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3 2 | L O U I S V I L L E . E D U It is no small undertaking. The array of microbes inhabiting each individual and their relative popu- lations are unique and change over time, and each of the thousands of different organisms may play a different role in health and disease. Most of the bacteria that coexist with us are considered beneficial, including strains of Lactoba- cillus and Bifidobacterium, common citizens of gut microbiota. However, when the relative populations of microbes shift out of bal- ance, referred to as dysbiosis, harmful microbes that normally are controlled by competing bacteria can run amuck, leading to illness. Antibiotic medications can kill off these malicious bacteria, but they an- nihilate vital good bacteria as well. The sacrificed beneficial bacteria may not be missed at first, but when the body needs them to address other diseases, their absence becomes a problem. "You are cured of your infection, but the long-term consequences of destroying the useful bacteria become apparent when you are attacked by cancer or obesity. Then the influence starts showing up as a lack of immune response," said Venkatakrishna Jala, PhD, assistant professor in the Department of M&I. "It's like an ecology. Once one is eliminated, you may not see the effect immedi- ately, but in the long term, they may not grow back." Jala is investigating how metabolites produced by bacteria in the gut affect inflammatory bowel disease (IBD) and colon cancer, a disease that af- fects Kentuckians at a higher rate than any other state. His goal is to use metabolites called urolithins to repair damage to the intestinal barrier, or epi- thelial cells, in order to decrease inflammation that contributes to IBD and colon cancer and to increase the cancer's sensitivity to chemotherapeutic drugs, increasing the drugs' effectiveness. IBD, autoimmune diseases and many other dis- orders are the result of inflammation in the body. Inflammation can occur when epithelial cells are damaged, allowing bacteria or other contents of the intestines out into the body, or as the result of an imbalance in the bacteria and their metabolites that naturally cross the intestinal barrier and enter the bloodstream. Michele Kosiewicz, PhD, associate professor in the Department of M&I, is exploring how gut microbiota and gender are related to systemic lupus erythematosus, an autoimmune disease that predominantly affects women. "We know that the gut microbiota seems to have an influence on autoimmune diseases — on rheu- matoid arthritis and on type 1 diabetes," Kosiewicz said. "An imbalance between beneficial bacteria and pathogenic bacteria — specifically, a decreased Firmicutes- to-Bacteroidetes ratio — is associated with and may predispose people to au- toimmune and inflammatory disease." Working with mice in which the females are genetically programmed to develop lupus, Kosiewicz has determined that gut microbiota in young male and female mice are similar. However, once the mice are older — the age at which the females start to develop lupus — the males' microbiota changes. When Kosiewicz transplants microbes from the males to the females, the females do not develop the disease. She is working to determine what it is about the microbiota that protects the female mice with the transplanted microbiota from developing lupus and what role male and female hormones may play in microbiota populations. Her team has identified about 90 metabolites produced by gut microbes that differ in males and females. "It could be that one or more of those metabolites is having a protective effect in males, and could be used to prevent or treat the females," Kosiewicz said. UofL researchers also have linked malaria to gut microbiota. Nathan Schmidt, assistant professor in the Department of M&I, is investigating the gut mi- crobiota's impact on the level of sickness suffered from an infection by Plasmodium, the parasite that causes malaria. Schmidt has published research showing that gut microbes can affect the severity of malaria illness in mice, and is investigating how the bacteria modulate the response to the parasite. "We are hoping to determine which bacteria or metabolites are interacting to influence the sever- ity or lack of severity of illness in the individual," Schmidt said. "If we can identify the bacteria, it "You are cured of your infection, but the long-term consequences of destroying the useful bacteria becomes apparent when you are attacked by cancer or obesity."

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