COVID-19-induced gastrointestinal autonomic dysfunction: A systematic review

Table 1 Factors affecting gastrointestinal autonomic nervous function

1 Psychological factors: Vigilance, stress, anxiety, and depression

2 Diet: A high-fat or protein diet slows digestion, while a high-fiber diet stimulates peristalsis

3 Exercise training: Moderate exercise can increase the motility and blood flow of the gastrointestinal tract. In contrast, prolonged or intense exercise can reduce blood flow to the gastrointestinal tract and shift blood flow to the muscles

4 Hormones: Cholecystokinin, gastrin, and secretin

5 Toxins: Such as toxic heavy metals (e.g., mercury or lead), alcohol, and industrial chemicals

6 Aging: Age-related neuronal loss in both intestinal myenteric and submucosal plexuses

7 Neurological disorders: Parkinson's disease, multiple sclerosis, amyloidosis, autonomic neuropathy, multiple system atrophy, amyotrophic lateral sclerosis, and autonomic dysreflexia such as in spinal cord injuries

8 Chronic metabolic disorders: Such as diabetes mellitus, hypothyroidism (hypothyroid gastroparesis and constipation), Addison's Disease (constipation, bloating, and abdominal discomfort), chronic kidney disease, chronic liver disease, Celiac disease, and inflammatory bowel disease

9 Infections: Viral gastroenteritis, bacterial infections (diphtheritic polyneuropathy, tetanus, and botulism), COVID-19, acute tick-borne encephalitis virus infections, Lyme disease, Chagas disease, human rabies, Guillain-Barre syndrome, and HIV/AIDS

COVID-19: Coronavirus disease 2019; HIV: Human immunodeficiency virus; AIDS: Acquired immunodeficiency syndrome.

Table 2 Summary of gastrointestinal symptoms encountered in patients with coronavirus disease 2019

Part of the digestive system	Symptoms
General symptoms	Anorexia (22.3%), early satiety
Oral cavity	Dysgeusia (early symptom 71% to 88.8%)
Esophagus	Heartburn, belching, chest pain, regurgitation, vomiting
Gastroduodenal tract	Epigastric burn, nausea, vomiting, peptic ulcer, bleeding
Pancreas	Elevated lipase, acute pancreatitis
Liver & biliary tract	Elevated liver enzymes, jaundice, acute cholecystitis
Lower gastrointestinal tract	Diarrhea (most common, 3% to 96%), abdominal pain (6.2%), bloating, irregular bowel movements, bleeding, ischemic colitis, constipation, intussusception

Table 3 Prevalence of gastrointestinal symptoms due to autonomic dysfunction in patients with coronavirus disease 2019, n (%)

Ref.	Type of Study	Number of patients		GIT manifestation(s)	Number & percentage
		Patients	Controls
Erdal et al[57], 2022	Cross-sectional	112	106	Diarrhoea	24 (21.8)
Varma-Doyle et al[58], 2023	Retrospective	6 (4 with previous dysautonomia and 2 with new onsets)	-	Nausea, vomiting, early satiety, bloating, irregular bowel movements, constipation	5 (83)
Scala et al[59], 2022	Observational, cross-sectional	38	38	Diarrhoea	10 (26.3)
Tan et al[60], 2020	Retrospective study	69 (without ACEI/ARB)	31 (ACEI/ARB)	Diarrhea (6.5% vs 14.5%), nausea and vomiting (9.7% vs 11.6%), abdominal pain (2.9% vs 6.5%)	40 (58)

ACEI: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin receptor blockers; GIT: Gastrointestinal tract.

Table 4 Risk factors of patients with coronavirus disease 2019 disease-induced gastrointestinal autonomic dysfunction

1 Severe disease

2 Presence of hyperinflammation and hypoxia

3 Longer duration of disease

4 Old age

5 Down-regulation of the IKBKAP gene

6 Up-regulation of N-type calcium channels

7 Presence of smell loss or dyspnoea

8 Presence of comorbidities characterized by high sympathetic activity, such as diabetes mellitus and hypertension

Table 5 Prevalence and underlying mechanism for common gastrointestinal autonomic dysfunction in patients with coronavirus disease 2019

Symptom(s)	Incidence	Underlying mechanism
Nausea and/or vomiting	Nausea: 1.0%-12.5%, vomiting 1.0%-27.5%	Release of neuroactive agents from enteroendocrine cells and inflammatory mediations → abdominal vagal nerve stimulation of dorsal medulla → projection of information to higher brain regions → nausea and vomiting
Diarrhea	2% and 50%	Targeting intestinal ACE2 by the virus → cytokine storms, increased intestinal barrier permeability, and gut dysbiosis → diarrhoea. Hepatic and pancreatic injuries may also cause diarrhea. Antibiotic-induced iatrogenic diarrhea caused by activating Clostridium spp. should also be considered
Anorexia	Up to 40%	Social pressure. Neuromodulation → miscommunication between brain-gut-adipose tissues → changes in brain serotonin and tryptophan concentrations → anorexia, anosmia, and related odor perception impairment → development and aggravation of anorexia
Abdominal pain	6.0% (vary depending on the population)	Inflammation-induced release of many cytokines and chemokines → activating pain-sensing neurons. ↑ Eosinophils → ↑eosinophil-derived neurotoxins → abdominal pain. Intestinal inflammatory infiltration → ↑ intestinal mucosal permeability and the direct effect of viruses can aggravate dysbiosis and cause changes in. Tryptophan metabolism → initiating peristaltic and secretory reflexes in the viscera and exacerbating inflammatory bowel disease symptoms, including abdominal pain. COVID-19 infection → ↓Na, K, Ca, and Mg → abdominal pain
Acid reflux	1.1%	Increased serotonin levels. Esophageal mucosal barrier damage caused by cytokine storms. Relaxation of the lower esophageal sphincter. Gastric and duodenal dysfunction leading to obstruction of gastric emptying
Gastrointestinal bleeding	1%-4.5%	Peptic and rectal ulcers. Impaired gastrointestinal mucosa integrity. Treatment-related (secondary bleeding)
Intestinal ischemia injury	Not well established	Venous thrombosis, pulmonary embolism, and mesenteric ischemia

ACE2: Angiotensin-converting enzyme 2; COVID-19: Coronavirus disease 2019.

Table 6 Different coronavirus disease 2019 vaccination-related autonomic dysfunction and gastrointestinal manifestations

Ref.	Type of Study	Country	Type of vaccine	Time-interval	Number of patients	Age	Sex	Main presentation	GIT manifestations
Hermel et al[79], 2022	Case report	United States	Pfizer-BioNTech	2 wk	1	46	F	POTS	Elevated AST
Reddy et al[80], 2021	Case report	United States	Pfizer-BioNTech	6 d	1	42	M	POTS	His symptoms increased after heavy meals
Lanman et al[81], 2022	Case report	United States	Pfizer/BioNTech mRNA-BNT162b2	3 d (1st dose)	1	58	F	GBS	Constipation
Eldokla et al[82], 2022	Case report	United States	Moderna (1) Pfizer/BioNTech (4)	1-3 wk	5	17- 46	F	POTS	Dry mouth (1), constipation (1), nausea (2), bloating (1)
Tahir et al[83], 2021	Case report	United States	Johnson & Johnson/Janssen	10 d	1	44	F	Transverse myelitis & Bell's palsy	Nausea
Hilts et al[84], 2022	Case report	United States	Moderna	3 d	1	58	M	GBS	Diarrhoea (stopped before symptoms)
Fitzsimmons et al[85],2021	Case report	United States	Moderna	1 d (2nd dose)	1	63	M	Transverse myelitis	Constipation
Akaishi et al[86], 2022	Retrospective cohort study	Japan	Moderna		131544	≥ 16	M/F 1.2:1	Variable	Nausea (0.27%); abdominal pain (0.006%)
Antonelli et al[87], 2022	Prospective community-based case-control	United Kingdom	BNT162b2, ChAdOx1 nCoV-19, mRNA-1273	1-2 wk	9462	> 18 Mean age: 52.9 years		Variable	Abdominal pain, nausea, diarrhoea

Johnson & Johnson/Janssen is Ad26.COV2. Pfizer-BioNTech is an mRNA SARS-CoV-2 vaccine, ChAdOx1 nCoV-19 is Oxford University Vaccine using chimpanzee adenoviral vector ChAdOx1, containing the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-19) gene. mRNA-1273 is the Moderna COVID-19 vaccine. POTS: Postural orthostatic tachycardia syndrome; Time-interval: The time between vaccination intake and the development of the symptoms. AST: Aspartate aminotransferase; BNT162b2: Pfizer-BioNTech mRNA severe acute respiratory syndrome coronavirus 2 vaccine; GBS: Guillain-Barre syndrome; GIT: Guideline-informed treatment; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; COVID-19: Coronavirus disease 2019.

Table 7 Differential diagnosis of gastrointestinal autonomic dysfunction in patients with coronavirus disease 2019

Condition		Comments
Gastrointestinal disorders	Gastrointestinal dysmotility	Gastrointestinal dysmotility refers to abnormal movement in the digestive system that can cause symptoms such as nausea, vomiting, abdominal pain, and bloating. COVID-19-induced gastrointestinal autonomic dysfunction can cause similar symptoms, making it essential to distinguish between the two
	Gastroesophageal Reflux disease	Gastroesophageal reflux disease is a common condition that occurs when stomach acid flows back into the esophagus, causing heartburn and other symptoms. It can be diagnosed by an upper endoscopy or an esophageal pH test
	Gastroparesis	Gastroparesis is a disorder in which the stomach takes too long to empty its contents, causing symptoms such as nausea, vomiting, and bloating
	Gastritis	This condition is inflammation of the gastric mucosa. It can cause abdominal pain, nausea, and vomiting
	Peptic ulcer disease	This condition is characterized by sores in the lining of the stomach or duodenum and can cause abdominal pain and vomiting
	Gastrointestinal infections	Viral, bacterial, or parasitic infections can cause similar symptoms to COVID-19-induced gastrointestinal autonomic disorders and may require specific testing and treatment. For example: Other viral infections, such as norovirus, adenovirus, and rotavirus, can also cause gastrointestinal symptoms like COVID-19-induced gastrointestinal autonomic disorders. Considering these infections in the differential diagnosis is important, especially if the patient has a recent travel history or exposure to infected individuals. Some bacterial infections, such as Clostridium difficile infection, can cause gastrointestinal symptoms like those of COVID-19. Clostridium difficile infection can also cause autonomic dysfunction, leading to symptoms such as dizziness and fainting. Other bacteria like Salmonella, Shigella, Campylobacter, and Escherichia coli can produce gastrointestinal symptoms. Parasitic infections such as infection with Giardia lamblia, Entamoeba histolytica, and Cryptosporidium can cause diarrhea and other gastrointestinal symptoms
	Acute pancreatitis	This condition can cause abdominal pain, vomiting, and diarrhea, which may be like COVID-19-induced gastrointestinal autonomic dysfunction. Blood tests and imaging studies can help diagnose pancreatitis
	Gallstones	Gallstones can cause abdominal pain, nausea, and vomiting
	Cholecystitis	It is gallbladder inflammation, which can cause symptoms such as abdominal pain, nausea, vomiting, and fever
	Inflammatory bowel disease	Crohn's disease and ulcerative colitis can cause diarrhea, abdominal pain, and vomiting, which may be like COVID-19-induced gastrointestinal autonomic dysfunction. Endoscopy and stool tests can help to distinguish inflammatory bowel disease from other causes
	Irritable bowel syndrome	Irritable bowel syndrome is a chronic condition that causes abdominal pain, bloating, and changes in bowel habits. These symptoms may be similar to COVID-19-induced gastrointestinal autonomic dysfunction, but irritable bowel syndrome is a non-inflammatory condition
	Post-infectious irritable bowel syndrome	Post-infectious irritable bowel syndrome is a subtype of irritable bowel syndrome that occurs following an infection. This condition can cause similar symptoms to COVID-19-induced gastrointestinal autonomic dysfunction
	Celiac disease	Celiac disease is an autoimmune disorder that affects the small intestine, causing symptoms such as diarrhea, abdominal pain, and bloating
	Small intestinal bacterial overgrowth	Small intestinal bacterial overgrowth is a condition in which there is an overgrowth of bacteria in the small intestine, leading to symptoms such as diarrhea, bloating, and abdominal pain. It can be diagnosed through a breath test and a physical exam
	Gastrointestinal malignancies	Gastrointestinal malignancies such as colon cancer, gastric cancer, or pancreatic cancer, can cause abdominal pain, bloating, nausea, vomiting, and changes in bowel habits
Food-related disorders	Food poisoning	Food poisoning is a bacterial or viral infection caused by consuming contaminated food, causing symptoms such as diarrhea, nausea, vomiting, and abdominal pain
	Food intolerance	Lactose intolerance or gluten intolerance can cause gastrointestinal symptoms
Endocrine disorders	Hyperthyroidism, diabetes, adrenal insufficiency	Certain hormonal imbalances, such as hyperthyroidism, diabetes, or adrenal insufficiency, can cause gastrointestinal symptoms and autonomic dysfunction. For example, in diabetic neuropathy, diabetes can damage the nerves that control the gastrointestinal system, leading to symptoms such as delayed gastric emptying and gastroparesis. Diabetic gastroparesis symptoms include nausea, vomiting, bloating, and early satiety
Psychiatric disorders	Stress, anxiety, somatization disorders, depression	Conditions such as stress, anxiety, somatization disorders, and depression can cause gastrointestinal symptoms such as nausea and vomiting and symptoms of autonomic dysfunction, such as rapid heartbeat and sweating. It is essential to assess the patient's mental health and history of psychiatric disorders to determine if psychological factors may contribute to the patient's presentation
Neurological disorders	Parkinson's disease, multiple sclerosis, multiple system atrophy, pure autonomic failure	Certain neurological disorders can cause autonomic dysfunction, including Parkinson's disease, multiple sclerosis, multiple system atrophy, and pure autonomic failure. For example, Parkinson's disease can cause gastrointestinal symptoms such as constipation and difficulty swallowing
Autonomic nervous system dysfunction	Postural orthostatic tachycardia syndrome	Postural orthostatic tachycardia syndrome is a condition that causes an abnormal increase in heart rate when changing position from lying down to standing up. Symptoms can include gastrointestinal symptoms such as nausea, vomiting, and abdominal pain
	Autonomic neuropathy	Autonomic neuropathy is a condition that affects the nerves that control the body’s automatic functions, including the gastrointestinal system. It can cause symptoms such as delayed gastric emptying, constipation, and gastroparesis
Metabolic disorders		Metabolic disorders such as liver disease, kidney disease, and electrolyte imbalances can cause gastrointestinal and autonomic symptoms
Medications		Certain medications include opioids, anticholinergics, antibiotics, antihypertensives (e.g., calcium channel and beta blockers), nonsteroidal anti-inflammatory drugs, corticosteroids, chemotherapy drugs, and proton pump inhibitors, which can cause gastrointestinal symptoms

COVID-19: Coronavirus disease 2019.

Table 8 Treatment of gastrointestinal autonomic dysfunction in patients with coronavirus disease 2019

Treatment	Comments
Infection control measures	To prevent the spread of COVID-19, following the public health guidelines, such as social distancing, wearing a face mask, and practicing ‎good hand hygiene
Treatment of COVID-19	Treatment of COVID-19 should be made on a case-by-case basis, based on the severity of COVID-19 and the patient's overall health status
	Antiviral therapy such as Remdesivir and Molnupiravir, could be used in patients with COVID-19 to reduce the severity and duration of the illness. However, there is limited evidence for the effectiveness of antiviral therapy for COVID-19-induced gastrointestinal autonomic dysfunction
	Immunomodulatory therapy in severe cases of COVID-19-induced gastrointestinal autonomic dysfunction, such as corticosteroids or monoclonal antibodies such as Tocilizumab, may be needed to reduce inflammation and prevent complications
	Oxygen therapy may be needed
	Manage any other COVID-19-related complications that may arise
Supportive management	ORT, intravenous fluids, and electrolyte replacement therapy
	Getting enough rest is crucial to enhance recovery
Symptomatic treatment	Management for abdominal pain with antispasmodics and analgesics such as acetaminophen or nonsteroidal anti-inflammatory drugs. Avoid using anticholinergics or opioids, as they can exacerbate gastrointestinal autonomic dysfunction
	For nausea and vomiting: Antiemetic and prokinetics such as ondansetron or metoclopramide
	For diarrhoea: Antidiarrheals such as loperamide or bismuth subsalicylate
	Constipation: Laxatives
	Caution should be taken as symptomatic treatment may mask underlying symptoms of COVID-19
Managing autonomic dysfunction	Using medications such as alpha-adrenergic agonists, beta-blockers, or anticholinergic medications to regulate the autonomic nervous system, depending on the specific symptoms and severity of autonomic dysfunction. However, these medications must be used cautiously, as they can induce side effects and interact with other medications. Specific treatment for orthostatic hypotension, tachycardia, and syncope should be according to the guidelines
Treatment of complications	Treatment of dehydration and electrolyte imbalances, especially in children and the elderly
	Treatment of gastroparesis: Prokinetic agents, such as erythromycin or metoclopramide, may be needed to promote gastric emptying, improve gastrointestinal motility, relieve gastroparesis symptoms, and relieve symptoms of constipation
	Treatment of malnutrition
	Treatment of bowel obstruction or perforation: Surgical management
	Treatment of bacterial superinfections and/or sepsis
	Severe disease may may require ICU admission, mechanical ventilation, or ECMO support
Treating underlying conditions	IBD: Anti-inflammatory drugs, immunosuppressants such as corticosteroids, immunomodulators, biologic therapies, and antibiotics with adjustments to their regular treatment regimen or referral to a specialist. Diet modifications by avoiding trigger foods that exacerbate symptoms may help manage IBD symptoms. A low FODMAP diet may be beneficial for some people with IBD. Stress management and regular exercise could help. Surgery may be indicated in severe cases
	IBS: Diet modifications medications such as antispasmodics, laxatives, and antidepressants to help alleviate symptoms, probiotics, stress management, and regular exercise
	Malignancy therapy should be personalized according to the type of malignancy by surgery, chemotherapy, radiotherapy, palliative therapy, immunomodulators, and supportive care
Nutritional support	Maintain adequate caloric intake, prevent malnutrition, follow a bland diet, and avoid spicy, fatty, or acidic foods that may worsen symptoms
	Nutritional support may be necessary for patients with decreased appetite or weight loss
	Nutritional supplements or enteral or parenteral nutrition according to the situation
	Probiotics positively affect the gut microbiota, improving gut dysbiosis that is common in gastrointestinal disorders and helping improve gastrointestinal symptoms such as bloating, constipation, and diarrhea. Prebiotics promote the growth of beneficial gut bacteria, which can improve gut health and potentially alleviate the associated symptoms. The optimal dosage, duration, and strains of probiotics/prebiotics could differ depending on the patient’s characteristics and the underlying pathophysiology of gastrointestinal autonomic dysfunction
Psychological support	Treatment of psychological distress induced by the symptoms of gastrointestinal autonomic dysfunction
	Psychological support, such as counseling or psychotherapy
Follow-up and Rehabilitation care	Regular check-ups with a healthcare professional may be necessary depending on the severity of the condition
	Aiming to monitor the resolution of symptoms, prevent long-term complications, and improve the patient's quality of life and functional status
	Rehabilitation may include occupational therapy, physical therapy, speech therapy, and psychological support to manage potential complications and improve the overall quality of life
	Physical therapy can help manage autonomic dysfunction symptoms, including gastrointestinal symptoms. Physical activities such as postural changes and deep breathing exercises can facilitate improved blood flow and reduce the symptoms

COVID-19: Coronavirus disease 2019; ECMO: Extracorporeal membrane oxygenation; FODMAP: Fermentable oligo-, di-, and monosaccharides and polyols; IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome; ICU: Intensive care unit; ORT: Oral rehydration therapy.