2003 BielefeldtBy: Klaus Bielefeldt, MD, PhD

University of Iowa,

Dr. Bielefeldt is the recipient of the IFFGD 2003 Research Award to Junior Investigator, Basic Science.

Dr. Bielefeldt's clinical interests are with functional diseases of the esophagus. Scientifically, he has used his training in cellular neurophysiology to explore mechanisms that change sensation with a focus on certain nerves that innervate the stomach and may contribute to the development of hypersensitivity, or pain and discomfort.

Pain, a burning or otherwise uncomfortable sensation in the upper abdomen, nausea, or fullness – all of these are symptoms many patients list when they seek medical advice.

While we may think of ulcers, gallstones or perhaps inflammation of the pancreas as the cause, all too often even extensive and sophisticated testing does not show any abnormalities. So, why do all these persons feel pain or any of the other symptoms they complain about? As a scientist, I am trying to find an answer to this important question.

What Causes Functional Diseases?

Physicians are trained to focus on identifying what we call organic diseases – diseases that are caused by bacteria or other infectious organisms we can isolate, structural changes we can determine with endoscopes or x-rays, inflammation we may see with microscopes, or biochemical abnormalities blood tests may reveal. Whatever does not fall into one of these categories, we tend to label functional.

Within the last few decades, we have learned that we need to divide these functional illnesses based on the underlying problem. The normal pattern of contractions may be altered, the balance between secretion and absorption may be offset, or sensory information from the intestine may not be processed properly. My research focuses on the last of the three listed mechanisms: how can nerve function change and lead to an increased sensitivity of inner organs? In the clinic, we call this visceral hyperalgesia, in the laboratory, we prefer the terms sensitization or visceral hypersensitivity.

What Causes Visceral Hyperalgesia?

In my clinic, I often meet patients who tell me about a bad "stomach flu" that resolved, but left them with pain or other problems that persisted for months or even years. If we do not find an organic disease, many physicians use the label post-infectious irritable bowel syndrome or post-infectious non-ulcer dyspepsia, depending on the type of symptoms present.

In the laboratory, I try to identify whether the initial inflammation changed the function of nerves that send information about the stomach or intestines to the spinal cord and brain. Because these nerves have their processes out in the wall of the gastrointestinal tract, we refer to them as peripheral nerves and call alterations in their function peripheral sensitization.

To understand mechanisms that lead to peripheral sensitization, we need to focus on the language of the nervous system: the action potential, an electrical signal, travels along the processes of the nerve cell until it comes to a connection with another nerve cell, called a synapse.

At this point, the electrical signal is translated into a chemical message, and the release of signaling molecules (i.e., neurotransmitters). The frequency and pattern of these action potentials, also called spikes, is the code of the nervous system. If a nerve cell can generate in response to a weaker stimulus or produces more of these spikes, it is more excitable.

We study the electrical currents that underlie the generation of action potentials. The main goal of our work is to determine whether injury and inflammation changes these currents, thereby making nerve cells more excitable.

And in fact, when we examined nerve cells that send their processes to the stomach, we were able to see many important changes in the electrical properties of nerve cells that were consistent with the development of peripheral sensitization.

Will disease processes stop here? The answer is clearly no. If peripheral nerve cells are sensitized, more information will flow to the spinal cord and brain, structures we collectively refer to as the central nervous system. This ongoing barrage may in turn change the properties of nerve cells in the central nervous system and lead to central sensitization.

What Causes Peripheral Sensitization?

Considering the potential importance of peripheral sensitization in the development of visceral hyperalgesia, we need to understand more about the signals that trigger changes in nerve function. Staying with the clinical scenario of acute inflammation causing chronic problems, we tried to identify some of the molecules that may affect nerve cells during such acute inflammation.

We narrowed in on one potential culprit, nerve growth factor. It increased after injury, thus satisfying one important criterion for a possible mediator of peripheral sensitization. When we examined its effect on nerve cells in the test tube, nerve growth factor changed the properties of these cells in ways that reminded us of findings we had originally obtained when we studied nerve cells after stomach injury. Finally, when we blocked the effects of nerve growth factor, we were able to blunt behavioral changes characterizing visceral hypersensitivity.

What About Patients?

In this short description, I tried to summarize a series of complex experiments we conducted to better understand mechanisms of peripheral sensitization. Can I translate this information into new treatments for patients? At this point, the answer is no. In our experiments, we focused on one of many redundant mechanisms.

We also intervened early in a cascade of effects, while our patients typically come at later points in the sequence of events. Moreover, blocking one signaling molecule, such as nerve growth factor, may lead to adverse effects and raise serious questions about the cost-benefit ratio of such treatments. However, we gained insight into important mechanisms that contribute to the development of symptoms.

We and many others have to use this information as we try to identify safe and effective therapies that will come back from the laboratory bench to the bed site.

Source: Adapted from IFFGD Publication #203 by Klaus Bielefeldt, MD, PhD, Associate Professor of Medicine, Roy and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.

Research Awards
2013 Award Recipients
Enrico Corazziari, MD
Jan Tack, MD, PhD
Gary Mawe, PhD
Ashley Blackshaw, PhD
Carlo Di Lorenzo, MD
Niranga Manjuri Devanarayana, MD
Report from Lukas Van Oudenhove, PhD: Solving the Biopsychosocial Puzzle in Functional Dyspepsia
Muriel Larauche, PhD
2011 Award Recipients
Report from Ronnie Fass, MD: Sleep and Gastroesophageal Reflux Disease (GERD)
Million Mulugeta, PhD
Adrian Miranda, MD
Samuel Nurko, MD
Sudarshan Jadcherla, MD
Shaman Rajindrajith, MD
2009 Award Recipients
Satish Rao, MD
Emeran Mayer, MD
Javier Santos, MD
Report from Martin Storr, MD, PhD: Functional Gastrointestinal Disorders: New Insights in Enteric Regulation
Report From Miguel Saps, MD: Functional Abdominal Pain in Children and Adolescents
2007 Award Recipients
Report from Bruce D. Naliboff, PhD: Symptom Based Psychology for Functional Gastrointestinal Disorders
Report from Magnus Simrén, MD, PhD: Irritable Bowel Syndrome: Searching for Underlying Causes
Report from Brennan M. R. Spiegel, MD, MSHS: Diagnostic Testing in Irritable Bowel Syndrome: Theory vs. Reality
Report from Sylvie Bradesi, PhD: Role of the Central Immune System in Functional Disorders
Paul E. Hyman, MD
Report from Miranda A. L. van Tilburg, PhD: Home Based Guided Imagery to Treat Pediatric Functional Abdominal Pain
Report from Fernando Azpiroz, MD, PhD: Understanding Intestinal Gas
2005 Award Recipients
Report from Yvette Tache, PhD: Stress and Irritable Bowel Syndrome: Unraveling the Code
Report from Shaheen Hamdy, MRCP, PhD: Adult Neurogenic Dysphagia -- Disorders and Conditions that Disrupt Swallowing
Report from Michael A. Pezzone, MD, PhD: Chronic Pelvic Pain and the Overlap of Pelvic Pain Disorders
Report from Bridget R. Southwell, PhD: Research into Treatment-Resistant Constipation in Children
Report from Rachel Rosen, MD, MPH: Symptoms Arising from Non-Acid Reflux in Children
2003 Award Recipients
Report from William E. Whitehead, PhD: Summary of Clinical Research Activities
Jyoti N. Sengupta, PhD
Report from Caroline Elder Danda, PhD: Biopsychosocial Perspectives on Assessment and Treatment
Report from Terry Buchmiller-Crair, MD: Using the Fetal Gastrointestinal Tract to Overcome Neonatal Disease
Report from Dan L. Dumitrascu, MD, PhD: The Psychosocial Adjustment to Illness in Irritable Bowel Syndrome
Report from Klaus Bielefeldt, MD, PhD: Understanding Pain and Discomfort in Functional GI Disorders
Research Grants
IFFGD Competitive Grants
2014 IFFGD Idiopathic Gastroparesis Research Grants
Leo Cheng, PhD
Braden Kuo, MD, MSc
Richard McCallum, MD
2008 IFFGD Competitive Research Grants
IFFGD Noncompetitive Grants
Other Research Grant Opportunities
Funding Research
Need for Funding Research
How to Make a Difference
The State of Research at NIH & NIDDK
Clinical Trials & Studies
IBS Studies
Guide to Randomized Clinical Trials
Industry Sponsored Clinical Trials and Studies
NIH/Other Sponsored Clinical Trials and Studies

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