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New Biomarker of Intestinal Permeability Could Lead to Dx for Gut Function

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NEW YORK – Researchers at the Medical University of Warsaw in Poland have developed a biomarker that they said could be the basis for a noninvasive test to assess intestinal function.

Intestinal diseases such as inflammatory bowel disease (IBD) are characterized by an impairment of the gut-blood barrier (GBB), colloquially known as "leaky gut." Leaky gut is an increased permeability of the intestinal walls that can allow bacteria and their products to pass from the gut into the bloodstream, sometimes triggering inflammation or an immune response.

But it isn't just associated with IBD and other intestinal conditions like Crohn's disease or celiac disease. Because intestinal wall integrity and the proper function of the GBB depend on interactions between the circulatory, immunological, and hormonal systems, leaky gut has also become increasingly associated with cardiovascular and metabolic diseases such as diabetes.

Despite the utility of assessing permeability as a marker of intestinal health or disease severity in patients with conditions like IBD, such assessments are not currently established clinical practice. That's because the only available methods have some significant limitations and risks, according to Marcin Ufnal, head of the department of experimental physiology and pathophysiology at the Medical University of Warsaw. Some methods to assess GBB rely on measuring non-functional biomarkers like the proteins zonulin or claudin-3, but these markers don't always accurately reflect the full breadth of a person's intestinal function.

Functional assessment methods rely on the oral administration of exogenous compounds such as radiolabeled dextran. But the risks of these compounds are not well defined, especially for certain patients.

"There are a few studies that show that in these diseases, we have increased permeability to radiolabeled substances like dextran, and they showed that in IBD and other diseases we have increased permeability to these exogenous compounds," Ufnal said. "However, these are exogenous radiolabeled compounds and the risk of using these compounds is not known, especially in children or people with kidney failure. [So, they're] not used in clinical practice because of that risk. We propose something which uses no exogenous compounds and is risk-free."

What Ufnal and his colleagues have discovered, as they reported today in Experimental Physiology, is that patients with increased intestinal permeability have an increased blood-to-stool ratio in the concentration of short-chain fatty acids (SCFA) produced by gut bacteria.

"One of the most important functions of the gut is to protect the bloodstream from penetration of gut bacteria products to the blood," Ufnal said. "So, we looked at the ratio of the concentration of these metabolites in the blood to concentration in the stool [and] we found that when we have a lesion of the bowel, this ratio goes up. So, without any exogenous markers or exogenous compounds, we can look at the permeability of the gut."

The researchers started by conducting an animal study on rats with acetic acid-induced colitis, assessing GBB permeability by analyzing the ratio of fecal SCFAs to SCFAs in blood taken from the portal vein, which carries blood from the gastrointestinal tract; and the ratio of SCFAs in systemic blood to fecal SCFAs. They also assessed the concentrations of fluorescent dextrans in portal blood and stool.

In a second experiment, the researchers evaluated concentrations of SCFAs in systemic blood and stool in six pediatric patients with IBD assessed as mild, moderate, or severe on the Pediatric Ulcerative Colitis/Crohn's Disease Activity Index, and nine age-matched healthy controls. They further evaluated the blood-to-stool ratio of SCFAs in the 15 pediatric individuals.

They found that rats with histologically confirmed IBD had significantly increased ratios of SCFAs between portal blood and stool and systemic blood and stool. This was positively correlated with plasma FITC-dextran concentration. Likewise, the IBD patients showed a significantly higher blood-to-stool ratio for SCFAs, including acetic, valeric, isocaproic, caproic, and propionic acids, in comparison to controls.

Importantly, Ufnal said, previous similar studies have shown that bowel diseases are associated with an increased concentration of bacteria metabolites in blood, but this is the first time a study has looked at the ratio of these metabolites between blood and stool.

How much bacterial product is in the blood depends on several factors, such as diet, the composition of the gut bacteria, and the metabolic activity of the bacteria, Ufnal said. "When you look only at the concentration of these metabolites in the blood, you don't actually know whether the increase is due to leaky gut, or whether it's due to a diet, or whether it's due to different gut bacteria composition," he noted. "So, that's why I think our marker is so revolutionary, that we are looking not at just concentrations of bacterial metabolites in the blood, but we are looking at the ratio of gut bacteria metabolites in the blood to the concentration in the stools."

This ratio makes an assessment that is independent of factors such as diet, which can affect the composition of a person's gut microbiome, he added. In fact, the team's study showed a large amount of variability in the gut bacteria concentration present in stool from the various study participants, but the SCFA blood-to-stool ratio was similar for all of them, despite that variability.

"I think it's very important that we are looking at the ratio, not only at a single value of blood concentration," Ufnal said.

The findings lay the groundwork for establishing a new, noninvasive diagnostic test for diseases associated with intestinal barrier malfunctions, the team concluded. Not only would it circumvent the limitations and risks of currently available methods, it would evaluate actual gut function — as opposed to relying on structural or morphological assessments of the gut made through methods such as colonoscopy — to make a determination of disease.

"We think that's important because at this moment, we mostly have markers of structural lesions of the gut, but we don't have markers of the function of the gut," Ufnal said. "And in pathological conditions, it often happens that this functional impairment precedes the structural lesion."

Importantly, he also noted that such a test could be used for conditions other than those associated with the intestines. "Increasing research shows that systemic diseases like heart failure, hypertension, or diabetes affect circulation of the blood in the intestines and make the intestines more permeable," Ufnal said. "We have some preliminary experiments that showed that in rats with hypertension and heart failure, we have increased permeability to other gut bacterial metabolites than we have tested here. We strongly believe that this permeability of the gut may be a very good marker for intestinal and for extraintestinal diseases."

Further, he added, leaky gut may be a marker of microangiopathy — an angiopathy affecting small blood vessels in the body. Systemic or lifestyle diseases like diabetes and hypertension are associated with microangiopathy, which affects not only the kidneys or retinas, but also the intestines.

"We think that even in all the diseases that are associated with disturbed blood flow for the guts, this [ratio] may be quite an early marker," Ufnal said, noting that lesions such as early colorectal cancer tumors could even be found through this leaky gut test.

Ufnal and his team are currently performing experiments in rat models of heart failure and diabetes and are doing clinical studies looking at GBB permeability in patients with cardiovascular diseases such as heart failure to analyze the utility of the blood-to-stool SCFA marker as a noninvasive functional assessment of disease.

Ufnal also noted that although some larger studies must be done to validate and replicate these findings, he and his colleagues would eventually like to partner with a diagnostics company to produce a test using both blood and stool, which could be used in the clinic.