Post-COVID Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that affects 9-23% of the global population. While the exact cause of IBS is unknown, it is believed to be a combination of genetic, environmental, and psychological factors. One potential trigger of IBS is infectious illness. Studies have shown that between 3% and 36% of enteric infections can lead to the development of new IBS symptoms, with post-viral IBS being more transient than post-bacterial or post-protozoal IBS. Meta-analysis of published literature found that the incidence of new IBS 12 months after infection was 10.1% (95% confidence interval (CI) 7.2–14.1). The incidence appears higher after parasitic or protozoan infections at 49% compared to 13.8% after bacterial gastroenteritis.

The COVID-19 pandemic has highlighted the potential link between infections and IBS, as many patients with COVID-19 have developed gastrointestinal symptoms, including diarrhea, nausea, vomiting, and abdominal discomfort. In fact, infection of the GI tract is thought to trigger symptoms in approximately 15% of COVID-19 patients. Post-COVID-vaccination gastrointestinal occurrences were reported in 10–20% of cases and the risk of a disease flare in IBS and IBD patients was close to 10%. 

Persistent symptoms after SARS-COV-2 infection, known as Post-acute Sequelae of COVID-19 (PASC) or long-COVID, may occur in anywhere from 10-55% of those who have had COVID-19, New study found that the most common new diagnoses caused by Long Covid were tachycardia, followed by Postural Orthostatic Tachycardia Syndrome (POTS), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and IBS.

This chart shows the 0roportion of individuals diagnosed with various conditions by severity of mobility disability. Red are cardiopulmonary diagnoses (AF - atrial fibrillation, Blood Clot, Cardiomyopathy, Pericarditis, PE – pulmonary embolism, POTS – postural orthostatic tachycardia syndrome, Myocarditis, Tachycardia), light green are gastrointestinal (Irritable Bowel Disease, Irritable Bowel Syndrome), blue-green are neurologic diagnoses (MS – multiple sclerosis, ME – myaligic encephalomyelitis/chronic fatigue syndrome, PN – peripheral neuropathy, Stroke), and dark green are metabolic/renal diagnoses (AKD - acute kidney disease, Hyperthyroid, Hypothyroid, Type 1 Diabetes, Type 2 Diabetes). A little over 3% of IBS sufferers do not feel disabled, while over 10% are severely disabled.  

There are several risk factors for the development of PI-IBS, including female gender, previous antibiotic treatment, anxiety, depression, somatization, neuroticism, and clinical indicators of intestinal inflammation. A history of Clostridioides difficile infection (CDI) may also increase the risk of PI-IBS by up to 25%. Underlying possible mechanisms include ongoing increased permeability, abnormal serotonin metabolism, and ongoing chronic immune activation together with altered microbiota. 

REFERENCES

Chan WW, Grover M. The COVID-19 Pandemic and Postinfection Irritable Bowel Syndrome: What Lies Ahead for Gastroenterologists. Clinical Gastroenterology and Hepatology. 2022 Aug 6. 

Gabashvili IS. The Incidence and Effect of Adverse Events Due to COVID-19 Vaccines on Breakthrough Infections: Decentralized Observational Study with Underrepresented Groups. JMIR Formative Research. 2022 Nov 4;6(11):e41914. doi: 10.2196/41914. PMID: 36309347; PMCID: PMC9640199.

Ghoshal UC. Postinfection irritable bowel syndrome. Gut and Liver. 2022 May 5;16(3):331.

Lau B, Wentz E, Ni Z, Yenokyan K, Coggiano C, Mehta SH, Duggal P. Physical and mental health disability associated with long-COVID: Baseline results from a US nationwide cohort. medRxiv. 2022 Dec. 7

Lau B, Wentz E, Ni Z, Yenokyan K, Coggiano C, Mehta SH, Duggal P. Physical and mental health disability associated with long-COVID: Baseline results from a US nationwide cohort. medRxiv. 2022 Jan 1.

Nazarewska A, Lewandowski K, Kaniewska M, Rosołowski M, Marlicz W, Rydzewska G. Irritable bowel syndrome following COVID-19: underestimated consequence of infection with SARS-CoV-2. Polish archives of internal medicine.:16323.

Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology. 2009 May 1;136(6):1979-88.

Thabane M, Marshall JK. Post-infectious irritable bowel syndrome. World journal of gastroenterology: WJG. 2009 Aug 8;15(29):3591.

 

Lipid dysregulation

Compared to control subjects, patients with IBS show significantly higher lipid levels in their blood. Elevated levels of certain lipids, such as arachidonic acid, in plasma may even serve as putative biological markers in this condition. Lipids have been shown to sensitize mechanoreceptor response and increase perception of gut distention. Some of probiotics beneficial to irritable bowel - such as Lactobacillus or Bifidobacterium - are related to the lipid metabolism displaying lipid-lowering effects.

Dysregulation of lipid metabolism has been a hallmark of many other diseases and conditions including cancer and COVID-19.

Lipids play a crucial role throughout the viral life cycle, and viruses are known to exploit lipid pathways to affect host metabolism. Numerous observational studies have shown potential beneficial effects of lipid-lowering treatment on the course of COVID-19 with significant improved prognosis and reduced mortality. On the other hand, bioactive lipids have been proposed as potential drugs helping to combat COVID-19.  

Here is what we know.

Glycerolipids and glycerophospholipids are markers of severe COVID-19, increased in ARDS (acute respiratory distress syndrome). Lipid storm can be self-destructive enhancing peptide-mediated cytokine storms. Dysregulation of lipid metabolism may be a defining feature of the severity of COVID-19. 

Shorter chain lipids were found at increased levels after successful COVID vaccination.

Sphingolipids, especially Sphingomyelin (SM) that associates with cholesterol to form lipid rafts that promote Coronavirus entry on the cellular surface (help viral S-protein to bind the cellular receptor ACE2) are decreased in asymptomatic patients. Other ether lipids [including PC O-35:4 (i), LPC O-18:1 (i) and LPE O-18:2], sphingomyelin (SM34:1; O2), and fatty acids (including FA 18:1 and FA 20:0) are also decreased in asymptomatic COVID.

Lysophospholipids including lysophosphatidylserine (LPS) 18:1, lysophosphatidic acid (LPA) 18:1 and LPA 18:0, lysophosphatidylcholine (LPC) 22:1, and lysophosphatidylinositol (LPI) 18:1 are generally decreased in asymptomatic COVID-19 patients. - Diacylglycerol (DG) 30:0 (14:0_16:0), DG 36:5 (18:2_18:3), phosphatidylcholine (PC) 36:5 (18:2_18:3), and phosphatidylethanolamine (PE) 36:2 (18:0_18:2) are increased. These lipids seem to have a protective effect in COVID-19.

Bioactive lipids - phospholipids including Plasmalogens and PAFs, gamma-linolenic acid (GLA), dihomo-GLA (DGLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) help cells of the innate immune system - macrophages - with phagocytosis. Targeting membrane sphingolipids and interfering with the virus lipid metabolism could represent a promising path to follow towards the development of COVID-19 treatments. 

REFERENCES

Lee SH, Kim KN, Kim KM, Joo NS. Irritable bowel syndrome may be associated with elevated alanine aminotransferase and metabolic syndrome. Yonsei medical journal. 2016 Jan 1;57(1):146-52.

Serra J, Salvioli B, Azpiroz F, Malagelada JR. Lipid-induced intestinal gas retention in irritable bowel syndrome. Gastroenterology. 2002 Sep 1;123(3):700-6.

Schwarz B, Sharma L, Roberts L, Peng X, Bermejo S, Leighton I, Casanovas-Massana A, Minasyan M, Farhadian S, Ko AI, Cruz CS. Cutting edge: Severe SARS-CoV-2 infection in humans is defined by a shift in the serum lipidome, resulting in dysregulation of eicosanoid immune mediators. The Journal of Immunology. 2021 Jan 15;206(2):329-34.

Hao Y, Zhang Z, Feng G, Chen M, Wan Q, Lin J, Wu L, Nie W, Chen S. Distinct lipid metabolic dysregulation in asymptomatic COVID-19. Iscience. 2021 Sep 24;24(9):102974.

Surma S, Banach M, Lewek J. COVID-19 and lipids. The role of lipid disorders and statin use in the prognosis of patients with SARS-CoV-2 infection. Lipids in Health and Disease. 2021 Dec;20(1):1-4.

Casari I, Manfredi M, Metharom P, Falasca M. Dissecting lipid metabolism alterations in SARS-CoV-2. Progress in Lipid Research. 2021 Feb 8:101092.

Demopoulos CA. Is Platelet-Activating Factor (PAF) a missing link for elucidating the mechanism of action of the coronavirus SARS-CoV-2 and explaining the side effects-complications of Covid-19 disease?.

Deng Y, Angelova A. Coronavirus-Induced Host Cubic Membranes and Lipid-Related Antiviral Therapies: A Focus on Bioactive Plasmalogens. Frontiers in Cell and Developmental Biology. 2021 Mar 12;9:551.

Martín-Fernández M, Aller R, Heredia-Rodríguez M, Gómez-Sánchez E, Martínez-Paz P, Gonzalo-Benito H, Sánchez-de Prada L, Gorgojo Ó, Carnicero-Frutos I, Tamayo E, Tamayo-Velasco Á. Lipid peroxidation as a hallmark of severity in COVID-19 patients. Redox biology. 2021 Dec 1;48:102181.

Das UN. Bioactive lipids-based therapeutic approach to COVID-19 and other similar infections. Archives of Medical Science. 2021.

Autoimmune diseases and COVID-19 vaccines

Autoimmune diseases occur when the immune system attacks the healthy body tissue within digestive track, joints, vasculature and other organ systems. This causes inflammation, pain, diminished mobility, fatigue, and other non-specific symptoms.  

Nearly 4% of the world’s population and 5-8% of U.S. is affected by an autoimmune diseases, the most common of which include type 1 diabetes, multiple sclerosis, rheumatoid arthritis, lupus, Crohn’s disease, and psoriasis. 

There is no evidence that any vaccines cause flares of autoimmune diseases, used to say doctors. However, there is limited data available since individuals with autoimmune diseases were excluded from phase I–III vaccine trials. And it is known that immunizations could cause flare ups (see, eg, this study of 2020/2021 flu vaccines). Preliminary data from smaller studies and case reports after emergency-use-authorization for SARS-CoV-2 suggest there is a possibility.

A case of a white 55-year-old male who has been in sustained remission from rheumatoid arthritis for more than 2 years describes him developing an acute flare of his rheumatoid arthritis 12 h after the second BNT162b2 vaccination (similarly to flares observed after COVID-19 infection). The patient was treated with intra-articular steroids with rapid improvement, and he is once again in clinical remission.

23-year-old woman who developed acute reactive arthritis on her left knee joint after COVID-19 vaccination with Sinovac CoronaVac was back on her feet in 2 days, after she was administered a single intra-articular injection of 1 ml compound betamethasone.

A 20-year-old man with a history of multiple sclerosis experienced acute myocarditis after the third dose of SARS-COV-2 vaccine (AstraZeneca vaccine). He had received the first and second dose of the SARS-COV-2 vaccine (Sinopharm vaccine) 5 and 4 months before.

More recently published, 27 case reports from Israel, US and UK described 17 flares and 10 new onset immune-mediated diseases. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female.

A study that compared 26 people with autoimmune disorders aged 24 to 89 (Rheumatoid arthritis, Crohn's disease, Psoriatic Arthritis, Sarcoidosis, Lupus, etc; none had been infected with SARS-CoV-2 prior to vaccination) with 42 healthy controls. Patients with autoimmune diseases had a marginal propensity towards more vaccine side effects compared with healthy controls: mild fatigue and myalgia were more frequent  (53.8% vs 43.2% and 42.3% vs 31.6%) and so was headache (38.5% vs 35.1%). Fever, on the other hand, was completely absent in patients with inflammatory diseases while being reported by 13.5% of the healthy cohort. Arthralgia was comparable in both groups. 

Researchers from two different rheumatology departments in Israel monitored 491 patients with autoimmune inflammatory rheumatic diseases (AIRD) and compared their reactions to 99 healthy controls. Shortly after receiving the vaccine, 1.2% of those with AIIRD (six patients total, age range: 36 to 61) developed their first case of shingles compared to none of the controls. Four of the six affected individuals had stable rheumatoid arthritis, one had Sjögren’s syndrome and another one had undifferentiated connective disease. Notably, one patient developed Herpes zoster despite being vaccinated for it two years prior to the reported event.

Multiple cases of apparent secondary immune thrombocytopenia (ITP), an unusual immune reaction triggered  after SARS‐CoV‐2 vaccination have been reported and reached public attention. 

One case was actually a flareup for a patient with a past medical history of  autoimmune bleeding disorder Immune thrombocytopenia (ITP). This patient received the first dose of SARS‐CoV‐2 mRNA‐1273 Moderna Covid‐19 vaccine 2 weeks prior to presentation. Three other individuals that experienced thrombocytopenia had known autoimmune conditions including hypothyroidism, Crohn's disease, or tested positive for anti‐thyroglobulin antibodies. Given that a small percentage of patients with lupus and antiphospholipid syndrome have been previously shown to display serum antibodies against PF-4 in association with thrombotic events constant vigilance is warranted.

Preliminary results of the COVID-19 Back to Normal study  show that some individuals with autoimmune diseases do experience flareups and higher frequency of adverse reactions such as enlarged lymph nodes. A smaller percentage of people claim they actually observed improvement in their autoimmune conditions after vaccinations You can help by submitting your observations about effects of vaccinations: https://forms.gle/5xs4XzFUFkhpa2TA9

REFERENCES

Buttari F, Bruno A, Dolcetti E, Azzolini F, Bellantonio P, Centonze D, Fantozzi R. COVID-19 vaccines in multiple sclerosis treated with cladribine or ocrelizumab. Multiple Sclerosis and Related Disorders. 2021 May 4:102983.

Geisen UM, Berner DK, Tran F, Sümbül M, Vullriede L, Ciripoi M, Reid HM, Schaffarzyk A, Longardt AC, Franzenburg J, Hoff P. Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort. Annals of the Rheumatic Diseases. 2021 Mar 24.

Furer V, Zisman D, Kibari A, Rimar D, Paran Y, Elkayam O. Herpes zoster following BNT162b2 mRNA Covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series. Rheumatology (Oxford, England). 2021 Apr 12.

Lee EJ, Cines DB, Gernsheimer T, Kessler C, Michel M, Tarantino MD, Semple JW, Arnold DM, Godeau B, Lambert MP, Bussel JB. Thrombocytopenia following Pfizer and Moderna SARS‐CoV‐2 vaccination. American Journal of Hematology. 2021 Feb 19.

Moutsopoulos HM. A recommended paradigm for vaccination of rheumatic disease patients with the SARS-CoV-2 vaccine. Journal of Autoimmunity. 2021 May 1:102649.

Terracina KA, Tan FK. Flare of rheumatoid arthritis after COVID-19 vaccination. The Lancet. Rheumatology. 2021 Mar 30. 

Toom S, Wolf B, Avula A, Peeke S, Becker K. Familial thrombocytopenia flare‐up following the first dose of mRNA‐1273 Covid‐19 vaccine. American Journal of Hematology. 2021 Feb 13.

Qi-jun An, De-an Qin & Jin-xian Pei (2021) Reactive arthritis after COVID-19 vaccination, Human Vaccines & Immunotherapeutics, DOI: 10.1080/21645515.2021.1920274

Watad A, De Marco G, Mahajna H, Druyan A, Eltity M, Hijazi N, Haddad A, Elias M, Zisman D, Naffaa ME, Brodavka M. Immune-Mediated Disease Flares or New-Onset Disease in 27 Subjects Following mRNA/DNA SARS-CoV-2 Vaccination. Vaccines. 2021 May;9(5):435.

Irritable Bowel and COVID-19

The first symptoms of Coronavirus disease  (day 0) begin from two to 14 days after exposure to the virus (marked as day –5 in the figure below, since median time is about five days). The disease affects

different people in different ways. A recent article identified 6 distinct types of COVID-19 with different symptoms,  some of which are hallmarks of the most severe forms of the disease. SARS-CoV-2-infected patients usually first experience a fever. The fever is often followed by a dry cough or fatigue and muscle pain, followed by GI tract symptoms, if they ever occur. Some people, experience nausea or have diarrhea in the days just before the fever begins. 

Gastrointestinal symptoms are reported in about one third of COVID-19 cases, the most common is loss of appetite  - it can happen even in the mildest form of the disease. Nausea/vomiting and diarrhea are slightly less common. Abdominal pain is even less widely known in COVID-19, yet it is  - along with shortness of breath and confusion - is a potential sign of the most severe form of COVID-19. In children, having gastrointestinal symptoms was more frequently associated with severe and critical phenotype (Giacomet et al, 2020). Hyperinflammatory syndrome was presenting with both cardiac and significant GI symptoms (diarrhea, vomit, abdominal pain).

Some researchers suggest that gut dysfunction may exacerbate the severity of infection by enabling the virus to access the surface of the digestive tract and internal organs. These organs are vulnerable to infection because they have widespread ACE2—a protein target of SARS-CoV-2 for its possible routes of entry —on the surface.  ACE2 is abundantly present in the epithelia of the lung and small intestine.

Yet, even if SARS-CoV-2 reaches the GI tract, it may not cause GI problems. An inflamed leaky gut, however, may be associated with a higher risk of severe illness and the microbial imbalance of the gut affecting gut barrier integrity can allow pathogens and pathobionts easier access to cells in the intestinal lining.

Several studies have already demonstrated that, when compared with healthy individuals, COVID-19 patients present a significantly reduced bacterial diversity and higher abundancy of opportunistic Streptococcus, Rothia, Veilonella, and Actinomyces compared to depleted levels of beneficial Agathobacter, Fusicatenibacter, Roseburia, and Ruminococcaceae UCG-013. Rothia was preeviously thought to contribute to the pathogenesis of pneumonia. Critically ill patients on mechanical ventilation who were given probiotics experienced decrease in viral colonization when compared with placebo. However, the efficacy of probiotics use in COVID-19 patients and other bowel remedies remains to be proved.

REFERENES

La Marca A, Capuzzo M, Paglia T, Roli L, Trenti T, Nelson SM. Testing for SARS-CoV-2 (COVID-19): a systematic review and clinical guide to molecular and serological in-vitro diagnostic assays. Reproductive biomedicine online. 2020 Jun 14.

Oshima T, Siah KT, Yoshimoto T, Miura K, Tomita T, Fukui H, Miwa H. Impacts of the COVID‐19 pandemic on functional dyspepsia and irritable bowel syndrome: A population‐based survey. Journal of gastroenterology and hepatology. 2020 Nov 16.

Sudre CH, Lee KA, Lochlainn MN, Varsavsky T, Murray B, Graham MS, Menni C, Modat M, Bowyer RC, Nguyen LH, Drew DA. Symptom clusters in Covid19: A potential clinical prediction tool from the COVID Symptom study app. MedRxiv. 2020 Jan 1.

Riphagen S, Gomez X, Gonzalez-Martinez C, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395:1607–1608.

Giacomet V, Barcellini L, Stracuzzi M, Longoni E, Folgori L, Leone A, Zuccotti GV. Gastrointestinal Symptoms in Severe COVID-19 Children. The Pediatric infectious disease journal. 2020 Aug 10;39(10):e317-20.

Cholankeril G, Podboy A, Aivaliotis VI, Tarlow B, Pham EA, Spencer SP, Kim D, Hsing A, Ahmed A. High Prevalence of Concurrent Gastrointestinal Manifestations in Patients With Severe Acute Respiratory Syndrome Coronavirus 2: Early Experience From California. Gastroenterology. 2020 Aug 1;159(2):775-7.

Gu, S.; Chen, Y.; Wu, Z.; Chen, Y.; Gao, H.; Lv, L.; Guo, F.; Zhang, X.; Luo, R.; Huang, C.; et al. Alterations of the Gut Microbiota in Patients with COVID-19 or H1N1 Influenza. Clin. Infect. Dis. 2020, 71, 2669–2678.

Dhar, D.; Mohanty, A. Gut microbiota and Covid-19- possible link and implications. Virus Res. 2020, 285, 198018. 

Sudre CH, Lee KA, Lochlainn MN, Varsavsky T, Murray B, Graham MS, Menni C, Modat M, Bowyer RC, Nguyen LH, Drew DA. Symptom clusters in Covid19: A potential clinical prediction tool from the COVID Symptom study app. MedRxiv. 2020, June 16. 

Kim HS. Do an Altered Gut Microbiota and an Associated Leaky Gut Affect COVID-19 Severity?. mBio. 2021 Feb 23;12(1).

Ferreira, C.; Viana, S.D.; Reis, F. Is Gut Microbiota Dysbiosis a Predictor of Increased Susceptibility to Poor Outcome of COVID-19 Patients? An Update. Microorganisms 2021, 9, 53.