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

Summary

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  

Dr. Ferguson discusses current research indicating that GI issues coincide with behavior problems in autism. He explains how the autonomic nervous system drives stress response and details its relationship with GI functionality. The speaker describes five studies investigating different aspects of Gi issues, anxiety, stress, and problem behaviors in autism. Ferguson touches on pharmacological, vagal, and behavioral treatment strategies before the Q&A. 

Handouts are online HERE

In this webinar: 

2:25 – Prevalence of GI disorders in autism
5:10- Autonomic nervous system and autism
8:12 – Study: GI and stress relationship in autism
10:55 – Study: Psychophysiological associations
13:20 – Study: GI problems, difficult behavior, and internalizing symptoms in autism
16:30 – Results
18:30 – Do GI symptoms predict internalizing or externalizing symptoms?
20:20 – Results
21:44 – Discussion
22:45 – Study: Electrodermal activity and problem behaviors in autism
26:00 – Study premise and outline
27:10 – Analysis of electrodermal activity
29:45 – Relationship between stress response and problem behavior
31:15 – What happens when we treat the stress response?
36:20 – Study: Effects of propranolol on the relationship between GI issues and amygdalar reactivity
39:00 – fMRI results
43:00 – Future directions
46:40 – Take-home messages
47:40 – Acknowledgements and thanks
48:05 – Q & A

Introduction

Ferguson explains that up to 91% of autistic people experience GI difficulties, highlighting the importance of studying GI issues in relation to autism (2:40). Two of the most common GI issues in autism are constipation and irritable bowel syndrome (3:50). Ferguson asserts that altered autonomic nervous system response to stress in autism is linked to these conditions. The speaker outlines the autonomic nervous system (ANS), which controls smooth muscles like those used in breathing and digestion. The ANS is composed of the parasympathetic (PYM) (i.e., rest and digest) and the sympathetic (SYM) (i.e., fight, flight, freeze) branches. Ferguson explains that our bodies strive for a balance between these two systems (7:16). He emphasizes that intestine function is inhibited when the SYM is activated and posits that this could be why individuals with high-stress responses are often constipated (6:40). Ferguson presents numerous studies supporting the assertion that ANS imbalances are associated with GI and behavior difficulties in autism. 

Study 1: GI and stress relationship in autism

This study correlated stress response scores with GI issues in autistic children and adolescents. Baseline cortisol (stress hormone) levels were compared to levels after participants dipped their hands in cold water. They correlated this stress response to GI problems and found that Lower GI issues (e.g., abdominal pain and constipation) positively correlated with cortisol levels (8:12). The study also found a positive correlation between Upper GI issues and inflammation (10:00). Ferguson states that these results suggest that autistic individuals with lower GI issues will likely have high cortisol response to stressors (9:40). 

Study 2: Psychophysiological associations

The presenter explains that heart rate variability (HRV) measures the balance between the PYM and SYM. This study correlated HRV scores with Lower GI issues in autistic children and adolescents. Findings showed HRV response to stressors is much higher than average in autistic individuals who have anxiety. The same relationship exists between regressive autism and HRV (12:00). Ferguson therefore asserts that co-occurring anxiety disorders or regressions in autism alter the relationship between the PYM and the GI tract. This transformed relationship, he continues, is likely the cause of many GI issues in autism (13:05). 

Study 3: GI problems, problem behavior, and internalizing symptoms in autism

This study aimed to look at the relationship between GI problems, problem behaviors, and internalizing symptoms (e.g., anxiety) in autism. The speaker outlines study methods (14:11) and explains how they correlated scores across two age groups (15:43). Results showed that overall, younger children (ages 2 – 5) have more dietary problems than the older group (ages 6 – 18). However, for both groups, the following data was presented (16:30):

• 65% experienced constipation
• 50% experienced stomach aches or pain
• 29% experienced diarrhea
• 23% experienced nausea
• 93% were not taking GI medication
• 53% were taking medications for other reasons (ADHD, aggression)

The study also assessed whether or not GI symptoms predict internalizing or externalizing symptoms (i.e., anxiety or problem behaviors) (18:44). Researchers found that the younger children acted out more with aggression while the older group had more internalized symptoms. This relationship, he continues, is compounded when an individual is minimally or non-verbal (20:20). Ferguson therefore asserts that GI issues must be addressed in this population, especially in those with communication difficulties (21:44). 

Study 4: Electrodermal activity and problem behaviors in autism 

Electrodermal activity, or sweating, is an indicator of stress. This study aimed to see if sweating predicts problem behaviors (22:45). Participants wore sweat monitors, and researchers observed their behaviors in an educational setting (26:00). Results showed (27:10) that there is a rise in skin conductance lasting an average of about 10 minutes leading up to problem behaviors (29:45). This change in conductance is called the anticipatory rise, and it occurred before problem behaviors in 60% of observations (28:30). Ferguson posits that this anticipatory rise is likely the result of discomfort or pain and that it presents an opportunity for caretakers to intervene in the stress response. He outlines two clinical trials using propranolol to treat anxiety (31:15) and constipation (35:10).

Study 5: Effects of propranolol on the relationship between GI issues and amygdalar reactivity

The amygdala is a part of the central nervous system responsible for ANS activation. This study examined the effect of three medications on amygdalar response to emotional faces using fMRI technology (36:20). Participants took three 12-day sessions of different medications: placebo, nadolol, and propranolol. Propranolol is the only one known to penetrate the blood-brain barrier. At the end of each session, participants completed a face-matching task to activate the amygdala (39:00). Researchers correlated GI issues to fMRI results. They found that with the first two medications (placebo and nadolol), there was a statistically significant positive relationship between GI symptoms and amygdalar activity. Contrastingly, after 12 days of propranolol, there was no relationship between GI symptoms and amygdalar activity (40:14). Therefore, Ferguson posits that GI stress is related to the central nervous system. He notes the limitations of this study (42:10). 

What’s next?

The presenter describes Transcutaneous Vagus Nerve Stimulation (tVNS) and its potential in treating atypical PYM activation and GI issues in autism. tVNS is a small device that fits in the ear and stimulates the vagus nerve, which is part of the PYM (rest and digest) system. This stimulation helps the body calm down (43:00). Ferguson underscores the difference between blocking SYM activity (i.e., propranolol) and stimulating the PYM (tVNS). He summarizes the presentation and reiterates that GI issues in autism are often associated with an enhanced stress response. This is particularly true for Lower GI issues like constipation. GI symptoms, he continues, have also been associated with internalizing symptoms (i.e., anxiety) and problem behaviors. Stress response activation may often proceed problem behaviors in autism, and much more research is needed on new treatment strategies. Ferguson provides thanks and acknowledgments before the Q&A.