Ulcerative colitis is a prevalent chronic inflammatory bowel disease (IBD) characterised by inflammation and ulcers in the large intestine that can potentially lead to life-threatening conditions like colon cancer. Although a definitive cure for ulcerative colitis remains elusive, certain medications can help manage its symptoms and alleviate its severity.

This disease has been the focus of a recent collaborative study led by Samir Kumar Pal at the SN Bose National Centre for Basic Sciences, Kolkata. The study, which also involved researchers from various other Indian institutes, Umm Al-Qura University in Saudi Arabia and Assiut University in Egypt, unveiled that chitosan-capped trimanganese tetraoxide nanoparticles have the potential to treat ulcerative colitis in mice.

To develop a disease model for ulcerative colitis, the researchers fed mice with a chemical called Dextran Sulphate Sodium (DSS) for 12 days, which induced the disease in these animals. However, the COVID-19 pandemic presented challenges in acquiring proper food pellets for the mice, prompting the team to use regular household groceries such as carrots instead. Susmita Mondal, the first author of the study, commented, ​“When we fed the mice with carrots and the DSS toxin, the model would not get established. We reasoned that the carrots could provide antioxidants and were quenching the effects of DSS.” They hypothesised that reactive oxygen species (ROS) might play a crucial role in ulcerative colitis.

ROS are highly reactive chemicals that form when molecular oxygen undergoes splitting reactions. They are byproducts of oxidation reactions that occur within the body, resulting in the loss of electrons from molecules. Conversely, antioxidants, are compounds that can counteract oxidation and hinder the formation of ROS. 

Monojit Das, an author of the study, explained, ​“In contrast to conventional belief, we think that ROS is not a ​“villain” in our body, but a double-edged sword. It can be either beneficial or harmful, depending on the concentration and microenvironment.”

The researchers used chitosan-capped trimanganese tetraoxide nanoparticles, which aids in the targeted delivery and absorption of these nanoparticles in the gut. Chitosan also made the nanoparticles soluble in water, enabling easy oral delivery.

Both diseased and healthy mice received a daily dose of the nanodrug for 15 consecutive days. The researchers evaluated their health conditions through a series of experiments. They observed significant improvements in clinical symptoms such as weight loss, bloody diarrhoea, reduced colon length, and a reduced mortality rate in diseased mice treated with the nanodrug.

Inflammatory markers (pro-inflammatory cytokines) are vital indicators of ulcerative colitis, an IBD. After the treatment, the levels of these markers and the severe gut damage of the diseased mice notably decreased, signifying a positive response.

Finally, they found the nanodrug could modulate ROS levels. Mondal expressed, ​“The theory of ROS balancing is not very well established, and many people have questions regarding this. In in vitro (outside living tissues) studies, we have observed that the nanoparticle can either quench or generate ROS, depending on the environment. From this, we are extrapolating the mode of action of these nanoparticles. But I think looking into the molecular mechanisms inside cells will be interesting.” This characteristic of the nanodrug also allows it to mitigate mitochondrial oxidative damage in the disease condition. Such mitochondrial dysfunction has also been previously linked to ulcerative colitis in another study.

Dipankar Nandi, Professor, Indian Institute of Science, Bangalore, who has extensive experience with DSS-induced colitis in mice, and is not associated with the study, emphasised the significance of the findings. He said, ​“This study is important as it highlights the use of newer materials to treat diseases. The authors have shown the efficacy of these nanoparticles in a mouse model of colitis. Further studies will be required to address the toxicity aspects of these nanoparticles and their efficacy after human clinical trials. However, it is a step forward in opening up newer therapeutic strategies to treat older diseases.”

The researchers have plans to conduct long-term studies to assess the potential relapse of ulcerative colitis in the mice population after treatment. They also aim to proceed towards human clinical trials after conducting additional experiments. Furthermore, they are exploring the application of this approach to discover potential cures for other diseases that can be treated by modulating the ROS balance within the body.