New research plan tackles deployment-linked digestive woes
August 21, 2019
By Mitch Mirkin
VA Research Communications
"We want to support studies that will help us move to clinical trials."
VA Research is planning a series of studies to gain insight into the gastrointestinal and liver problems that beset many Veterans after deployments. The goal is to bring new treatments to bear as soon as possible.
The studies will be coordinated in the framework of a “roadmap” hammered out by GI and liver experts from VA and elsewhere. Many took part in a VA-sponsored conference in San Diego in May. A report detailing the meeting and the resulting roadmap is in-press at the journal Gastroenterology, reflecting the input of more than 20 clinicians and biomedical scientists, including meeting attendees and others.
Dr. Arun Sharma, a health science officer in VA’s Office of Research and Development (ORD), says VA patients have a “very high incidence” of GI conditions like irritable bowel syndrome, inflammatory bowel disease, and infectious diarrhea. Liver diseases such as cirrhosis are also common.
“Much of the discussion at the meeting focused on how many of these diseases can be triggered by severe stress and infections in military personnel who are deployed in different overseas environments,” says Sharma. He notes that combat exposure adds to the problem, both because of the emotional impact and the risk of physical wounds to the gut.
Deployment-triggered GI problems could become chronic
Like many other wounds of war, these ailments don’t necessarily get better once the service member is back home. They can become chronic. How and why that happens is of particular interest to the researchers. Some have already been studying how war-related conditions like PTSD worsen gut health over time.
“Emerging evidence indicates that deployment-related diseases such as PTSD, Gulf War illness, and traumatic brain injury can change the composition of gut microbes and further exacerbate GI and liver diseases,” notes Sharma, summarizing one of the themes in the journal paper.
These gut problems, in turn, lead to other health problems, both mental and physical.
The purpose of the San Diego summit, says Sharma, was to “examine the mechanisms underlying these service-related disorders and their association with other deployment-related conditions, identify new therapeutic targets, and create a roadmap for developing new strategies for clinical intervention.”
Roadmap promotes coordinated research
Long-range plans known as roadmaps are increasingly popular among research agencies, including VA. The idea is to carefully coordinate studies in a particular area over time so they build on each other and progress more quickly toward clinical advances. The roadmap lays out the problems to be solved, the best routes to address them, and the milestones to be met along the way.
As a result of the meeting and journal paper, ORD expects to fund several study proposals from VA researchers. The focus will be on the gut microbiome. That refers to the bacteria and other tiny organisms that live inside the intestines. Some bugs are friendly and vital to life. Others are harmful invaders.
The first step is gaining more knowledge of how these microbes play into GI and liver health and distress. Clinical trials will build off that knowledge, testing and refining therapies such as probiotics or fecal transplants.
ORD aims to fund work that synergistically meshes the know-how of scientists and clinicians across different groups and academic disciplines.
“We want to see if they can figure out ways to put things together and eventually come up with better therapeutic strategies than if we were to just work on these diseases in isolation,” says Sharma.
His colleague Dr. Zafar Iqbal, also a health science officer in ORD, adds: “We’re looking for solutions to help Veterans. Certain studies have to be performed first so we have a clear idea of what combinations of bugs [therapies like probiotics—essentially, live bacteria that are helpful to the gut] need to be used, which are the most effective for treating different diseases. We want to support studies that will help us move to clinical trials. We’re interested in not only treating GI disease, but also helping pain, and other symptoms that impact quality of life. The end goal is to improve Veterans’ overall health.”
To learn more about the links between deployment and gut health, VA Research Currents spoke with two GI experts from VA who took part in the meeting and co-authored the journal article:
Jasmohan Bajaj, M.D., physician-researcher, McGuire VA Medical Center, Richmond, Va.; professor, Virginia Commonwealth University.
Pradeep K. Dudeja, Ph.D., senior research career scientist, Jesse Brown VA Medical Center, Chicago; professor, University of Illinois at Chicago.
Q: One could see how the combination of stress—emotional and physical—and various environmental factors could trigger GI illnesses in troops. But what makes some of these illnesses persist, and become worse, long after deployment?
Dudeja: As you know, many troops serve in very difficult conditions. They may get exposed to foodborne and waterborne pathogens. There are injuries and many psychological and physical stresses they go through. Our feeling is that many of these conditions change their microbiome, and that these changes could trigger long-term functional bowel disorders like irritable bowel syndrome.
Also, repeated bouts of infectious diarrhea can lead to increased incidence of irritable bowel syndrome (IBS) and/or inflammatory bowel disease (IBD). And there are hospital-acquired infections in which the gut microbiome plays a key role. If you have a good microbiome, you can overcome this disease, but if your microbiome has become abnormal, you keep getting persistent diarrhea. Some of the older patients with hospital-acquired infections such as C. difficile can die with this diarrhea. One treatment option is a fecal microbial transplant, in which you try to restore a healthy microbiome.
Bajaj: There’s the notion of the altered gut-brain axis. If your brain is diseased, your gut is diseased. If your gut is diseased, the brain is diseased. If we think about people with IBS, even a little bit of stimulation in the gut is perceived as painful, whereas the same amount of sensation in someone without IBS would not be even noticed. So I think the psychological, physical, and mental stress, along with combat exposure and other unsafe conditions, all help determine who comes back with a battle inside them that is still raging many years, even decades, after the combat had stopped. And microbes play an important role in this.
Q: It seems GI microbiota problems could affect not only the digestive system but virtually every other area of the body.
Dudeja: Yes, there’s been research coming out showing how the gut microbiome plays a role in heart disease, kidney disease, and many other conditions. One of my colleagues has even expressed the view that all diseases begin in the GI tract. Diet is always important, but now we’re starting to look at this in this way: Not “feed yourself the right foods,” but “feed your microbes the right foods,” so that you have healthy microbes. If you have healthy microbes, you are better able to maintain a healthy body.
Q: It also seems these connections work in many directions. For example, a Veteran could have underlying problems with the microbiota that trigger illness. Or, he or she could sustain an injury that harms the microbiota, which in turn causes other health problems. By the same token, restoring the microbiome can heal various conditions.
Dudeja: That’s correct. There’s the gut-brain axis, the gut-liver axis, the gut-liver-brain axis—all these different angles investigators are exploring. If you have dysbiosis [an imbalance in the microbes], that will affect your brain. Your brain, in turn, can again affect the microbiome and also many other things in the body, such as your nervous system and your hormones, which can then affect the functioning of other systems in the body. It is a complex system and our knowledge is evolving. We're still learning all these different connections. And they are all important for Veterans’ health.
Q: One of the experimental approaches you mention in the journal paper involves “humanized mice.” Could you explain that?
Dudeja: We start with mice that have normal microbiota, or with “germ-free” mice, which have been raised under completely germ-free conditions. We then transfer human microbial samples into these mice [via a solution, made from the human fecal matter, that is given through a tube so it directly enters the digestive system]. We then expose them to the pathogens that our Veterans encounter in their deployments. Along with that, we could subject the mice to stress in the lab that simulates the stress our troops go through.
One possible approach along these lines is to transplant microbial samples from post-deployment Veterans, and then see how certain pathogens interact with the intestines or the overall animals when they have these same microbial signatures as the Veterans with deployment-related ailments.
Using this approach, you could also test the effects of different therapeutic interventions, like probiotics or fecal transplants.
Q: What about liver health? Your article suggests that the links to deployment have more to do with negative lifestyle behaviors that may develop down the road, such as alcohol use.
Bajaj: We see a lot of liver disease, unfortunately, and most of it is related to drug use, alcohol use, or obesity, or all three at one point or another in the Veteran’s life. More often than not, these conditions are associated with depression or PTSD. Of course, people's livers can be injured directly—they can have a gunshot wound, for example—and some cases can involve exposure to pathogens that show immediate effects. But by and large, the connection we are seeing between deployment and liver health plays out over several years.
It’s interesting to note that the medical approach to hepatic encephalopathy [brain abnormalities that occur in some patients with cirrhosis of the liver] does not involve treating the liver, nor the brain. It's actually helping patients experience large bowel movements by fixing their gut. This is the finest and clearest example of the gut-brain axis that you can ever find in human beings: You have a comatose person, you help them have a bowel movement, and they wake up.
These are very difficult situations to deal with, and that's why we need more help. We thank ORD for putting us all together to figure out the gut microbiota as one way, perhaps the major way, to approach not only GI and liver conditions but potentially also a wide variety of other deployment-related health issues.