Kara Gross Margolis, MD, explores recent studies surrounding the role of serotonin and the more extensive gut microbiome in gastrointestinal (GI) and inflammatory conditions related to autism. She presents case studies highlighting the different presentations of GI issues in individuals with autism and how those behaviors relate to the gut-brain links. Margolis outlines research on fecal transplant, multi-omics of brain-gut-microbiome disease, correlated bacterial communities, serotonin reuptake transporters (SERT), and new longitudinal pilot studies. She notes limitations and key findings for each study and discusses their impact on current and future research avenues. She concludes by recognizing ongoing serotonin drug development before the question and answer session.
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In this presentation
8:35 – Common GI issues in autism and how they present
11:10 – Case studies (2): self-injurious behaviors associated with GI stress
16:50 – Screening techniques for GI issues in autism
23:50 – Study: Fecal transplant
27:40 – Study: Distinct microbiome-neuroimmune signatures
29:50 – Study: Multi-omics analysis of brain-gut-microbiome disease
34:35 – Study: Longitudinal pilot study
37:45 – Study: Genetic study of SERT variants in mice
42:18 – SERT 5-HTP drug development
46:00 – Q & A session
Gastrointestinal (GI) issues are up to 4 times more common in individuals with autism spectrum disorder than their neurotypical counterparts (7:50) and is one of the most common comorbid ASD conditions diagnosed. Due to poor sensory localization and/or communication difficulties, presentation of GI issues in autistic individuals may not signal abdominal pain (9:10). Presentation of GI pain in autism can vary (10:08) but is most often associated with self-injurious behavior and vocal tics or subtle unexplained behaviors (i.e. sleep disturbance, mood, tapping on chest). The presenter notes that self-injury and aggression are often seen in individuals with autism however, they are not central to an autism diagnosis. Therefore, when patients present with such behavior, screening for GI issues should be a top priority (11:35).
The gut microbiome and peripheral serotonin (serotonin in the gut) are thought to be critical modulators of the gut-brain links important in autism spectrum disorder (18:30). The gut microbiota is a huge ensemble of bacteria, fungi, and viruses – up to 100 trillion species – impacting virtually every bodily system (20:55). A small fecal transplant study (23:50) showed decreased GI issues and associated behaviors during and after treatment. However, due to the incalculable differences in gut biomes, studies have shifted focus to understanding correlations of specific bacterial communities with conditions (26:27).
A slightly larger study (27:40) correlated GI symptoms with bacterial communities in the gut and compared blood and rectal biopsies across populations. They found that children with autism have very different gut biomes to their neurotypical counterparts with and without GI issues (28:18). Margolis discusses future research avenues by outlining a multi-omics analysis of brain-gut microbiome disease (29:50) that should be published in the coming year and a new longitudinal pilot study that will shed light on how behavior changes and shifts in microbiome/metabolome interplay (34:35).
95% of serotonin in the body is located in the gut/intestine, where the presence of particular organisms or medications can stimulate the formation or breakdown of serotonin (37:00). The serotonin uptake transporter (SERT) is a critical part of the link pathway that modulates the balance of serotonin in the gut and the brain by inactivating serotonin. Abnormalities in this connection are overexpressed in individuals with autism (37:45). In a genetic model experiment (38:25) researchers found the most common SERT variants found in families with ASD and pushed it into mice models. The affected mice presented with core autism-related behavioral abnormalities, high blood serotonin levels, constipation (39:25), and small bowel bacterial overgrowth (40:00) – all of which are common characteristics of GI distress in children with autism. Researchers then selectively activated the 5-HT4 receptors (40:48) (increased GI speed, increased neuron development in GI tract, etc. (41:30)), which in turn corrected the defects in the gut and nervous systems, normalized constipation effects, and prevented abnormalities in the intestinal microbiome (42:18). These findings have been pivotal in shifting focus to the role of serotonin in brain-gut disease, which has opened pathways to creating a slow-release form of serotonin 5-HTP, which is currently in the drug development phase (42:44).
Margolis concludes by emphasizing the prevalence of GI problems in individuals with autism and the relative differences in clinical presentation compared to neurotypical children. She discusses current large-scale GI studies surrounding the microbiome and serotonin and reemphasizes the future potential for drug development. She then answers questions surrounding gastroenterologist availability, comments on the value of building relationships with patients and families, and discusses GI issues across cultures and diets, and finally emphasizes that families should seek care from more than one professional as various comorbidities cannot likely be treated in one place or by one clinician.
If you are interested in taking part in clinical trials, visit clinicaltrials.gov
Kara Gross Margolis, MD is an Associate Professor of Pediatrics and a pediatric gastroenterologist with a clinical expertise in brain-gut axis disorders, and particularly autism spectrum disorders (ASD). She has published highly novel observations on the roles that enteric neurotransmitters, specifically serotonin and oxytocin, play in enteric nervous system (ENS) development and how, when signaling of either of these neurotransmitters is abnormal, result in intestinal inflammation and/or motility dysfunction. She has more recently leveraged her expertise to study disorders of the brain-gut axis from the perspective of the ENS. Her studies in this area thus far have focused on two disorders that have been classically thought of as central nervous system (CNS)-centric, ASD and developmental antidepressant (selective serotonin reuptake inhibitor; SSRI) exposure. Her overall goals are to pursue translational research that interrogates basic mechanisms underlying important clinical conditions, in order to utilize this knowledge to develop novel therapeutic strategies.
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