Activating Bile Acid Receptor May Be Therapy Target for MG, Study Reports

Activating the bile acid receptor TGR5 was found to reduce the number of immune cells that secrete proinflammatory proteins, suggesting that this receptor may be a therapeutic target for people with myasthenia gravis (MG), a study reported. 

The study, “Modulation of immune responses by bile acid receptor agonists in myasthenia gravis,” was published in the Journal of Neuroimmunology. 

The chief cause of MG is antibodies that attack acetylcholine receptors (AChR) within the neuromuscular junction — the place where nerve cells connect with muscles.

Acetylcholine is a molecule released by nerve endings that binds to receptors on muscle cells’ surfaces, inducing muscle contractions. In MG, antibodies mistakenly block the receptors, impairing their function.

In addition to such antibodies, studies show that mechanisms regulating immune responses are impaired in MG, including defects in regulatory T-cells (Tregs) or regulatory B-cells (Bregs). Both Tregs and Bregs act to control immune responses by suppressing the action of other immune cells. 

Bile acids are produced at high concentrations in the large intestine to help dissolve dietary fat. Studies also have implicated bile acids as signaling molecules that interact with immune cell receptors — called TGR5 and FXR-alpha — that have been linked to inflammation as well as immunosuppressant activity.

The goal of this study, conducted by researchers at the University of Chicago, was to investigate whether the levels of TGR5 and FXR-alpha are altered in immune cells isolated from people with MG. The team also measured whether molecules that activate these receptors impact the activity of immune cells such as Tregs and Bregs.

Blood samples were collected from 19 adults with MG — eight men, 11 women, ages 18-79 — and 17 age- and sex-matched healthy individuals (controls). 

All patients tested positive for anti-AChR antibodies and were receiving pyridostigmine, an approved MG medication marketed under the brand name Mestinon, among others. Some patients also were taking additional immunosuppressants, including prednisone. Six participants had undergone a thymectomy and had their thymus surgically removed.

Compared with the healthy controls, the levels of TGR5 and FXR-alpha receptors from MG patients were higher only in cells known as monocytes — a type of white blood cell that can become either a macrophage that engulfs and digests microbes or a dendritic cell, a messenger cell important for immune system communication and function. 

Treatment of isolated immune cells with BAR-501, a molecule that activates the TGR5 receptor (agonist), led to a reduction in T-cells that secrete the immune signaling proteins IFN-gamma and TNF-alpha, both of which are associated with autoimmune diseases. 

In contrast, no effects were seen when cells were treated with an FXR-alpha activator, called OCA. 

In isolated B-cells, and before treatment with activators, the percentage of cells secreting a proinflammatory molecule, or cytokine, known as interleukin-6 (IL-6), tended to be higher in those from MG patients than controls. 

Treatment of immune cells from the healthy controls with BAR-501 or OCA decreased the number of IL-6 secreting cells, while only BAR-501 reduced the IL-6 cell count in immune cells isolated from MG patients.

“Collectively, these findings would argue against nonspecific effect of BAR [bile acid receptors] agonists on [immune cell] expression/production,” the researchers wrote. 

Before treatment, the number of Breg cells that suppress immune responses was reduced in MG patients compared with controls. BAR-501 reduced the numbers of Bregs in control cells but not in cells from the MG group. OCA did not affect the frequency of Bregs in either group. 

Finally, the secretion of the anti-inflammatory molecule interleukin-10 (IL-10) was blocked by BAR-501 and OCA in control cells, but not in cells isolated from people with MG. 

“We found that TGR5 is a more potent negative regulator of T cell cytokine response than [FXR-alpha] in both groups,” the scientists wrote. “In contrast, TGR5 and [FXR-alpha] agonists elicit distinct B cell responses in myasthenia compared to controls.” 

“We propose that TGR5 is a potential therapeutic target in myasthenia,” they concluded.