On September 13, 2018, the 24th session of the UW School of Medicine and Public Health’s Mini Med School, which offers three public talks per year about medical research and clinical breakthroughs at UW-Madison, brought more than 600 people to campus to hear about improving digestive health. Four speakers covered different areas of gastroenterology and hepatology.
Freddy Caldera, DO, assistant professor (CHS), Gastroenterology and Hepatology, described his research on optimizing vaccine schedules for people living with inflammatory bowel disease who are undergoing immunosuppressive therapy. Richard Halberg, PhD, associate professor, Gastroenterology and Hepatology, recounted his efforts to use mouse models of colon cancer to advance precision medicine approaches for treating cancer. John Rice, MD, assistant professor (CHS), Gastroenterology and Hepatology, explained how the obesity epidemic is leading to a subsequent epidemic in non-alcoholic fatty liver disease, and steps that individuals and populations can take to reduce the rates of liver cancer. And Nasia Safdar, MD, PhD, professor, Infectious Disease and vice chair for research, discussed her research on treating Clostridium difficile (C diff) infections using fecal microbiota transplants. Introducing each speaker was "master of ceremonies" Michael Lucey, MD, professor and head, Gastroenterology and Hepatology.
Series co-founder Richard Page, MD, George R. and Elaine Love Professor and chair, Department of Medicine, presided for a final evening. He was presented with an honorary “graduating diploma” for Mini Med School by Dean Robert Golden, MD, who explained to attendees that Dr. Page will soon be dean of the Larner College of Medicine at the University of Vermont. “We are going to miss Rick so dearly. He's been a remarkable leader, a remarkable colleague, and a remarkable friend,” said Dr. Golden, prior to inviting Dr. Lucey to the podium to begin the lectures.
Optimizing Immunization Regimes for Adults with IBS
Inflammatory bowel disease (IBS) is a not a single disorder; rather, it is a group of disorders that all involve ongoing inflammation of the digestive tract. Dr. Caldera described the two primary categories: ulcerative colitis, which affects the colon only, and Crohn’s disease, which can affect the entire gastrointestinal tract. “These conditions are probably caused by the immune system acting against the body’s own intestinal tissue,” explained Dr. Caldera. The conditions are common, affecting between 3 and 4 million Americans and resulting in 70,000 new cases each year.
While genomic studies have identified 163 genes that are associated with IBD, the conditions are not strictly hereditary; most people with IBD-associated alleles (gene versions) do not end up having ulcerative colitis or Crohn’s disease. It’s more likely, said Dr. Caldera, that there is an interconnection between environmental conditions and genetic susceptibility that sets the stage for IBD. When the immune response generates intestinal inflammation, there’s a tipping point. “Inflammation occurs, and once it happens you can’t go back,” he said, emphasizing that these are chronic diseases.
If not brought under control, ulcerative colitis can cause rectal bleeding, diarrhea, abdominal pain, incontinence, anemia, and can even lead to colorectal cancer and bowel perforations. Crohn’s disease can cause many similar complications, as well as intestinal obstructions, infections (abscesses), sections of narrowed intestines (strictures), and abnormal connections between the gut and surrounding organs (fistulas).
Since these are autoimmune disorders, a successful treatment strategy has been to dial down the immune response by using immunosuppressive drugs. “This really changes how the disease behaves, and the majority of patients can lead a normal life. That's the goal: we want to keep patients safe, in remission, and feeling well. But there is a price: the risk of infection goes up,” said Dr. Caldera. This means that adults taking medication to treat their IBD face higher rates of communicable diseases such as pneumonia, influenza, and shingles (which is caused by varicella – the chicken pox virus).
Dr. Caldera and his colleagues began to investigate whether the adult vaccination schedule could be optimized for people with IBD to reduce these risks. Recent clinical studies indicate that this can indeed be a helpful approach. “We've found that patients with IBD don't respond to the regular flu vaccine, and we showed that high-titer influenza vaccine was beneficial,” he said. Similarly, he is investigating whether adults with IBD may be helped by pertussis vaccination boosters every 10 years and by starting shingles vaccinations at an earlier age than those without IBD. “Crohn’s disease and ulcerative colitis are serious diseases, but they are treatable, and we are focusing on ways to prevent infections that can occur as a complication of being on immunosuppressants,” he said.
Research on Mice Allows Clearer Understanding of Human Colon Cancer
Dr. Halberg’s unwavering focus on colon cancer is driven by the enormous impact of the disease. As the second-leading cause of cancer death in the United States, approximately 150,000 people are diagnosed with colon cancer each year. There’s a big problem with current standard treatment options of surgery and chemotherapy with fluorouracil, though. “Half of the people who receive this treatment won’t be cured, and we don’t know beforehand who will be cured and who won’t be,” said Dr. Halberg.
To illustrate why, Dr. Halberg draws a comparison between tumor cells and different models of cars. While all car types have common features like tires, bumpers, doors, and windshields, the shapes and styles are entirely different – ranging from a Model A Ford to a Volkswagen Beetle. “Just like cars, colon cancer is not just one disease. Just like cars, there are many makes and models. We call them subtypes,” he said.
By creating mouse lines that harbor each of four different subtypes of colon tumor cells – or a combination of subtypes – the Halberg lab has been able to study responses to different chemotherapy drugs in living mice. In the process, they disproved a theory that had been believed for over a century. “For over 100 years, scientists had said that cancers come from a single cell. We were able to show that ‘mixed cancers’ exist – in other words, that some tumors can be derived from multiple rogue cells, disproving an enduring theory in biology,” said Dr. Halberg. Importantly, his group also showed that mixed tumors do not respond to a drug that only affects one of the subtypes present in the tumor. When combined together, the subtypes provide a protective effect for each other.
“These animal studies inform us about personalized medicine. You have to target all the cells in a tumor, and you have to know what the structure of the tumor is,” he said.
When Fat Leads to Scars
Rapidly rising rates of obesity in the United States over the past 30 years has captured public attention, but there is an accompanying consequence that is less-recognized. Fatty liver, explained Dr. Rice, is exactly what it sounds like: the accumulation of fat droplets in hepatocytes (liver cells). Metabolic syndrome - which is a threatening combination of high cholesterol, insulin resistance, obesity, and hypertension – is associated with several health complications, including non-alcoholic fatty liver disease (NAFLD).
The condition isn’t trivial. “Fat deposition in the liver can lead to inflammation, which over time can result in scarring of the liver - which is called cirrhosis,” said Dr. Rice. While cirrhosis of the liver is often provoked by alcohol use, in the case of NAFLD, it’s lipid that takes down the liver. “And the scary thing is that the early stages of developing cirrhosis are asymptomatic,” he said. The upward trend in NAFLD is now so pronounced that fatty liver is now the most common cause of liver cancer, and has surpassed hepatitis C as the main cause of liver transplantations.
There is a remarkably effective treatment, though – one has an astounding success rate. It’s also highly accessible and doesn’t even require a prescription. “The cornerstone treatment for fatty liver is a healthy diet and regular exercise,” said Dr. Rice. “Weight loss via dietary restriction of caloric intake and regular exercise can lead to improvement in liver blood tests, decreased liver inflammation and injury on liver biopsy, and improved insulin sensitivity.”
The challenge is that many people with early-stage fatty liver disease are not easily persuaded to change lifestyle habits, because the disease is asymptomatic at this stage. But the data on effectiveness are clear, and the investment in adopting a healthy lifestyle is demonstrably worthwhile – because for NAFLD, there is no other option. “There are no FDA-approved treatments for NAFLD or nonalcoholic steatohepatitis (NASH),” said Dr. Rice. And because people with NAFLD are also at high risk for heart disease, diabetes, kidney disease, and sleep apnea, addressing obesity is a tremendously efficient strategy for reducing the incidence of all of these disorders at once.
The Importance of Balance: Gut Microbiota in Health and Disease
“We are more bacterial than we are human. I think that's worth chewing on for a little bit, don't you?,” queried Dr. Safdar, who explained that the number of bacterial cells inside our body – primarily in the colon – is ten-fold higher than the number of human cells. “Gut bacteria have one role: to defend us from insults that come into our body. Any imbalance in the normal, harmonious relationship between bacteria and humans may result in illness and disease,” she said.
Our understanding of the specific roles of gut bacteria is still at an early stage, but recent studies have shown that there are clear differences in the population of microbes in the gut at different stages of life, and under different dietary practices. Formula-fed infants and breast-fed infants, for example, have markedly altered populations of gut bacteria, as do non-obese and obese adults.
Studying microbes in the intestine and colon has been technically challenging in laboratory settings. “Most gut bacteria are very difficult to culture. it's only been in the last couple of decades that we have developed molecular techniques to determine what actually exists within the tract, and now that we know they exist, we are beginning to find out what they do,” said Dr. Safdar.
One bacterial species that is particularly challenging to culture also happens to be an organism that is not at all desirable to host: Clostridium difficile, often called C diff, named for the difficulty with which it is grown in the lab. Ironically, however, its spores are extremely hard to kill. Highly concentrated bleach solutions are somewhat effective, but the spore is resistant to nearly all other disinfectants. Combating C diff contamination is exceptionally challenging, and people who have been treated with antibiotics are susceptible to infection because the treatment eradicates many of the beneficial bacteria in the gut, giving C diff an opportunity to take over.
For this reason, C diff infections are one of the most common hospital-associated infections. Half a million new cases occur each year in the United States. C diff infection leads to debilitating bouts of diarrhea, and even when it resolves, the infection recurs in nearly one-third of patients - resulting in suffering and a major impact on quality of life. It also causes 29,000 deaths per year.
Studying the gut microbiota profile of healthy people, patients with a single occurrence of C diff infection, and patients with recurring C diff infection showed that C diff causes tremendous imbalance and disturbance in patterns of microbes that reside in the gut. “This gives us an idea for therapeutic manipulation. Fecal microbiota transplant, or FMT, means taking healthy stool from a donor and putting it into the intestine of a C diff patient. Nothing else seems to work, but this does,” said Dr. Safdar.
In fact, the cure rate is astounding. Treating C diff infection with an antibiotic called vancomycin works 30 percent of the time. In contrast, FMT works between 81 percent and 94 percent of the time. And there is an increasing emphasis on identifying FMT donors, although the criteria are so rigorous – donors must not be taking any medications, have any chronic diseases, or have any infectious diseases – that only 2 percent of prospective donors are accepted.
Wryly, Dr. Safdar concluded by stating the benefits of FMT as a therapeutic option. “For this drug, there is no production shortage. And there is no potential for addiction.”
- "Mini Med School - A Matter of Timing: Atrial Fibrillation and Arrhythmias," Department of Medicine, October 5, 2017
- "Mini Med School - Tools to Improve Communication Between Physicians and Patients," Department of Medicine, June 16, 2017
Photo credits: Clint Thayer/Department of Medicine