Mind Over Gut: The Impact of Stress and Sleep on Peptic Ulcer Disease

Everyone is impacted by the pervasive condition known as stress. H. Selye is credited for defining stress as an immediate danger to an organism's balance. Real (physical) or perceived (psychological), it might be caused by internal or external events. Stress is significant because it triggers adaptive reactions that protect the internal environment's stability and guarantee the organism's existence(1). Stress-induced gastritis is also known by several other names, such as stress-related erosive syndrome, stress ulcer syndrome, and stress-related mucosal disease. It is very important in critically ill patients or in those subjected to severe physiological stress. This condition leads to the development of mucosal erosions along with superficial hematomas, thus giving rise to gastrointestinal bleeding that may range from trivial to severe and requiring blood transfusions if not managed promptly(2). Stress can impact various gastrointestinal functions, which includes gastric acid production, intestinal movement, mucosal permeability, barrier function, visceral sensitivity, and mucosal blood circulation(3-5)(Fig.1).

Fig 1: Effect of stress on gastrointestinal functions. Stress has impact on important physiological functions of gut including gut motility, secretion, visceral sensitivity, mucosal blood flow. In addition, stress modifies gut microbiota and enhances paracellular permeability

According to initial research, emotional factors play a part in the formation of stomach ulcers(6-7).There have been reports that psychological stress can cause the production of stomach acid(8).The significant relationship between the gut microbiota and stress has been demonstrated recently. It's interesting to note that bacteria may react directly to host signals associated with stress. Catecholamines have been shown to change the pathogenicity, proliferation, and movement of both commensal and pathogenic bacteria. Therefore, stress may have an impact on how these germs infect various hosts(9).

TYPES OF STRESS ULCER

1. PHYSIOLOGICAL STRESS
   Any unforeseen circumstance that compromises a cell's or an organism's equilibrium is referred to as physiological stress. It can be separated into three categories: ageing, intrinsic developmental stress, and stress from the environment.
2. THE ULCER OF CUSHING
   A Cushing's ulcer is a single, deep ulcer in the oesophagus, duodenum, or gut that may be brought on by damage to the central nervous system.
3. CURLING'S ULCER
   Acute gastric erosion, or Curling's ulcer, is a consequence of catastrophic burns when ischemia and gastric mucosal cell necrosis (sloughing) are caused by decreased plasma volume(Fig. 2).

Fig 2: Type of Peptic Ulcer Disease and common risk factor

Regarding the connection with stress and gastroenteritis, the vast majority are aware of the close relationship between the gut and the central nervous system. The appearance of various gastrointestinal symptoms, including dyspepsia, diarrhoea, or abdominal discomfort, is known to occur when people are under stress. William Beaumont's preliminary evaluation of the injured soldier with the gastric fistula demonstrated that anxiety or fury can have a major impact on the physiology of the stomach, particularly on the release of acid(10).The nineteenth-century discovery of the enteric nervous system (ENS) was a significant advance in our understanding of the relationships between the gut and the central nervous system (CNS). The ENS (sometimes referred to as the "little brain") is essential for controlling the physiological processes of the gut, such as the release, secretion, and motility of several hormones and neuropeptides(11).

Fig. 3. Impact of stress on brain-gut-microbiota axis. There is a bidirectional interaction between braingut axis and gut microbiota

The brain-gut axis (BGA) refers to the various parallel channels that the brain and gut use to interact, including the autonomic nervous systems (ANS), the hypothalamus pituitary-adrenal axis (HPA), and other linkages(12-13) (Fig. 3). There is compelling evidence from earlier research that stress exposure may be the cause of the dysregulation of the BGA, which in turn may result in various gastrointestinal disorders(14).Corticotrophin releasing factor (CRF) is a key regulator of the immunological, behavioural, and endocrine responses to stress. The CRF family of peptides exhibits strong biologic effects and is expressed in both the stomach and the central nervous system. By modifying inflammation, increasing gut permeability, contributing to visceral hypersensitivity (increased pain perception), and altering gut motility, CRF has strong impacts on the gut. The beginning phase of HPA activation involved in the stress response is CRF production in the hypothalamus. This is the main endocrine system that reacts to stress. In response to CRF, the pituitary gland releases adrenocorticotropic hormone (ACTH), which causes the adrenal glands to release more cortisol, a stress hormone(15).

FIG  4: The central nervous system (CNS, brain, and spinal cord) and the enteric nervous system (ENS) communicate continuously and in both directions.

The central nervous system (CNS, brain, and spinal cord) and the enteric nervous system (ENS) communicate continuously and in both directions. Through the sympathetic nervous system's efferent motor routes of the prevertebral ganglia and the parasympathetic nervous system's afferent sensory pathways of the vagus nerve, the gut and the brain can communicate. The intestinal microbiome also influences the brain-gut axis. By affecting the ENS and producing chemicals that can pass through the blood-brain barrier, the microbiota can either directly or indirectly affect the central nervous system (CNS) through the vagus nerve. As

a neurotransmitter in the ENS and CNS and a hormone that circulates throughout the body, serotonin (5-HT) plays a crucial role in brain-gut communication. Tryptophan hydroxylase 1 (TPH1) in enterochromaffin (EC) cells and TPH2 in neurones synthesise 5-HT, which is mainly inactivated by the serotonin reuptake transporter (SERT) following reuptake. TPH, tryptophan hydroxylase; MAO, monoamine oxidase; 5-HT, 5-hydroxytryptamine; 5-HIAA, 5-hydroxyindoleacetic acid; Trp, tryptophan(Fig. 4).

Additionally, there is proof that gut bacteria maintain the two-way communication between the gut axis and brain components. Stated differently, stress alters the bacterial ecology, but the gut bacteria also alter motility, permeability, and visceral sensitivity, which may have a significant impact on the BGA. The BGA and microbiota interact via a variety of methods: 1) endocrine message by direct contact with mucosal cells, 2) immune message through immune cells, and 3) neural message through contact with neural terminals(16). Stress alters the microbiota's makeup by causing alterations to neurotransmitter and proinflammatory cytokine levels, which may have an indirect or direct impact on the microbiota. For instance, norepinephrine makes certain bacteria, such as C. jejuni or E. coli, more virulent. Certain probiotics may prevent intestinal permeability and hypersensitivity brought on by stress exposure, and gut bacteria may regulate pain perception. The remarkable interplay of stress, the immune system, and the gut microbiota is demonstrated by several lines of evidence(17).Mast cells are crucial for the translation of stress signals to the human stomach. Remarkably, these cells carry CRF receptors on their surface and release several significant mediators, suggesting a significant connection between stress and these cells(18,19).

 Lastly, prolonged and excessive activation of the CNS's stress response regions is linked to chronic stress exposure. The brain regions in charge of gut pain perception may possibly undergo irreversible alterations as a result of this exposure. Techniques known as functional magnetic resonance imaging (MRI) can be used to demonstrate these changes(20).

Pathophysiology: Clinical Consequences Of The Dysregulation Of Brain-Gut-Microbiota Axis In The Upper Gastrointestinal Tract

The development of a wide range of gastrointestinal disorders, including gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), IBD, IBS, and even food allergies, may result from the dysregulation of BGA brought on by stress(21,22)(Fig. 5). PUD may develop as a result of exposure to stressful life events. Patients with ulcers have a greater tendency to be bereaved, divorced, or separated. It has been demonstrated that stress exposure may contribute to PUD and may hinder the gastric and duodenal defences against the damage caused by an attack from acid and pepsin damage, even though Helicobacter pylori (Hp) and nonsteroidal anti-inflammatory drugs (NSAID) are the major causes of the condition(23).

Fig 5: pathophysiological effects of stress-induced alteration of the brain-gut microbiota axis. Stress exposure disrupts the brain-gut axis (BGA), which contributes to the development of several gastrointestinal disorders, such as food allergies, irritable bowel disease, inflammatory bowel disease, peptic ulcer disease, and gastroesophageal reflux disease.

Variations in gastric acid production, decreased mucosal blood flow, decreased HCO3-secretion, decreased acid back diffusion, decreased proliferation and restitution of the wounded mucosa, and changes in stomach motility are some of the potential contributing variables. Stress was thought to be one of the main risk factors for peptic ulcers prior to the discovery of HP(24). Stress ulcerations, a unique type of ulceration brought on by prolonged exposure to stress, are frequently seen among patients in intensive care units(25).

Through the manipulation of several key neuropeptides (such as CGRP) involved in the protection of the gastric mucosa, changes in the secretion of gastric contents, regenerating of the gastric mucosa, and changes in mucosal blood flow, our own research showed that stress may have a significant impact on the BGA(26,27)(Fig.6).

Fig. 6.  Effect of disruption of brain-gut axis on ulcer healing. Exposure to stress and the resulting disturbance of brain-gut axis may have negative effect on ulcer healing including changes in gastric secretion, proliferation rate at the ulcer edge and angiogenesis

According to  analysis, the number of prevalent cases of PUD in 2019 was 8.09 million (95% UI 6.79 to 9.58 million), a 25.82% increase from 1990 [6.43 million (95% UI 5.41 to 7.63 million)]. Additionally, the age-standardized prevalence rate decreased from 1990 [143.37 per 100,000 (95% UI 120.54 to 170.25 per 100,000) population] to 99.40 per 100,000 (95% UI 83.86 to 117.55 per 100,000) population in 2019. There was a 27.3% increase in the number of PUD incident cases worldwide between 1990 and 2019, rising from 2.82 million (95% UI 2.36 to 3.30 million) to over 3.59 million (95% UI 3.03 to 4.22). At 63.84 (95% UI 54.09 to 75.54) per 100,000 people in 1990 and 44.26 (95% UI 37.32 to 51.87) per 100,000 population in 2019, the global age-standardized incidence rate of PUD, however, shown a declining trend. With an age-standardized rate of 74.40 (95% UI 68.96 to 81.95) DALYs per 100,000 population in 2019, PUD was responsible for over 6.03 (95% UI 5.59 to 6.64) million DALYs worldwide. Compared to 1990, the age-standardized rate of DALYs dropped by 60.64%. Deaths from PUD also showed similar patterns.

Males had a higher age-standardized prevalence rate and more prevalent cases than females in every year between 1990 and 2019. Nonetheless, the gap between the two groups narrowed, primarily as a result of boys' age-standardized prevalence rate and prevalent case count declining more quickly than females'. In total, there were 4.17 (95% UI 3.49 to 4.97) million prevalent cases in males and 3.92 (95% UI 3.29 to 4.64) million prevalent cases in females in 2019.

Between males and females, the prevalence of cases was 1:0.94. In 2019, the age-standardized prevalence rates for males and females were 104.98 (95% UI 88.26 to 124.10) and 94.23 (95% UI 79.10 to 111.93) per 100,000 population, respectively(28)(Fig. 7).

Fig 7: Prevalence rates and deaths with age-standardized rate changes in all years from 1990 to 2019. a The numbers of prevalent cases and age-standardized prevalence rates in males and females. b The numbers of deaths and age-standardized death rates in males and females

PROGNOSIS

Studies reveal a robust correlation between the prevalence of PUD and perceived stress. According to a long-term study of adults in the United States, those who reported high levels of stress were 1.8 times more likely to get ulcers than those who reported lower levels of stress. Additionally, the study revealed a graded association between ulcer occurrence and stress levels(29).In a similar vein, a Danish cohort study found that those who felt a lot of stress were more than twice as likely to get PUD than people who felt less stress. Even after controlling for variables including age, gender, socioeconomic level, use of NSAIDs, and smoking, this link persisted(30).

Prognostic Elements

Stress Level and Corresponding Illness:

Stress-related PUD is more likely to occur in critically ill patients, particularly those  in intensive care units with illnesses like sepsis or multiple organ failure syndrome. Ulcers can develop as a result of severe physical stressors including major operations, severe burns, or severe brain trauma(31).

Aspects of Psychology

An elevated risk of PUD has been associated with psychiatric disorders such as depression and anxiety as well as emotional stress. According to studies, psychological stress may have an impact on PUD's development and course.

Complications

Gastrointestinal Bleeding: Hematemesis (blood in the vomit) and melena (black, tarry faeces) are signs of bleeding ulcers, which is a serious problem in PUD associated with stress. In severe cases, surgery or blood transfusions can be required.(Fig 8)

Fig 8: Gastrointestinal Bleeding

Perforation: An incision in the stomach or duodenal wall caused by an ulcer may result in peritonitis, a serious abdominal infection that needs to be treated right once(Fig 9).

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