how this gene may be participating in ear development and how the inner ear development is affecting brain development has tremendous applicability,” said Cowan.

In future studies, the researchers aim to discover how exactly MEF2C causes the changes that were identified in this study. The research team also hopes to explore these findings in patients with MEF2C deficiency using noninvasive hearing tests.

Lang and Cowan both emphasize the importance of collaboration across disciplines for allowing studies like this to take place.

“The power of collaboration is tremendous for a place like MUSC,” said Cowan. “This collaboration, for us, was ideal because Dr. Lang is an expert in hearing function and development, whereas I am more the genetics and molecular development person. These kinds of collaborations are ideal, and it’s precisely what MUSC is encouraging a lot of us to think about doing more and more.”

“In other words, we each play different instruments so, together, we can make a better harmony,” said Lang.

In a new study, Arizona State University researchers and their colleagues deeply explore changes in the gut microbiota following microbiota transfer therapy — a novel treatment for children with autism. Specifically, by using whole genome sequencing, they looked at alterations in bacterial species and genes involved with microbial metabolism. The researchers discovered that microbial taxa and genes that are important for microbial pathways associated with improvements in the physical and behavioral symptoms of autism , improved following microbiota transfer therapy. CREDIT Shireen Dooling/Arizona State University

Autismcurrently affects 1 in 44 children in the U.S., according to the Centers for Disease Control and Prevention. For reasons that remain murky, these numbers appear to be trending upward as researchers and clinicians struggle to find effective treatments.

Recently, a new approach to treat symptoms associated with this disorder has emerged, thanks to the explosion of research on the trillions of non-human cells inhabiting the gastrointestinal tract—collectively known as the gut microbiome. The treatment, called microbiota transfer therapy, is a process where healthy gut bacteria are transferred to children with autism.

In a new study, Arizona State University researchers and their colleagues deeply explore changes in the gut microbiota following microbiota transfer therapy — specifically, by using whole genome sequencing, they looked at alterations in bacterial species and genes involved with microbial metabolism. 

The researchers discovered that microbial taxa and genes that are important for microbial pathways associated with improvements in the physical and behavioral symptoms of autism, improved following microbiota transfer therapy.

In first-of-its-kind research, the research team used a whole genome sequencing technology known as “shotgun metagenomics” to extract detailed data from more than 5,000 bacterial species found in the gut of children with autism spectrum disorder before and after microbiota transfer therapy. The researchers then compared these results with bacterial populations in the guts of healthy children.  

The results showed considerable improvement in overall abundance of bacteria following the microbiota transfer therapy, and this confirmed previous findings. Also, there were substantial increases in populations of beneficial bacterial species typically found in lower numbers in children with autism.

Additionally, two genetic indicators of dysregulation in the gut microbiome of children with autism improved following microbiota transfer therapy. These key genetic markers are the metabolism of sulfur and the failure to detoxify oxidative stress.

The findings are encouraging because the severity of gastrointestinal dysfunction in autistic children appears proportional to the degree of behavioral and cognitive issues, highlighting the importance of the gut-brain axis—a topic of intense interest in the world of microbiomics. The gut-brain axis is the communication system between your brain and your gut.

“This study highlights altered levels of important bacterial species and metabolic genes in children with autism and improvements after microbiota transfer therapy,” says Khemlal Nirmalkar, lead author and post-doctoral fellow working in theRosa Krajmalnik-Brown lab at the ASU Biodesign Institute. Our long-term goal is to understand the functional role of the gut microbiome, fill the knowledge gap of the gut-brain axis in autism, and identify therapeutic targets to improve GI health and behavior in children with autism.”

“Completing more in-depth microbiome sequencing is important because it can help us better understand what microbes in the gut are doing and why they are an important part of the gut-brain axis,” said Krajmalnik-Brown, who directs the newly established Biodesign Center for Health Through Microbiomes. She is also a professor with the ASU School of Sustainable Engineering and the Built Environment in the Ira A. Fulton Schools of Engineering.

Collaborators include James Adams, President’s Professor with the ASU School for Engineering of Matter, Transport and Energy, and researchers with the Rensselaer Polytechnic Institute in New York. The study appears in a special issue of the International Journal of Molecular Sciences titled “The Microbiota–Gut–Brain Axis in Behavior and Brain Disorders.” 

The research team used shotgun metagenomics, or whole genome sequencing, to better understand the bacterial populations at the species level. They also wanted to understand bacterial genes before and after microbiota transfer therapy. The treatment not only increased the abundance of beneficial bacteria but also helped to normalize altered levels of bacterial genes, particularly those related to the synthesis of folate, oxidative stress protection and sulfur metabolism, and importantly, became similar to typically developing children.

Autism remains an enigmatic disorder, often emerging in early childhood and causing lifelong developmental disabilities that affect social skills, communication, personal relationships and self-control. So far, there is no cure for the affliction and therapies for treating associated symptoms remain limited.

The microbiota transfer procedure involves the transfer of gut microbiota from healthy donors to autistic patients over a period of seven to eight weeks. The procedure begins with a 2-week antibiotic treatment and bowel cleanse, followed by an extended transplant of fecal microbiota, applying a high initial dose followed by daily and lower maintenance doses for 7–8 weeks. This treatment was initially studied in children with autism ages 7-16 years old.

In a follow-up study, the same 18 participants were examined two years after treatment was completed. Most improvements in gastrointestinal symptoms were maintained, while autism-related symptoms continued to improve even after the end of treatment, demonstrating the long-term safety and efficacy of microbiota transfer therapy as a therapy for autism.

The treatment reduced the severity of gastrointestinal symptoms by roughly 80% and signs of autism by about 24% by the end of treatment. After two years, the same children showed an approximate 59% reduction in gastrointestinal symptoms and 47% reduction in autism symptoms, compared with baseline levels established prior to treatment.

Krajmalnik-Brown and Adams are currently working on phase-2 double-blind placebo-controlled studies of microbiota transfer therapy for children and adults with autism, and they plan to verify whether these findings hold true in those two studies.

Future research will further explore the role of specific microbial species, functional gene expression and the production of a range of autism -related metabolites before and after microbiota transfer therapy.

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