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.
How should doctors measure how messed up someoneâ€™s intestinal microbiome is?
This is the topic of a recent paper in American Journal of Infection Control from Colleen Kraft and colleagues from Emory and the Centers for Disease Control and Prevention. The corresponding author is epidemiologist Alison Laufer Halpin at the CDC.
A â€œmicrobiome disruption indexâ€ could inform decisions on antibiotic stewardship, where a patient should be treated or interventions such as fecal microbial transplant (link to 2014 Emory Medicine article) or oral probiotic capsules.
What the authors are moving towards is similar to Shannonâ€™s index, which ecologists use to measure diversity of species. Another way to think about it is like the Gini coefficient, a measure of economic inequality in a country. If there are many kinds of bacteria living in someoneâ€™s body, the disruption index should be low. If there is just one dominant type of bacteria, the disruption index should be high.
In the paper, the authors examined samples from eight patients in a long-term acute care hospital (Wesley Woods) who had recently developed diarrhea. Using DNA sequencing, they determined what types of bacteria were present in patients’ stool. The patientsâ€™ samples were compared with those from two fecal microbial transplant donors. Read more
Bacterial spores in capsules taken by mouth can prevent recurrent C. difficile infection, results from a preliminary study suggest.
Clostridium difficile is the most common hospital-acquired infection in the United States and can cause persistent, sometimes life-threatening diarrhea. Fecal microbiota transplant has shown promise in many clinical studies as a treatment for C. difficile, but uncertainty has surrounded how such transplants should be regulated and standardized. Also, the still-investigational procedure is oftenÂ performed byÂ colonoscopy, which may be difficult forÂ some patients to tolerate.
The capsule study, published Monday in Journal of Infectious Diseases, represents an important step in moving away from fecal microbiota transplant as a treatment for C. difficile, says Colleen Kraft, MD, assistant professor of pathology and laboratory medicine and medicine (infectious diseases) at Emory University School of Medicine.
Kraft and Tanvi Dhere, MD, assistant professor of medicine (digestive diseases) have led development of the fecal microbiota transplant program at Emory. They are authors on the capsule study, along with investigators from Mayo Clinic, Massachusetts General Hospital, Miriam Hospital (Rhode Island), and Seres Therapeutics, the study sponsor.
While this study involving 30 patients did not include a control group, the reported effectiveness of 96.7 percent compares favorably to published results on antibiotic treatment of C. difficile infection or fecal microbial transplant. Read more
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
AÂ Emory News item on a helpful part of the microbiome focuses on how the same type of bacteria â€“ lactobacilli â€“ activates the same ancient signaling pathway in intestinal cells in both insects and mammals.Â It continues a line of research from Rheinallt Jones and Andrew Neish on how beneficial bacteria stimulate wound healing by activating ROS (reactive oxygen species).
Asma Nusrat, MD
A idea behind this research is: if we know what parts of the bacteria stimulate healing, perhaps doctors can deliverÂ that material, or something very close, to patients directly to treat intestinal diseases such as Crohn’s or ulcerative colitis.
This ideaÂ has advanced experimentally, as demonstrated byÂ twoÂ papers from Jones and Neishâ€™s frequent collaborator, Asma Nusrat, who recently moved from Emory to the University of Michigan. This team had shown that a protein produced by human intestinal cells called annexin A1 activates ROS, acting through the same N-formyl peptide receptors that bacteria do.
Nusrat told me Friday her team began investigatingÂ annexins a decade ago at Emory, and it was fortuitous that Neish was working on beneficial bacteria right down the hall, since it is now apparent that annexin A1 and the bacteria areÂ activating the same molecular signals.Â (Did you know there is an entire conference devoted to annexins? I didn’t until a few days ago.)
In aÂ secondÂ Journal of Clinical Investigation paper published this February, NusratÂ and herÂ colleagues show that intestinal cells release vesicles containing annexin A1 following injury. The wound closure-promoting effects of these vesicles can be mimicked with nanoparticles containing annexin A1. The nanoparticles incorporate a form of collagen, which targets them to injured intestinal tissue. 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 studiesÂ of microbial byproducts of meatÂ 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.Â 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 Emoryâ€™s first microbiome symposium in November, organized by Jennifer Mulle (readÂ herÂ 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:Â ACTSI, Hercules Exposome Center, Emory University School of Medicine, Omega Biotek, CFDE, Ubiome. Read more
Alzheimer’s protein pathology
While a wise Dane once proposed that predictions are dangerous, especially concerningÂ the future, it’s usuallyÂ helpful to plan ahead. Here are five biomedical research topicsÂ we think will occupy our attention in 2015.
1. Alzheimer’s Weâ€™re hearing discordant music coming from Alzheimerâ€™s researchers. Large pharmaceutical companies are shutting down clinical trials in frustration, but researchers keep coming forward with biomarkers that mightÂ predict future disease. This confusing situation calls for some new thinking. Allan Levey, Jim Lah and colleagues have been preparing the way for a â€œbeyond the usual suspectsâ€ look at Alzheimerâ€™s disease. We are looking forward to Leveyâ€™s appearance at the 2015 AAAS meeting and to drug discovery wizard Keqiang Yeâ€™s continuing work on new therapeutic targets.
2. Ebola While the scare over Ebola in the United States may be over (we hope so!), the outbreak continues to devastate countriesÂ in West Africa. Clinical trials testingÂ vaccines and experimental drugs are underway or will be soon. Read more