The Oxidative Stress and Nervous Distress Connection in Gastrointestinal Disorders

Abstract

Oxidative stress is increasingly recognized as a central player in a range of gastrointestinal (GI) disorders, as well as complications stemming from therapeutic interventions. This article presents an overview of the mechanisms of oxidative stress in GI conditions and highlights a link between oxidative insult and disruption to the enteric nervous system (ENS), which controls GI functions. The dysfunction of the ENS is characteristic of a spectrum of disorders, including neurointestinal diseases and conditions such as inflammatory bowel disease (IBD), diabetic gastroparesis, and chemotherapy-induced GI side effects. Neurons in the ENS, while essential for normal gut function, appear particularly vulnerable to oxidative damage. Mechanistically, oxidative stress in enteric neurons can result from intrinsic nitrosative injury, mitochondrial dysfunction, or inflammation-related pathways. Although antioxidant-based therapies have shown limited efficacy, recognizing the multifaceted role of oxidative stress in GI diseases offers a promising avenue for future interventions. This comprehensive review summarizes the literature to date implicating oxidative stress as a critical player in the pathophysiology of GI disorders, with a focus on its role in ENS injury and dysfunction, and highlights opportunities for the development of targeted therapeutics for these diseases.

Enteric neuropathy in diabetes: Implications for gastrointestinal function

“…Furthermore, hyperglycemia-induced mitochondrial stress plays a significant role in this pathology. In enteric neurons, such stress leads to impaired energy production and an elevated generation of reactive oxygen species (ROS), which contribute to neuronal damage[ 41 - 43 ]. This mitochondrial dysfunction is a critical factor in the degeneration of neuronal health under diabetic conditions.…”

“…Chronic hyperglycemia exacerbates ROS production, overwhelming the body’s inherent antioxidant systems. This suggests that enhancing these defenses could be a viable strategy to protect enteric neurons from oxidative damage[ 41 , 43 ]. Strengthening these antioxidant defenses could be a therapeutic approach to protect enteric neurons from oxidative damage.…”

“…Moreover, autophagy, a process essential for cellular maintenance and stress response, may be altered in diabetes, leading to impaired maintenance and increased vulnerability of enteric neurons[ 41 , 43 ]. This alteration in cellular processes underscores the complexity of diabetic enteric neuropathy’s pathophysiology.…”

“…Colonic function is similarly impacted, primarily through weakened muscular contractions and oxidative stress induced by persistent hyperglycemia[ 41 , 98 ]. This condition disrupts the normal functioning of ICC and neuronal cells, leading to colonic motility issues like chronic constipation or diarrhea[ 30 , 99 ].…”