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Inflammatory Bowel Disease – A Condition of our Culture, or Cultures of our Condition?

By Allison Dostal, PhD

Gastrointestinal problems are one of the most common unpleasant issues that we all experience at some time or another. But what if your upset stomach wasn’t just a passing discomfort? What if severe abdominal pain, cramping, fatigue, and diarrhea became more of your norm and less of a passing annoyance? For more than 1.4 million Americans, these symptoms typify their experience with inflammatory bowel disease (IBD), a disorder characterized by chronic inflammation of the gastrointestinal (GI) tract. The specific cause (or causes) of IBD remain unknown, but one leading hypothesis is that the bacteria that inhabit our GI system – termed the gut microbiome – play a central role. In this post, we’ll take a closer look at this condition and highlight research aimed at elucidating the impact of the microbiome in IBD development, progression, and treatment.

Characteristics, Diagnosis, and Treatment of IBD

Inflammatory bowel disease is unique in that its symptoms vary from person to person, and an individual’s own experience with their condition can differ markedly from another affected person. Most people are diagnosed with one of the two most common types of IBD, which are ulcerative colitis (UC) and Crohn’s disease (CD). The primary distinguishing factor between the subtypes is that in UC, symptoms are limited to the colon. In contrast, any part of the GI tract – from the mouth to the anus – can be affected in CD. In addition, UC only involves the innermost layer of the colon, while CD can extend deeper into the cell layers of the GI tract. Lastly, in CD, the inflammation can “skip”, leaving normal areas between patches of affected GI tract.

Making a clear IBD diagnosis isn’t always as easy as meeting – or not meeting – these criteria. There is no gold standard available for a clear-cut diagnosis, and 5-15% of cases do not meet strict criteria for either UC or CD. These patients fall into the “IBD type unclassified” (IBDU) group. And in up to 14% of patients, the diagnosis changes over time. Despite the difficulty in specific diagnosis, all subtypes of IBD have one strong feature in common: an abnormal response by the body’s immune system. The immune system is composed of various cells and proteins that usually protect our bodies from infection. However, in people suffering from IBD, the immune system reacts inappropriately, and mistakes benign or beneficial cells and bacteria for harmful foreign substances. When this happens, the immune system produces an inflammatory response within the GI tract and produces the symptoms of IBD. This adverse reaction is termed a “flare”, and can result in symptoms such as abdominal pain and cramping, diarrhea, fever, and blood in the stool. People with IBD often have deficiencies in vitamins, minerals and macronutrients stemming from loss of appetite, reduced food intake, and malabsorption from the GI tract. The lack of nutrients can lead to worsening of symptoms or development of new complications.

Treatment for IBD is centered around two goals: achievement of remission and prevention of flares. Anti-inflammatory drugs such as aminosalicylates and antibiotics are often the first line of treatment, and can be followed by corticosteroids, immunomodulators, and/or biologic agents. In severe cases, removal of the affected part of the GI tract is needed if a patient is not responsive to other treatments.

The Role of the Microbiome in IBD

In recent years, it has become clear that the microbes in our gut have a key role in IBD, but the bacteria involved and their associated functions remain largely unknown. An imbalance of the normal gut bactera due to loss or overabundance of certain species is important in the persistence of the inflammatory responses seen in IBD. The role of the gut microbiota in IBD pathogenesis has been demonstrated by studies showing that antibiotic use can reduce or prevent inflammation – antibiotics work by reducing the number and types of bacteria found in the gut, therefore killing microbes that are causing IBD symptoms. Also, results from studies with UC patients who underwent a transfer of stool collected from healthy donors – called a fecal microbiota transplant – had notable disease remission. However, results have not been consistent between studies, due to differences in populations studied, official diagnosis, treatment methods and doses, and methods of assessing study endpoints. Therefore, no consensus on the microbiome’s relationship to IBD has been reached.

Research Endeavors

As you can imagine, the combination of unpleasant, potentially severe symptoms and an uncertain diagnosis or treatment can result in significant stress on IBD sufferers, their caregivers, and health care providers. The scientific efforts dedicated to identifying causes and cures for IBD have rapidly expanded in recent years due to advances in technology that allow researchers to work toward refining a clear diagnosis, map specific gut bacteria associated with disease development and symptoms, and identify defined targets for therapy. One of these initiatives is the Crohn’s and Colitis Foundation of America (CCFA) Microbiome Initiative, which is dedicated to understanding the role of the gut microbes in IBD, IBD families, and disease flares. Thus far, there are 7 active projects and 30 published manuscripts stemming from the Initiative, which have determined that different subsets of IBD are characterized by signature bacterial compositions and that people carrying different IBD genes have different microbiome compositions, among other accomplishments.

Other organizations are also supporting IBD research endeavors, including the Kenneth Rainin Foundation, whose Innovator Awards program provides $100,000 grants for one-year research projects conducted at non-profit research institutions, and the NIH’s Human Microbiome Project, which has funded several projects aimed at genetic and metabolomic elucidation of risk for Crohn’s disease. Several randomized trials are ongoing at this time, and their results will inform future directions for diagnosis, treatment, and eventual resolution of IBD.

References

Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakas S. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol.2004;38(6):475–483.

Bull MJ, Plummer NT. Part 1: The Human Gut Microbiome in Health and Disease. Integr Med. 2014 Dec; 13(6):17-22.

Crohn’s and Colitis Foundation of America:http://www.ccfa.org/

Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H. Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease.J Clin Microbiol. 2005;43(7):3380–3389.

Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H. Differential diagnosis in inflammatory bowel disease colitis: state of the art and future perspectives. World J Gastroenterol. 2015 Jan 7;21(1):21-46.

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Gut Microbes and the Brain: What is the Effect on Human Behavior?

By Teresa L. Johnson, MSPH, RD

W. Allan Walker, MD, and Emeran Mayer, MD chaired a symposium during ASN’s Scientific Sessions and Annual Meeting on March 30 that considered the role the gut microbiome plays in human behavior.

Mark Lyte, PhD, MS, a professor at Texas Tech University, provided insights into aspects of gut-brain communication pathways. He introduced the idea that gut bacteria, as neuroendocrine organisms, are more interactive with their human hosts than previously believed. Lyte then pointed out that the gut is highly innervated, and information flows in a bi-directional but asymmetrical fashion between the gut and the brain, with as much as 90 percent of the information flowing from the gut. He suggested that neuroendocrine chemicals naturally present in foods might influence gut bacteria responses, and mechanisms that were previously considered immunological might be neuroendocrinal instead. The take-home message, Lyte said, was that these food-derived neurochemicals, when absorbed in gut, likely interact with the microbiota. In response, the microbiota produce neurochemicals that affect behavior and cognition in a sort of feedback loop. He cautioned that much of the data are correlational, and causation cannot be assigned.

Sarkis Mazmanian, PhD, California Institute of Technology, focused his remarks on specific molecular communications between the gut and brain. He explained that our bodies are in contact with trillions of microbes. “This microbial fingerprint has effects on many aspects of our biology,” said Mazmanian. He noted that in recent decades, the prevalence of autism spectrum disorder (ASD) has increased dramatically, and he presented data demonstrating that in rodents, maternal immune activation during pregnancy yields offspring with ASD and dysbiosis, suggesting a possible gut-microbiome-brain connection in ASD.

Premysl Bercik, MD, a gastroenterologist and associate professor at McMaster University, noted that while individuals with inflammatory bowel disorders commonly have abnormal gut function and low-grade inflammation, they also experience psychiatric comorbidities such as depression, stress, and anxiety. The trigger for this chain of events has not been identified, Bercik said, but some have hypothesized that infections or abnormal gut flora might be responsible. He then presented data from animal models that demonstrate the bi-directional communication between the gut and brain, and described recent research indicating that both microbial and host factors influence behavior.

Mayer, a professor at the David Geffen School of Medicine at UCLA, began his presentation with a historical perspective on the perceived gut-brain connection, which dates back several millennia. He then described notable limitations to using rodent models to study the gut-brain connection due to structural differences between rodent and human brains, and added that the germ-free mouse, a common model for understanding gut microbiome function, introduces many confounders into the research due to its altered metabolism. Mayer presented data that indicate that pre- and post-natal stress alters the gut microbiome in animals, as evidenced by both behavioral and biological changes, and he raised the idea that the gut microbial organization might influence brain structure. Attempts to modulate behavior with probiotics are promising, Mayer said, because intake blunts the reactivity of several internal organs, including those in the gut. Mayer concluded his presentation by cautioning that although enthusiasm to extrapolate findings from rodent models to human conditions including obesity, autism, and others is high, many questions remain about the role the gut microbiome plays in human health.