Meenakshi Rao, an assistant pediatric professor at the Children’s Hospital in Boston, recently expressed his opinion to the RNA-Seq blog that inflammation, not bacteria, should be targeted, as infections associated with Clostridioides difficile (C. diff) are not easy to eradicate.
The long-term effect of staying on the medications, however, causes patients to become resistant to many mainstream antibiotics. Often the infection breaks loose during the tapering period, and the patient is again fighting the infection. This time, however, with an added burden of having developed a resistance to certain antibiotics.
Prof. Rao adds that infections can drive runaway inflammation, most notably affecting inflammatory bowel disease. C. Diff may cause debilitating diarrhea in patients being given immunosuppressive treatment as outpatients or when they are hospitalized. As previously noted, these infections are difficult to control. Prof. Rao indicated that treatment with antibiotics is not only insufficient, it may even cause the problem.
A New Approach
Professors Rao, Dong, and their associates suggest focusing on controlling intestinal inflammation instead of trying to control the bacteria. The concept would be to use drugs that are now FDA-approved to treat migraine and nausea.
The body has trillions of viruses, bacteria, and fungi collectively known as the microbiome.
Prof. Dong further explained that when C. diff is attacked with antibiotics, the gut microbiome is affected, and a person is again vulnerable to infection. Hence, the vicious cycle.
Looking Towards the Future
Prof. Rao has plans to create a clinical trial based on their success in treating mice models that had virulent C. diff. The next step would be to test the drugs on humans who have C. Diff infections.
Prof. Dong knows that C. diff produces a very potent toxin called toxin B. Yet he did not know the relationship to colonic inflammation. Prof. Dong and his team worked out a solution using RNA sequencing data that showed how toxin B can bind to CSPG4 and FZD1/2/7 receptors.
The team went a little further. Two types of cells were discovered in gut tissue (pericytes and sensory neurons). Prof. Dong said that several years ago the team would have been unable to find these cell types, but now they can be observed thanks to single-cell technology.
Professors Rao and Dong found that the sensory neurons release neuropeptides and the pericytes that encircle the blood vessels release pro-inflammatory cytokines.
The team discovered that in the mouse model, neurogenic inflammation and damage to tissue occurred just as it does in human patients.
Prof. Dong further explained that the strong inflammatory response results in dilation in vessels, cytokines, and immune cells, as well as inflammatory mediators. This response is usually protective. However, the professor explained that in this case, it is overexaggerated, disrupting the bacteria and the host cells.
As aforesaid, drugs used for vomiting and nausea currently exist that block the triggering of neuropeptides, and the drug Aprepitant blocks substance P signaling. The drug olcegepant seemed promising but difficulty in formulating oral olcegepant eventually led to discontinuance.
Several drugs successfully reduced tissue and inflammation damage in the mouse model. The team noted that the same drugs reduced C. diff bacteria in the mouse model’s intestines.
Other researchers have recently discovered that damaged intestinal cells induced certain nutrients to be released that are beneficial to C. diff. According to Prof. Dong, once this immune response is under control, C. diff will not survive.
Prof. Rao plans to join gastroenterology colleagues in developing a clinical trial that would begin by using the FDA-approved drugs. Patients who have C. diff that is antibiotic-resistant would be eligible to participate. Prof. Rao points out that these drugs have already been proven safe.
