An influential theory about the anatomical trajectory of Parkinson’s disease is getting a microbial boost. The idea, first proposed by neuroanatomist Heiko Braak in 2003, is that pathology and neurodegeneration start in the intestines and then travel to the brain. See this article in Scientific American for background.
Illustration showing neurons with Lewy bodies, depicted as small red spheres, which are deposits of aggregated proteins in brain cells
Timothy Sampson, in Emory’s Department of Physiology, was first author on a recent paper in eLife, which explores the idea that prion-like proteins produced by intestinal bacteria can accelerate the aggregation of similar proteins found in our cells. The findings suggest that interventions targeting intestinal bacteria could modulate neurodegeneration.
Sampson, a former Emory graduate student who did postdoctoral work in Sarkis Mazmaniam’s lab at Caltech, says he will continue the project here. He and his colleagues were looking at the interaction between a bacterial protein called Curli – involved in adhesion + biofilms — and the aggregation-prone mammalian protein alpha-synuclein, known as a main component of the Lewy body clumps seen in Parkinson’s. The experiments were in a mouse model of Parkinson’s neurodegeneration, in which human alpha-synuclein is overproduced.
Looking ahead, Sampson says he is interested in what signals from the microbiome may trigger, accelerate or slow synuclein aggregation. He’s also looking at where in the GI tract synuclein begins to aggregate, possibly facilitated by particular cells in the intestine, and whether the observations with alpha-synuclein hold true for other proteins such as amyloid-beta in Alzheimer’s.
Helpful intestinal bacteria may stimulate bone formation via butyrate, according to a recent paper in Immunity. Butyrate increases bone formation through its regulation of T cells, Emory researchers report.
The finding adds to evidence for beneficial effects of butyrate and other SCFA (short chain fatty acid) metabolites, which are produced by bacterial fermentation of fiber in the intestines.
Roberto Pacifici and colleagues had observed that probiotic supplements protected female mice from the loss of bone density occurring after ovary removal, a simulation of the hormonal changes of menopause. Probiotic bacteria could also stimulate bone formation in mice with intact ovaries, the researchers found.
The new Immunity paper shows how this effect is produced. The probiotic bacteria do not make butyrate themselves, but they encourage the growth of other Clostridum bacteria that do produce butyrate. Read more
Frank Anania, MD
Lots of people in the United States consume a diet that is high in sugar and fat, and many develop non-alcoholic fatty liver disease, a relatively innocuous condition. NASH (non-alcoholic steatohepatitis) is the more unruly version, linked to elevated risk of cardiovascular and metabolic diseases, and can progress to cirrhosis. NASH is expected to become the leading indication for liver transplant. But only a fraction of people with non-alcoholic fatty liver disease go on to develop NASH.
Thus, many researchers are trying to solve this equation:
High-sugar, high-fat diet plus X results in NASH.
Emory hepatologist Frank Anania and colleagues make the case in a recent Gastroenterology paper that a “leaky gut”, allowing intestinal microbes to promote liver inflammation, could be a missing X factor.
Anania’s lab started off with mice fed a diet high in saturated fat, fructose and cholesterol (in the figure, HFCD). This combination gives the mice moderate fatty liver disease and metabolic syndrome (see this 2015 paper, and we can expect to hear more about this model soon from Saul Karpen). Leaky gut, brought about by removing a junction protein from intestinal cells, sped up and intensified the development of NASH.
The authors say that this model could be useful for the study of NASH, which has been difficult to reproduce in mice.
The researchers could attenuate liver disease in the mice by treatment with antibiotics or sevelamer, a phosphate binding polymer that soaks up inflammatory toxins from bacteria. Sevelamer is now used to treat excess phosphate in patients with chronic kidney disease, and is being studied clinically in connection with insulin resistance.
In injured mouse intestines, specific types of bacteria step forward to promote healing, Emory scientists have found.Â One oxygen-shy type of bacteria that grows in the wound-healing environment,Â Akkermansia muciniphila, has already attracted attention for its relative scarcity in both animal andÂ human obesity.
An intestinal wound brings bacteria (red) into contact with epithelial cells (green). The bacteria can provide signals that promote healing, if they are the right kind.
The findings emphasize how the intestinal microbiome changes locally in response to injury and even helps repair breaches. The researchers suggest that some of these microbes could be exploited as treatments for conditions such as inflammatory bowel disease.
The results were published on January 27 inÂ Nature Microbiology.Â Researchers took samples of DNA from the colon tissue of mice after they underwent colon biopsies. They used DNA sequencing to determine what types of bacteria were present.
â€œThis is a situation resembling recovery after a forest fire,â€ says Andrew Neish, MD, professor of pathology and laboratory medicine at Emory University School of Medicine. â€œOnce the trees are gone, there is an orderly succession of grasses and shrubs, before the reconstitution of the mature forest. Similarly, in the damaged gut, we see that certain kinds of bacteria bloom, contribute to wound healing, and then later dissipate as the wound repairs.â€ Read more
At what point did the human microbiome become such a hot topic?
When it was shown that babies born by Cesarean section are colonized with different bacteria than those born vaginally? With the cardiovascular studies of microbial byproducts of meat digestion? With the advent of fecal transplant as a proposed treatment for Clostricium difficile infection?
The bacteria and other microbes that live within the human body are thought to influence not only digestive health, but metabolic and autoimmune diseases as well, possibly even psychiatric and neurodevelopmental disorders. The field is being propelled by next-generation sequencing technology, and Nature had to publish an editorial guarding against hype (a major theme: correlation is not causation).
At Emory, investigators from several departments are involved in microbiome-related work, and the number is expanding, and assembling a comprehensive list is becoming more difficult. Researchers interested in the topic are planning Emory’s first microbiome symposium in November, organized by Jennifer Mulle (read her intriguing review on autism spectrum disorders and the microbiome).
Microbial genomics expert Tim Read, infectious diseases specialist Colleen Kraft and intestinal pathologist Andrew Neish have formed an Emory microbiome interest group with a listserv and seminars.
Microbiome symposium sponsors: ACTSI, Hercules Exposome Center, Emory University School of Medicine, Omega Biotek, CFDE, Ubiome. Read more
Guest post from Courtney St Clair Ardita, MMGÂ graduate studentÂ andÂ co-author of the paper described. Happy Halloween!
In the past, reactive oxygen species were viewed as harmful byproducts of breathing oxygen, something that aerobic organisms just have to cope with to survive. Not any more. Scientists have been finding situations in humans and animals where cells create reactive oxygen species (ROS) as signals that play important parts in keeping the body healthy.
One example is when commensal or good bacteria in the gut cause the cells that line the inside of the intestines to produce ROS. Here, ROS production helps repair wounds in the intestinal lining and keeps the environment in the gut healthy. This phenomenon is not unique to human intestines. It occurs in organisms as primitive as fruit flies and nematodes, so it could be an evolutionarily ancient response. Examples of deliberately created and beneficial ROS can also be found in plants, sea urchins and amoebas.
Researchers led by Emory pathologist Andrew Neish have taken these findings a step further and identified the cellular components responsible for producing ROS upon encountering bacteria. Postdoctoral fellow Rheinallt Jones is first author on the paper that was recently published in The EMBO Journal. Read more
Pathologist Andrew Gewirtz and his colleagues have been getting some well–deserved attention for their research on intestinal bacteria and obesity.
Briefly, they found that increased appetite and insulin resistance can be transferred from one mouse to another via intestinal bacteria. The results were published online by Science magazine.
Previous research indicated intestinal bacteria could modify absorption of calories, but Gewirtz and his colleagues showed that they influence appetite and metabolism (in mice)
“It has been assumed that the obesity epidemic in the developed world is driven by an increasingly sedentary lifestyle and the abundance of low-cost high-calorie foods,” Gewirtz says. “However, our results suggest that excess caloric consumption is not only a result of undisciplined eating but that intestinal bacteria contribute to changes in appetite and metabolism.”
A related report in Nature illustrates how “next generation” gene sequencing is driving large advances in our understanding of all the things the bacteria in our intestines do to us.
Gewirtz’s laboratory’s discovery grew out of their study of mice with an altered immune system. The mice were engineered to lack a gene, Toll-like receptor 5 (TLR5), which helps cells sense the presence of bacteria.