Gut-Immune System-Brain Axis and Neuropsychiatric Disorders

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A recent review highlights burgeoning research pointing to the interplay of the gut, immune system, and brain in the development of neuropsychiatric disorders.¹

While research suggests that genes probably lie at the root of many neuropsychiatric disorders, not everyone who is genetically susceptible develops these diseases. Recent research points to the gut-immune-brain axis as a trigger for these disorders in susceptible individuals. Environmental factors, like bacteria, certain foods, psychosocial issues, pesticides and other environmental toxins-may also influence the gut-immune-brain axis.

In the review, authors Shannon Delaney, MD, and Mady Hornig, MD, of Columbia University Medical Center (New York, NYC), discussed recent evidence about environmental and immune contributions to neuropsychiatric disease, as well as the role of the microbiome.

The Role of the Microbiome
Studies suggest that changes in the gut microbiome may trigger autoimmunity against the CNS, contributing to the development of neuropsychiatric disorders. Evidence consistently shows increased levels of inflammatory cytokines associated with various disorders, including psychosis, bipolar disorder (BPD), post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), and depression.

Changes in the type and quantity of gut bacteria may be involved. Decreased diversity of certain gut bacteria have been linked to ASD, BPD, depression, and chronic fatigue syndrome. Studies in patients with schizophrenia (SCZ) have focused on the oropharyngeal microbiome. These, too, have found decreased diversity.

The gut microbiome is dynamic. Ingested items, like foods, pesticides and drugs, can harm or benefit it. For example, research suggests the Mediterranean Diet may protect against depression, while the Western diet may increase the risk for depression.

Intestinal Barrier Compromise
While mechanisms remain unclear, studies suggest that imbalances in the microbiome may contribute to gut inflammation and intestinal barrier compromise, termed “leaky gut.” Gut bacteria play an important role in maintaining the integrity of the gut wall. They also make compounds like lipopolysaccharides (LPS), which can gain access to the circulation when the gut wall is leaky. Once inside the circulation, LPS’s may trigger an immune response that can influence the nervous system. Neuropsychiatric diseases linked to increased levels of LPS include major depressive disorder (MDD) and chronic fatigue syndrome. Antibodies against LPS have been found in SCZ.

The Immune System as a Bridge
But it’s probably not just about changes in the microbiome. Research points to a bidirectional relationship between the gut and the brain, with the immune system acting as a bridge.

Evidence suggests immune cells can use neurotransmitters to communicate with cells in the nervous system, and that nerve cells may have surface receptors that receive these signals. Nerve cells may also produce a wide range of immune molecules themselves, while immune cells probably release neurotransmitters.  For example, T cells likely release serotonin, norepinephrine, dopamine, and acetylcholine. Gut bacteria have also been shown to make neurotransmitters.

Research also points to a role for the vagus nerve. Studies in mice suggest that probiotics may decrease anxious behavior, but the vagus nerve may be necessary to transmit the signal from the brain to the CNS.

Changes in the gut microbiome and altered gut permeability may also affect the blood brain barrier. Animal studies show that LPS, pathogens, and inflammatory cells can all cross the blood brain barrier. Alterations in the blood brain barrier have been found in a number of neuropsychiatric disorders, and are central to the pathogenesis of AD and MS.

(Please click “next” for the role of probiotics, precision medicine, and Take Home Points)

The Role of Probiotics
Clinical trials point to potential benefits of probiotics in neuropsychiatric disorders, although the jury is still out on which bacteria, or which combination, are likely to produce the most benefit.

Some evidence points to a potential role for Lactobacillus and Bifidobacterium. One study in 75 infants treated for 6 months with Lactobacillus rhamnosus GG showed a significantly decreased incidence of Asperger’s disorder and ADHD at age 13, compared to placebo. The study also found that the children who developed these disorders had lower levels of Bifidobacterium in their stool during the first 6 months of life.2 Studies in SCZ and BPD, however, have failed to find a benefit with Lactobacillus and Bifidobacterium.

The Future: Paving the Way for Precision Medicine
Continued research into the gut-immune-brain axis may provide an opportunity for precision medicine that can identify environmental triggers as well as tailored interventions for changing the gut microbiome and treating neuropsychiatric disorders.

“Environmental modifications involving diet, pre- and probiotics, and microbiota-based interventions (eg, fecal microbiota transplantation) may serve as conduits through which therapeutic influences may be exerted on the composition of the gut microbiome; subsequently, beneficial gut microbiome changes may mitigate neuropsychiatric manifestations through regulation of immune, metabolic, and neural signaling pathways,” the authors concluded.

Take Home Points
• Review article highlights research suggesting that the gut-immune-brain axis may contribute to the development of many neuropsychiatric disorders
• Alterations in the gut microbiome may trigger autoimmunity against the CNS, contributing to the development of neuropsychiatric disorders
• Imbalances in the gut microbiome may contribute to leaky gut, which may contribute to inflammatory responses that influence the CNS
• Research points to a bidirectional relationship between the gut and the brain, with the immune system acting as a bridge
• Further research is needed into environmental modifications that may contribute to precision medicine aimed at the gut-immune-brain axis

References:

1. Delaney S, Hornig M, et al. Environmental Exposures and Neuropsychiatric Disorders: What Role Does the Gut-Immune-Brain Axis Play? Curr Environ Health Rep. 2018 Feb 8.
2. Partty A, Kalliomaki M, Wacklin P, et al. A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial. Pediatr Res. 2015;77:823–828.