In multiple sclerosis (MS), the immune system attacks the nervous system, causing nerve and brain damage. Yet the problem might actually originate in another place entirely: the gut. Yale researchers are among those teasing apart how MS and other autoimmune diseases may arise as a result of complex interactions among genes; the intestines’ ability to maintain a tight boundary between its contents and the rest of the body; and the bacteria that live there.
To begin with, genetic mutations in MS “lead to changes in the interactions between the immune system and the microbiome in the gut,” says David A. Hafler, MD, the William S. and Lois Stiles Edgerly Professor of Neurology and professor of immunobiology.
A renowned researcher responsible for a number of seminal discoveries in MS, Hafler was first to describe the immune cells that attack myelin in the nervous system. He has also identified MS-specific genetic variants—most of them related to immune genes—and unraveled signaling pathways that make potential targets for drug treatment. In 2013, he and his colleagues published the landmark discovery that sodium chloride can lead to autoimmunity in MS. He is preparing papers for Science and Cell that map out the disease’s genetic architecture, a culmination of almost two decades’ work.
Hafler is among a group of scientists who are uncovering genetic clues linking MS to the gut. In 2011, he co-authored a paper listing scores of culprit MS genes, one called INAVA, whose products show up in the gut. Researchers recently found that INAVA also plays a key role in Crohn’s disease—a type of inflammatory bowel disease (IBD) that often accompanies MS. In a March 2018 paper in Science, a team at the Broad Institute of MIT and Harvard reported that the INAVA variant seems to loosen the integrity of the intestinal barrier, rendering it permeable to molecules that shouldn’t be able to pass through.
That phenomenon is sometimes called “leaky gut.” Findings like the Broad team’s hint at the importance of the gut lining to autoimmune disease. The digestive tract is lined by epithelial cells that are tightly connected to one another, forming a barrier between the food being digested and the bloodstream. Abnormal permeability of that layer has been observed in people with IBD, as well as in mice suffering from a version of MS.
Though leaky gut has become a popular scapegoat in complementary medicine circles for everything from autism to acne, it likely constitutes a real link to inflammation, says Noah Palm, PhD ’11, FW ’15, assistant professor of immunobiology, who studies the links between autoimmune disease and the gut microbiome. His lab explores how communities of gut bacteria may influence not only the immune system, but also neurodevelopmental disorders like autism.
“There’s a lot of suggestive evidence in the literature that at least some sort of barrier disruption co-occurs with a lot of these [autoimmune] diseases,” Palm says.
Leaky gut seems to arise in a number of ways. In some cases, bacteria may drill down to the barrier and loosen it directly, Palm says.
Chronic high blood sugar can also do it, according to a team led by former Yale postdoctoral associate Eran Elinav, MD, PhD, now at Israel’s Weizmann Institute of Science. Elinav’s group linked leaky gut to obesity and to type 1 diabetes, an autoimmune disease, in a March 2018 paper in Science.
When the gut’s barrier comes down, it can let in bad actors. In genetically susceptible mice, certain bacterial species can traverse the intestinal barrier; travel to the liver and lymph nodes; and trigger a lupus-like autoimmune disease, according to a group led by Martin Kriegel, MD, PhD, FW ’06, adjunct assistant professor of immunobiology at the School of Medicine. The team members, who found the same bacteria in liver biopsies of human patients with lupus, also published their results in a March 2018 issue of Science.
There’s strong evidence to suggest that bacteria are central to what goes wrong in MS and other autoimmune diseases.
“One of the things that we’re doing very intensively is looking at the microbiome in MS,” Hafler says. “We and others have found that there are clearly abnormalities.”
For instance, MS patients have a lower-than-normal abundance of Lactobacillus species—the kind found in yogurt—and a higher abundance of Ruminococcus, a group of bacteria that can break down resistant starches. Exactly how such differences translate into disease is still unclear. But in mouse models of MS, inflammatory cells involved with the disease have been observed to be influenced by gut bacteria.
Moreover, a microbiome “transplant” from MS patients into mice can actually provoke MS-like symptoms, according to two papers appearing last fall in Proceedings of the National Academy of Sciences. The patients’ bacteria seem to alter immune T cells’ behavior in the mice, leading to a type of encephalitis similar to MS.
Bacteria also seem to influence brain cells. Tryptophan is an essential amino acid found in protein-rich foods like meat, oats, and peanuts. It is converted in the body into the neurotransmitter serotonin and the sleep-related hormone melatonin. But in a March 2018 paper in Nature, a multinational group of researchers reported that molecules from bacteria that metabolize tryptophan were also controlling microglia cells in the brain that can stimulate astrocytes to produce an MS-like disease in mice. Such bacterial influence, the authors suggested, may help explain why problems with the gut microbiome can impair recovery from spinal cord injury—and why certain other species seem to help recovery instead.
“The most important questions are: What is the microbiome? And what metabolites is it making in relation to the genetic architecture of the individual?” Hafler says. “That’s what I think it comes down to.”