Elucidating the Gut-Brain Axis
Regina Kelder

Elucidating the Gut-Brain Axis

Symposium delves into the latest research about how the immune system and inflammatory responses might be driving diseases of the brain

The human brain contains 100 billion neurons—with 100 trillion connections.  It also contains immune cells, a surprise to anyone who might have thought, i.e. me, that this “mental” organ was divorced from the rest of the body.

How immune cells cross-communicate with the brain is a complicated and complex puzzle that researchers haven’t fully solved. Three years ago, researchers from the University of Virginia’s School of Medicine in Charlottesville discovered a central nervous system lymphatic pathway able to carry both fluid and immune cells from the cerebrospinal fluid. The pathways are connected to the deep cervical lymph nodes.

While these findings helped to shed new light on the causes of neuroinflammatory and neurodegenerative diseases associated with immune dysfunction, there has also been a real renaissance in studying potential links between the immune system and brain health, including CNS diseases like Alzheimer’s and Parkinson’s not typically associated with immune dysfunction.

“The idea that the brain is an immune-privileged organ has gone out the window,” said Malu Tansey, PhD, Professor of Physiology & Director of Center for Neurodysfunction & Inflammation at the Emory University School of Medicine.

Dr. Tansey, an expert in Parkinson’s disease, was the keynote speaker at a June 13 symposium, Neuroinflammation: Advancing Therapies for Neurological Disease, sponsored by Charles River Laboratories. 

The talks, in different ways, focused on different ways of countering the consequential effects of inflammation that are triggered by jazzed up or unresponsive components of the immune system. One talk examined more effective ways of targeting the adaptive immune system in patients with multiple sclerosis, another looked at how we can inhibit an innate immune signaling receptor involved in the assembly of inflammasome protein complexes—which ordinarily helps protects us from pathogens but can also spring into action when there is not threat, with disastrous results.

There was also a panel discussion centered on the role of the gut microbiome in brain function and neuroinflammation, and a heartbreaking talk about a rare disease, called Multiple System Atrophy (MSA), that appears to be linked to neuroinflammation. (Proceeds from Charles River symposium were donated to the Multiple System Atrophy Coalition, which assists researchers in finding a cure and provides support to patients and caregivers.)

If there was a common thread among all of these talks it was that better drugs are needed for diseases of the central nervous system, and that inflammatory processes in the brain and spinal cord, prominent in many of CNS conditions, are a good place to look.

Tansey’s lab, one of the first to suggest that intestinal inflammation could be the silent driver of Parkinson’s disease pathogenesis, began exploring this theory because constipation, dysbiosis and intestinal permeability—common features of people with the movement disorder—are also consistent with an inflammatory condition, as is increased levels of alpha-synuclein, the pathological hallmark of PD.

Tansey said the study, led by Emory graduate student Madelyn Houser, found elevated levels of  three inflammatory molecules—vascular endothelial growth factor receptor 1, interleukin-1α, and CXCL8—in the stool samples of PD patients compared to matched controls. Two of those—interleukin-1α and CXCL8—remained statistically significant even after accounting for potential confounding factors.

Tansey says there are other factors supporting the gut-brain connection. The kinase LRRK2, which has been genetically linked to development of PD and is now a hot therapeutic target by a number of labs, had much earlier been associated with Crohn’s disease and inflammatory bowel disease.

According to Tansy, it could be that infection or some other assault in the gut might trigger inflammatory responses that then upregulate levels of alpha-synuclein in surrounding nerve cells that are part of the enteric system.

“We are trying to define what causes alpha-synuclein aggregate so it can be used as a model for developing potential drugs that modulate it,” said Tansey.

Mirror-image diseases? Not quite

People with multiple system atrophy or MSA mimic many of the symptoms of people with PD—progressive gait imbalance, slurred speech and some cognitive impairment—so it’s not unusual for clinicians to misdiagnose.

But this rare disease—only about 1,900 cases are diagnosed yearly in the US—is quite distinct from PD, noted Vikram Khurana, MD, PhD, Chief of the Division of Movement Disorders at  Brigham & Women’s Hospital, which is developing treatments for both MSA and PD.

One of the biological differences, says Khurana, is where alpha-synuclein accumulates. In PD and Lewy Body dementia, it is brain neurons. In MSA, it is primarily in oligodendrocytes, which produce the myelin sheath that electrically insulates axons. Oligodendrocytes are also glia cells, which perform a role similar to that of the peripheral immune system, and can also contribute to exaggerated pain responses.

Khurana said there is now growing interest in how distinct proteins cause different conformations (variants) within different cells types and cause different diseases. “Maybe different strains, different conformations of alpha synuclein will lead to different diseases,” he said.

Khurana also noted that lysates from the brains of MSA patients look strikingly different from the lysed cells of people with PD or Lewy body dementia. Citing findings from University of Pennsylvania Virginia Lee’s group, Khurana said the glia cytoplasmic inclusions (GCIs) found in MSA appeared to be more successful at coaxing cells to take up toxic forms of the alpha synuclein proteins.

Khurana’s lab is developing alpha-synuclein maps within oligodendrocytes generated from MSA patient stem cells. They also plan to use MSA patient brain tissue to capture the distinct types of misfolded alpha-synuclein implicated in this disease.  The ultimate goal is to use the findings from these studies to better understand the mechanisms within distinct cell types of brain and hopefully find new targeted therapies for MSA.

Sadly, there are no disease modifying therapies for MDA, PD or Lewy body dementia, now. “But making a correct diagnosis early can greatly help clinical care and relieve anxiety of patients, said Khurana.