COVID-19-Induced Diarrhea: Pathogenesis and Mechanisms

COVID-19 has likely had a tremendous impact on each and every one of our lives. As a novel pathogen that changed the world, its molecular mechanisms are still being investigated today. Although the havoc of the initial days of this virus has passed, there is still a great deal to learn about how it operates and how it can be best treated. Despite the main focus of this virus being its pulmonary symptoms, it has been shown to affect virtually all organ systems, including the GI tract. A 2024 study by Donowitz et al. has revealed the molecular mechanisms behind COVID-induced diarrhea, providing further insight about the effects of the virus on the gastrointestinal system.

Diarrhea as a GI Symptom of COVID-19

GI involvement is relatively common in COVID patients. The main gastrointestinal symptom associated with this virus is diarrhea. Up to 50% of patients with acute COVID infection report diarrhea as a symptom. Interestingly, it also has a notable impact on patients with long COVID. Diarrhea is seen in approximately 30% of long COVID cases, and having diarrhea was found to be a predictive factor for continuation of the chronic infection beyond 2 years. 

Diarrhea as a COVID symptom seems to negatively impact patients with severe COVID as well, as recent studies have found the virus in intestinal samples of about half of patients who died from COVID infection. Because having COVID-19-associated diarrhea is a potentially negative prognostic factor for patients, more research has recently been conducted regarding the mechanisms of this symptom on a molecular level. 

General Classification and Mechanism of Diarrhea

In order to understand how COVID-19 causes diarrhea, it is important to first review the various types of diarrhea and their classification. Although there are a wide variety of ways to categorize this symptom, 2 major methods discussed by Donowitz et al. divide it by its location and by its general mechanism. 

The location of the diarrhea can be divided into colonic or small intestinal, depending on where in the GI tract it originates. Small intestinal diarrhea is typically more watery and produces large volumes of stool, while colonic diarrhea is usually lower in volume but more frequent. Colonic diarrhea is more likely to have blood or mucus content. Patients with diarrhea from the small bowel will often experience weight loss as a symptom, which is less likely in colonic diarrhea. This is because small intestinal diarrhea is typically a result of malabsorption, most commonly from Celiac disease, lactose intolerance, or small intestinal bacterial overgrowth (SIBO). In contrast, major causes of colonic diarrhea include IBD, IBS, or colonic infection. Viral infection can cause either type of diarrhea, although COVID-19 in particular is more associated with the small intestine than the colon. 

In addition to location, diarrhea can also be divided into 2 primary mechanisms: secretory and inflammatory. Secretory diarrhea is caused by an imbalance in electrolyte transport, usually involving sodium and chloride, which leads to a watery diarrhea. On the other hand, inflammatory diarrhea is caused by an infection and results in bloody diarrhea with systemic symptoms such as fever, abdominal pain, and increased urgency in bowel movements. In the Donowitz et al. 2024 study, COVID-19 diarrhea was found to be inflammatory. The authors further illustrated the molecular mechanisms of COVID-19 diarrhea in their research, which they found to be a result of both direct viral effects and the viral-induced inflammatory response.

Direct Viral Effects

The most significant way in which COVID-19 infection leads to diarrhea is by direct effects of the virus on intestinal cells. Similarly to other causes of watery diarrhea, COVID-induced diarrhea causes decreased sodium absorption and increased anion secretion, mainly in the form of chloride. However, the unique aspect of diarrhea caused by Sars-CoV2 is the way it triggers increased anion secretion. 

The main player in this process was found to be calcium. The Donowitz et al. study illustrated that there is an acute rise in calcium immediately after COVID-19 infection in 3D cultures of human intestinal cells called enteroids. Interestingly, this calcium increase is not constant and instead occurs in waves. The calcium waves were unrelated to inflammatory effects of the virus and were thus concluded to be caused directly by infection with the viral organism. 

Impact of Virus-induced Inflammatory Response

Many of the systemic symptoms of COVID-19, including its well-known respiratory effects, are mediated by the immune system’s response to the virus rather than the organism itself. In the study, the immune response was modeled via key cytokines, including IL-6 and IL-8, which cause systemic inflammation at high concentrations. It was discovered that these cytokines are necessary in order for the decreased sodium reabsorption and increased chloride secretion associated with Sars-CoV2 infection to occur. However, they were not implicated in the calcium wave production that occurs with initial COVID infection, suggesting that 2 separate processes are at play. 

Conclusions

The 2024 study by Donowitz et al. led to the categorization of COVID-19 diarrhea as inflammatory. More importantly, it was a landmark article that explained the molecular mechanisms by which COVID-19 infection causes diarrhea: direct viral effects and virus-induced inflammatory response. These findings are clinically significant because of the impact of COVID-19 diarrhea on half of COVID-patients and its negative prognostic value as a symptom. Thus, preventing or treating it could potentially lead to improved patient outcomes. Furthermore, the authors suggest that their methods and findings could also be applied to investigate the pathogenesis of other inflammatory diarrheas, such as IBD, on a cellular level. 

Summary

A landmark 2024 study by Donowitz et al. explored the mechanisms behind COVID-19-induced diarrhea. The authors identified it as an inflammatory form of diarrhea caused by both direct viral effects and the immune system's inflammatory response. COVID-19 primarily affects the small intestine, disrupting sodium absorption and increasing chloride secretion. The study demonstrated that viral infection triggers calcium waves in intestinal cells, independent of inflammation. Inflammatory cytokines operate separately and further disrupt electrolyte balance. COVID-related diarrhea has been associated with poorer prognoses, particularly in severe cases and long COVID, which illustrates this study’s clinical significance. In the future, this research may also provide a foundation for studying other inflammatory diarrheal conditions, such as IBD, at the molecular level.