Antibiotics are a Risk but Offer Promising Therapies, Too
The past 12 months have not produced any startling breakthroughs when it comes to pinpointing the cause or causes of autism, but 2017 did bring much of the research full circle, with scientists returning to an earlier focus on the composition of human gut microbiota and its impact on brain development, and to antibiotics as an environmental risk factor.
Before 2005, there was much discussion about the common occurrence of multiple ear infections - and the repeated use of antibiotic regimens - in children who later developed autism. That promising path of research was soon overwhelmed by other investigatory priorities, though it has remained a part of the risk-factor literature.
In the past several years, though, researchers have been taking another look, especially at the role antibiotics might play in altering the gut microbiota, which has an established association with autism spectrum disorders (ASD).
In his 2017 peer-reviewed study "The Gut Microbiota and Autism Spectrum Disorders," Qinrui Li and Ying Han of Peking University First Hospital in Beijing, China; Angel Belle C. Dy of the School of Medicine and Public Health in Quezon City, Philippines; and Randi J. Hagerman of the University of California Davis Medical Center in Sacramento reviewed 157 studies and academic reports and articles released since 2002. Many found that an abnormal gut microbiota is associated with ASD.
The review is important because of the accumulation of findings it summarizes, many of which point to a role in the depletion of gut microbiota diversity. As Li and his colleagues noted, gastrointestinal (GI) symptoms are a common comorbidity in patients with autism spectrum disorder, though the underlying mechanisms are unknown.
While the researchers stress that the studies did not show a cause-effect relationship between GI symptoms and ASD, the findings do suggest the gut plays an important role in the etiology of ASD.
"The gut microbiota influences brain development and behaviors through the neuroendocrine, neuroimmune, and autonomic nervous systems," they wrote. "In addition, an abnormal gut microbiota is associated with several diseases, such as inflammatory bowel disease (IBD), ASD, and mood disorders."
The intent of the study was to not to pinpoint a cause of autism but to review the relationship between the gut microbiota and the central nervous system, define the role of the gut microbiota in ASD, and describe some potential therapies for modulating the gut microbiota in those patients.
So while the scientists did not attempt to discover the cause or causes of ASD, their work inevitably led them to explore some potential risk factors, and antibiotics surfaced as one of those.
"Maternal factors, such as maternal diet and delivery mode, and postnatal factors, including antibiotics, breastfeeding, diet and host genetics, structure the neonatal microbiome in humans and animal models," the scientists wrote.
A maternal high-fat diet during pregnancy could play a role in the alteration of gut microbiota in primates, they observed from some studies, and maternal obesity during pregnancy and gestational diabetes alter the gut microbiota and might be associated with ASD in humans.
Another study they reviewed showed a maternal high-fat diet induces dysbiosis and autism-like phenotypes in mice. But birth mode and antibiotics also shape the gut microbiota, the scientists observed.
For example, they observed, the gut microbiota of infants who were delivered vaginally resembles their mother's vaginal microbiota, while the gut microbiota of babies who were born by Cesarean section is similar to their mother's skin microbiota.
And the use of antibiotics, both by mothers during pregnancy and by children after birth, seems to play a role.
"(T)he composition of the microbiota of children who were treated with antibiotics during the first 3 years of life is less diverse in terms of both bacterial species and strains," they wrote. "A population-based cohort study revealed the use of various antibiotics during pregnancy as a potential risk factor for ASD/infantile autism."
Early feeding patterns also influence the gut microbiota of infants and are associated with ASD, they found other studies reporting: Formula-fed infants presented an increased species richness compared with breastfed infants, and breastfeeding for more than six months is associated with a lower risk of developing ASD.
In particular, the scientists pointed to two studies showing that children with ASD have a history of using significantly more antibiotics. One study they cited came from those early days of interest in ear infections, a 2006 report from the University of Michigan Autism and Communication Disorders Center, in which children with ASD were found to have significantly more ear infections than typically developing children as well as to use significantly more antibiotics.
A 2012 study out of the University of Aarhus, Aarhus, Denmark, located a small increased risk for ASD and infantile autism after the use of different antibiotics during pregnancy, but scientists could not blame the antibiotics as the cause of the autism.
"We do not know whether the antibiotic treatment itself caused the observed association or whether the antibiotic use functioned as a proxy variable for an underlying disease, disease severity, a maternal immune response to a disease, or whether this was a chance finding," the scientists wrote. "The association between antibiotics and autism is a novel finding, which requires confirmation. However, sulfonamides are known folate antagonists, and impaired folate status has been implicated as a risk factor for ASD."
Thus, the Li and his colleagues wrote, early life events such as delivery mode and antibiotic exposure that can alter the composition of the microbial community are risk factors for ASD, though they observed that some studies have not found an association between ASD and the gut microbiota.
Other studies in 2017 have implicated the early use of antibiotics in other diseases.
For example, a new research report in the Journal of Leukocyte Biology implicated antibiotic use very early in life with the alteration of the normal development/growth of gut bacteria and could contribute to the development of inflammatory bowel disease, and potentially other inflammatory diseases like asthma and multiple sclerosis, the study stated.
The study also adds more evidence suggesting that altering gut flora may be a viable treatment strategy for some inflammatory diseases, the author stated.
"Our study demonstrates that gut bacteria in early life do affect disease development in adulthood, but this response can be changed," said Colby Zaph of Monash University in Australia. "This has important ramifications for the use of pre- and probiotics, the administration of antibiotics to neonates, and our understanding of how gut bacteria play a critical role in influencing the development of inflammatory diseases such as IBD."
A 2016 study, "Modulatory Effects of Gut Microbiota on the Central Nervous System," observed that normal gut microbiota is essential in preventing colonization of harmful bacteria by competing with them for vital resources such as food and growth factors and that antibiotics can alter that composition.
"If the population of normal gut microbiota is reduced, for example, due to antibiotic therapy, pathogenic organisms find the opportunity to colonize the gut epithelium," the paper stated. "Toxins produced by pathogenic microorganisms and the focal inflammation created by immune responses to them can increase gut permeability."
And permeability is not a good thing, the researchers found.
"Alteration in the composition of the gut microbiome can potentially lead to increased intestinal permeability and impair the function of the intestinal barrier," the researchers, led by Shadi S Yarandi of Johns Hopkins University, wrote. "Subsequently, neuroactive compounds and metabolites can gain access to the areas within the central nervous system that regulate cognition and emotional responses. Deregulated inflammatory response, promoted by harmful microbiota, can activate the vagal system and impact neuropsychological functions. Some bacteria can produce peptides or short chain fatty acids that can affect gene expression and inflammation within the central nervous system."
In a study in a rodent model, the researchers wrote, the composition of gut microbiota in animals with ASD-like behavior is significantly changed compared with control animals.
And, Yarandi and her colleagues continued, children with ASD also show the altered composition of gut microbiota with a reduced population of Bacteroides and increased levels of Clostridium species.
"It has been postulated that altered gut microbiota in children with ASD can lead to potential imbalances in the metabolism of carbohydrates and amino acids in the gut, and altered levels of metabolites in the blood and urine," she wrote.
So far, scientists have pinpointed repeated rounds of antibiotic regimens, especially for ear infections, in young children and also those taken by pregnant women as risk factors for ASD. But antibiotics have another route into the bodies of very young children: vaccines. Generally, antibiotics are infused in vaccines to prevent contamination during the manufacturing process.
A 2016 post on the website of the Children's Hospital of Philadelphia lists the number of contemporary vaccines containing various antibiotics. For example, the Measles-Mumps-Rubella (MMR) vaccine continues to contain the antibiotic Neomycin.
Flu shots run the gamut. Some flu shots contain no antibiotics, while others contain more than one.
Pertussis, diphtheria, tetanus and hepatitis B vaccines contain both Neomycin and Polymyxin B, the latter an antibiotic sometimes used as a drug of last resort to assault superbugs that have become resistant to drugs.
Neomycin and Polymyxin B are both also used to treat ear infections in young children.
Good Antibiotic, Bad Antibiotic
But could antibiotics play good cop as well as the bad cop in the human gut? Very possibly, scientists say.
If antibiotics can be considered risk factors - especially the repeated use of them by pregnant woman and by young children - other studies indicate later on some antibiotics, as well as probiotics and prebiotics, can be used to treat the symptoms of autism.
That that might be the case is not contradictory because of bidirectional interactions between the central nervous system and the gastrointestinal tract, what Li in his 2017 paper called the brain-gut axis.
Indeed, as Li and his colleagues pointed out, while the gut microbiota influences brain development and behaviors through the neuroendocrine, neuroimmune, and autonomic nervous systems, and while abnormal gut microbiota is associated with several diseases, such as inflammatory bowel disease, ASD, and mood disorders, there is evidence microbiome-mediated therapies might be a safe and effective treatment for ASD.
Diet might be one way to modulate the gut microbiota in patients with ASD, Li and his colleagues postulated, but so might a regimen of antibiotics.
"Children with regressive-onset autism who are treated with vancomycin, a broad-spectrum oral antibiotic, for a short period exhibit improvements in diarrhea and autistic behaviors," the researchers found, citing a 2000 study. "Based on a prospective, double-blind, placebo-controlled trial, 3-month treatment with levocarnitine improves ASD symptoms in children with ASD."
They also called attention to microbiota transfer therapy, which the researchers said is a modified protocol comprising 14 days of antibiotic treatment followed by bowel cleansing and the administration of a high initial dose of standardized human gut microbiota for seven to eight weeks.
"An open-label clinical trial showed that MTT improved both GI symptoms (e.g., constipation, diarrhea, indigestion and abdominal pain) and ASD-related symptoms and normalized the microbiota of ASD patients," Li and his colleagues wrote, citing a 2017 study led by Dae-Wook Kang of Arizona State University.
Though they lack multicenter, large-sample, randomized controlled trials, the researchers suggested that probiotic and prebiotic treatment for ASD patients can normalize the gut microbiota, enhance gut barrier, and relieve ASD-like behaviors in animal models or ASD patients, though their use is still controversial.
A 2012 study led by Mason Kuhn of the University of North Dakota found that a regimen of antibiotic therapy relieved both symptoms of Lyme disease and ASD. As the researchers observed, patients diagnosed with Lyme disease share many of the same physical manifestations as those diagnosed with an ASD.
In the study, the researchers wrote, four male children between the months of 26 and 55 months who had an ASD diagnosis and one male child aged 18 months who displayed behaviors consistent with an ASD were assessed using a process that met state and federal requirements for providing a comprehensive, ongoing assessment of a child with an ASD.
"The assessment measured children's abilities using observational, authentic assessment procedures in the domains of joint attention, symbol use, mutual regulation, and self-regulation via observations of specific behaviors in familiar settings," the researchers wrote.
The five children tested positive for Lyme disease and their score was evaluated before and after six months of antibiotic therapy. Each child was prescribed 200 mg of amoxicillin three times per day and three of the five children were prescribed an additional 50 mg of Azithromycin once per day.
The results were significant.
"All of the children's scores on the SAP-O assessment improved after six months of antibiotic therapy," the researchers wrote. "The assessors also reported anecdotal data of improved speech, eye contact, sleep behaviors, and a reduction of repetitive behaviors."
Five years later, a 2017 report of a case study in the Journal of Psychiatry and Psychiatric Disorders, whose lead author was Kelly Barnhill of the Johnson Center for Child Health and Development in Texas, found that a 34-month-old boy with ASD showed significant reduction in repetitive and ritualistic behaviors after taking the antibiotics amoxicillin, cefazolin, and bactrim for several infections across a six-month period.
"Short-term improvements were observed during multiple concurrent and short-term post-therapy evaluations," the report stated.
However, shortly after a 10-day course of amoxicillin ended, behavioral deterioration was reported, the report acknowledged.
"Improvements were temporary and the patient's behavior deteriorated after the antibiotic treatment was completed," the researchers wrote. "Similar behavioral changes were reported for 8 out of 10 children with ASD who were participating in a clinical trial of another antibiotic, vancomycin."
The authors speculated that the observed behavioral effects were associated with changes to the subjects' microbiome composition, induced by the antibiotic treatment, the researchers wrote, adding to an emerging consensus that gut microbiota plays a major role in regulating the human brain, modulating mood and behavior: "The case study being reported further supplements recent literature suggesting an association, in at least a subset of children, between ASD and the gut microbiome," they wrote.
The authors acknowledged several limitations to the study.
"First, given the clinical nature of this work, there is limited quantitative data to show the decrease in ritualistic behaviors observed in the patient," they wrote. "Further, the study is also limited in that most of the data collected was from observations documented by the patient's parents, therapists, and treating pediatrician. While the benefits of antibiotics at this time appear to be short-term and cannot be a consistent source of reliable long-term treatment, more research is required to fully understand the clinical effects of antibiotics on ASD/OCD behaviors."
Ongoing research is continuing to look into the potential connections between antibiotics and ASDs - whether as a potential cause or as potential treatments.
In late 2016, Baylor College of Medicine initiated a national study funded by N of One: Autism Research Foundation, a non-profit founded by John Rodakis, a father of a child with autism.
Over the Thanksgiving holiday in 2012, Rodakis observed that his son's condition dramatically improved while taking a common antibiotic, the foundation reports. He began a four-year quest to understand how an antibiotic might affect behaviors associated with autism.
This study will investigate why some children with autism spectrum disorder (ASD) experience improvements or changes in their autism symptoms when taking antibiotics, while others report worsening symptoms. The study is following children over a two-year period and capturing information anytime antibiotics are prescribed by their regular physicians. Researchers will then compare changes in the gut microbiome during antibiotic use of those who experience a change in symptoms to those who do not.
The study seeks to understand when and why these changes occur and how this information can be harnessed for future interventions.
The study marks the first collaboration between N of One: Autism Research Foundation and Baylor College of Medicine and is the brain-child of two parents of affected children, Dr. Ruth Ann Luna and Rodakis.
Luna is one of the nation's leading investigators of the role of the microbiome in autism and is the director of medical metagenomics at the Texas Children's Microbiome Center at Texas Children's Hospital in Houston. She is also an assistant professor in the Department of Pathology & Immunology at Baylor College of Medicine.
Rodakis is a former medical venture capitalist. Both Luna and Rodakis have observed changes in their children's autism symptoms while taking antibiotics, though the antibiotics worsened the symptoms in Luna's child.
"Working with Dr. Luna has been very energizing because as a fellow affected the parent, we share a real passion to get this right for our children as well as millions of others," says Rodakis.
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