Bacteria in the intestines – collectively termed the gut microbiome – may affect the course of amyotrophic lateral sclerosis (ALS), the progressive, incurable neurological disease also known as Lou Gehrig’s disease.
Researchers at the Weizmann Institute of Science in Rehovot have shown this in mice and reported their findings in the prestigious journal Nature. The progression of an ALS-like disease was slowed after the mice received certain strains of gut microbes or substances known to be secreted by these microbes. Preliminary results suggest that the findings on the regulatory function of the microbiome may be applicable to human patients with ALS.
Also known as motor neurone disease, it is known as Lou Gehrig’s disease among the North American public because in 1941, it killed Lou Gehrig, the famed New York Yankees baseball team’s first baseman at the age of 37. The cause is not known in the vast majority of cases, but is believed to involve both genetic and environmental factors.
The disease, which can affect adults of any age, causes the death of neurons controlling voluntary muscles. The initial symptoms are stiff muscles, muscle twitching and gradually worsening weakness due to arms and leg muscles decreasing in size. There is also difficulty speaking or swallowing,, and about half of victims develop at least mild difficulties with thinking and behavior and most people experience pain. Most eventually lose the ability to walk, use their hands, speak, swallow and breathe.
“Our long-standing scientific and medical goal is to elucidate the impact of the microbiome on human health and disease, with the brain being a fascinating new frontier,” explained Prof. Eran Elinav of the institute’s immunology department. His team performed the study together with that of Prof. Eran Segal of the computer science and applied mathematics department.
“Given increasing evidence that the microbiome affects brain function and disease, we wanted to study its potential role in ALS,” noted Segal. The study was led by postdoctoral fellows Drs. Eran Blacher and Stavros Bashiardes, and by staff scientist Dr. Hagit Shapiro, all in the Elinav lab. They collaborated with Dr. Daphna Rothschild, a postdoctoral fellow in Eran Segal’s lab, and Dr. Marc Gotkine, head of the motor neuron disease clinic at the Hadassah University Medical Center, as well as with other scientists from Weizmann and elsewhere.
The scientists started out demonstrating in a series of experiments that the symptoms of an ALS-like disease in transgenic mice worsened after these mice were given broad-spectrum antibiotics to wipe out a substantial portion of their microbiome. The scientists also found that growing these ALS-prone mice in germ-free conditions (in which, by definition, mice carry no microbiome of their own), is exceedingly difficult, as these mice had a hard time surviving in the sterile environment. Together, these results hinted at a potential link between changes in the microbiome and accelerated disease progression in mice that were genetically susceptible to ALS.
Next, using advanced computational methods, the scientists characterized the composition and function of the microbiome in the ALS-prone mice, comparing them to regular mice. They identified 11 microbial strains that became altered in ALS-prone mice as the disease progressed or even before the mice developed overt ALS symptoms. When the scientists isolated these microbial strains and gave them one by one – in the form of probiotic-like supplements – to ALS-prone mice following antibiotic treatment, some of these strains had a clear negative impact on the ALS-like disease. But one strain called Akkermansia muciniphila significantly slowed disease progression in the mice and prolonged their survival.
To reveal the mechanism by which Akkermansia may be producing its effect, the scientists examined thousands of small molecules secreted by the gut microbes. They zeroed in on one molecule called nicotinamide (NAM): Its levels in the blood and in the cerebrospinal fluid of ALS-prone mice were reduced following antibiotic treatment and increased after these mice were supplemented with Akkermansia, which was able to secrete this molecule.
To confirm that NAM was indeed a microbiome-secreted molecule that could hinder the course of ALS, the scientists continuously infused the ALS-prone mice with NAM. The clinical condition of these mice improved significantly. A detailed study of gene expression in their brains suggested that NAM improved the functioning of their motor neurons.
Finally, the researchers examined the microbiome and metabolite profiles of 37 human ALS patients and compared them to those of family members sharing the same household. A detailed genomic analysis suggested that the gut microbiomes of ALS patients were distinct in composition and functional features from those of healthy controls. In particular, numerous microbial genes involved in the synthesis of NAM were significantly suppressed in ALS patients. An analysis of thousands of small molecules in the blood also disclosed a distinct pattern in ALS patients as compared to the control group.
Here too, many of the intermediary molecules involved in the NAM synthesis were altered in the blood of ALS patients. When the researchers tested the levels of NAM itself, they found these to be significantly reduced in both the blood and the brain of 60 human ALS patients as compared to controls. Moreover, there was a correlation between reduced NAM levels and the degree of muscle weakness in the patients.
“These findings are only a first step towards achieving a comprehensive understanding of the potential impact of the microbiome on ALS,” Elinav concluded, “but they suggest that in the future, various means of altering the microbiome may be harnessed for developing new therapeutic options for ALS.”