Antibiotics and Bowel Disorders

Frequent use of antibiotics can increase the risk of developing microbiome-associated diseases in all age groups.

Studies have shown that antibiotic exposure in the prenatal period and during the first 2 years of life can significantly impact the risk of developing atopic and metabolic disorders later in life. The first 6 months of life appeared to be a critical period, as this is when the microbiome is most susceptible to irreversible changes. 

Studies of older children (such as 11,000 teens and pre-teens from Finland) have found that, instead of a specific age, the frequency of antibiotic use in the two years prior to the diagnosis of autoimmune disorders, was more strongly associated with risk. Exposures to cephalosporins, macrolides, and amoxicillin-clavulanic acid throughout childhood seemed to increase the likelihood of Juvenile Arthritis (JIA). Exposures to macrolides within two years before diagnosis showed minor association with other autoimmune disorders, including type 1 diabetes (DM), autoimmune thyroiditis (AIT), JIA, and inflammatory bowel diseases (IBD)). 

An article recently accepted for publication found that frequent use of antibiotics later in life also increased the risk of IBD. This study of more than 6 million individuals followed for close to 20 years analyzed 87112328 person-years including 36017 new cases of ulcerative colitis (UC) and 16881 new cases of Crohn’s disease (CD) - two primary types of IBD with different characteristics. This risk was predominantly driven by those diagnosed with CD and was strongest within the first few months of antibiotic use. In a nationwide case–control study of individuals 16-years or older in Sweden, similar results were seen for three or more antibiotic dispensations.

The authors of the study hypothesized that antibiotics contribute to the development of IBD by modulating the intestinal microbiome, but more research is needed to fully understand the mechanism behind this association.

REFERENCES

Semeh Bejaoui, Michael Poulsen, The impact of early life antibiotic use on atopic and metabolic disorders: Meta-analyses of recent insights, Evolution, Medicine, and Public Health, Volume 2020, Issue 1, 2020, Pages 279–289, https://doi.org/10.1093/emph/eoaa039

Räisänen L, Kääriäinen S, Sund R, Engberg E, Viljakainen H, Kolho KL. Antibiotic Exposures and the Likelihood of Developing Pediatric Autoimmune Diseases: a Register-based Matched Case-control Study. (2021). DOI: 10.21203/rs.3.rs-1110501/v1

Faye AS, Allin KH, Iversen AT, et al Antibiotic use as a risk factor for inflammatory bowel disease across the ages: a population-based cohort study Gut Published Online First: 09 January 2023. doi: 10.1136/gutjnl-2022-327845

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.

 

Microbiome in Complex Disease

An imbalance between microorganisms in human microbiome is responsible for many complex diseases. The relationship is complex. In a new review article published in the International Journal of Molecular Sciences, researchers analyzed over 24,000 scientific papers on gut microbiome in metabolic (n=6109 papers), immune (n=7434), autoimmune (n=1927), cardiovascular (n=2605), brain diseases (n=4216) and various cancers (n=5564).  Most papers were written about the role of microbiome in obesity (n=5342), while the smallest subset was about heart failure (n=261). 

Complex diseases occur due to interaction of genetic and environmental factors.

Gut microbes and their metabolites play important roles as environmental factors. The metabolites - such as short-chain fatty acids (SCFAs), the end products of fermentation of dietary fibers by the anaerobic microbes in the gut, can protect us from pathogen invasion by activating immune defense. Lactobacillus rhamnose, for example, strengthens the ability of the T cell response. Lactobacillus sakei reduces the level of serum IgE and IL4. Acinetobacter iwoffii improves respiratory hyperresponsiveness by blocking the recruitment of dendritic cells in the lungs. Lactobacillus casei ATCC334 can produce iron pigment, which plays a role in inhibiting tumor progression. Some microorganisms may be also used in the treatment of hypertension, cardiovascular and other diseases. 

Bacterial biofilms (bacterial colonies self-organized in complex structures), on the other hand, can interrupt human immune system in many harmful ways. Bacteroides fragilis biofilms are implicated in destruction of mucosal epithelium, thus promoting migration of harmful species and helping them escape body's defense mechanisms. Small metabolites such as trimethylamine oxide (TMAO) produced by some gut bacteria could induce cardiac hypertrophy and fibrosis. 

Some proteases secreted by microbes are contributing to developing diseases, such as arterial sclerosis, skin disease, enteritis and cardiovascular disease and others. M. globosa (a common skin color fungi), on the other hand, secretes proteinase MgSAP1 that rapidly hydrolyses Staphylococcus protein A (SpA) and prevents S. aureus biofilm formation, helping to maintain a healthy skin. Bacteria can also secrete amino acid-derived antibiotics to fight diseases - e.g., Clostridium scindens and C. sordellii that help to inhibit the growth of C. difficile. 

The new review discusses these and many other mechanisms in complex disease as well as potential cures and dietary interventions.

REFERENCES

Yu D, Meng X, de Vos WM, Wu H, Fang X, Maiti AK. Implications of Gut Microbiota in Complex Human Diseases. International Journal of Molecular Sciences. 2021, 22(23):12661.

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.

The FODMAP diet

"Functional gut" symptoms (bloating, wind, abdominal distension, discomfort, pain, altered bowel habits) can be controlled by diet, but most theories of how exactly food components are linked to symptoms are lacking consistency. In 2005, Peter Gibson and Susan Shepard gave us food for thought by defining highly fermentable but poorly absorbed short-chain carbohydrates and polyols as an important dietary factor contributing to these symptoms ( see their original article that coined the term FODMAPs - Fermentable Oligo-, Di- and Mono-saccharides And Polyols).

Their studies of different patient groups (Irritable Bowel Syndrome, Irritable Bowel Disease, celiac disease, fructose malabsorption, patients who underwent colectomy, etc) showed that reduction of the intake of FODMAPs may help to reduce symptoms, depending on other things these people usually eat.

FODMAPs are types of sugars and fiber, found in wheat-based and other foods:

Fructans and Galactins	Polyols
Fructose Lactose Fructooligosaccharides Galactooligosaccharides	Sorbitol Mannitol Xylitol Maltitol

There is a cumulative effect of these foods, of their osmotic (water moving) and fermentative (bacteria feeding) actions, on IBS symptoms such as  abdominal pain, bloating, gas, altered bowel movements and lethargy. Irritable Bowel Syndrome symptoms could result from many different (and independent) reasons including  low absorptive capacity of the small intestinal epithelium, increased sensitivity of the bowel, rapid transit through the small bowel, and bacterial overgrowth in the distal small bowel.

This means that you may eat some of the problem foods listed in the tables and still fill fine. It's not about the foods eaten in isolation, it's about hundreds of food components that are adding up. To follow the right diet, you need to identify your individual sensitivities and dietary combinations.


For informational purposes only, we are listing candidate dietary components contributing to osmotic load and rapid fermentation thus increasing luminal pressure and distension, along with common high and low FODMAP foods - as listed in scientific publications. Red and green tables were compiled by a FODMAP-sensitive IBS sufferer based on his own experiences - check his post: "Printable FODMAP Diet Chart for your Convenience".  Another FODMAP list compiled by trial and error can be found here.

Fruits: 

•  Serving size is ½ cup 

•  Limit to 1 to 2 servings per day.  

•  Fresh or fresh frozen fruit may be better tolerated than canned fruit. 

•  Keep in mind tolerance may depend on the amount you eat at one time.  

•  Limit concentrated sources of fruit--such as dried fruit and fruit juices  

•  Avoid eating large amounts of any fruit. 

Intestine Friendly	Avoid if FODMAP Intolerant	Questionable May Need to Limit
Bananas (could be gas forming), blackberries, blueberry, grapes (if half a serving or less than 10), grapefruit, honeydew, kiwifruit, lemons, limes, mandarin orange, melons, oranges, papaya, passion fruit, pineapples, raspberries, rhubarb, strawberries, tangelos	Apples, apple cider, apple juice, applesauce, apricots, cherries, dates, grapes, lychee, mango, peaches, pears, pear juice, plums, prunes, watermelon	Other fruit juices or drinks, sugar-free jam/jelly, dried fruit, canned fruit in heavy syrup, other fruits

                                                     Vegetables:
•  Serving size is ½ cup (most vegetables) or 1 cup of leafy green vegetables
•  Limit to 1 ½ to 3 servings per day.
•  Cooked vegetables may be tolerated best as cooking causes a loss of free sugars.
•  Keep in mind tolerance may depend on the amount you eat at one time.

Intestine Friendly	Avoid if FODMAP Intolerant	Questionable
Bamboo shoots, bok choy, carrots, cauliflower (gas forming), celery, cucumber (gas forming), eggplant (gas forming), green beans (gas forming), green peppers (could be gas forming), leafy greens, parsnip, pumpkin, spinach, sweet potatoes, white potatoes, other root vegetables	Artichokes, asparagus, some beans (baked beans, chickpeas, kidney beans, lentils) beetroot, broccoli, Brussels sprouts, cabbage, cauliflower, fennel, garlic, sugar snap peas, leeks, soy products, okra, onions, peas, shallots	Avocado, corn, mushrooms, tomatoes, other beans

Other

Intestine Friendly	Avoid if FODMAP Intolerant	Questionable
Meat, Fat, Yogurt and hard cheeses, Eggs, Aspartame (Equal® and Nutrasweet®), Saccharin (Sweet ‘n Low®), Sucrose (table sugar), Glucose, Maple syrup	Honey, Flavorings with fructose or sorbitol, Desserts (ice cream, candy, cookies, bars, popsicles) sweetened with fructose or sorbitol, Cereal or other processed foods with sorbitol or fructose on the label, Wheat, Sherry and port wine, Sweeteners such as sorbitol, mannitol, xylitol, maltitol, and isomalt used in sugar-free gum, candies and mints	High-fructose corn syrup, Lactose

And here are two more tables with foods already listed above, just to show why they are problematic for FODMAP-sensitive people.

Note that some of the foods listed as intestine friendly may be less friendly for some people inducing functional gut symptoms. Inulins - often included in prebiotic supplements - are longer chain fructans thus are expected to be more intestine-friendlier than fructans with low degree of polymerization.  Yet inulins often lead to increased wind.

Scientific publications:

Gibson PR, Shepherd SJ. Personal view: food for thought--western lifestyle and susceptibility to Crohn's disease. The FODMAP hypothesis. Aliment Pharmacol Ther. 2005 Jun 15;21(12):1399-409. Review.  

Barrett, J.S., Gibson, P.R.  Nutrition issues in Gastroenterology, Series # 52  Clinical Ramifications of Malabsorption of Fructose and Other Short-chain Carbohydrates.  Practical Gastroenterology 2007 XXXI:51-65

Gibson PR, Newnham E, Barrett JS, Shepherd SJ, Muir JG. Review article: fructose malabsorption and the bigger picture. Aliment Pharmacol Ther. 2007 Feb 15;25(4):349-63. Epub 2007 Jan 8.


Gibson, P. & Shepherd, S. Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach. Journal of Gastroenterology and Hepatology 2010 25:252-258.

Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, Gibson PR. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011 Mar;106(3):508-14. Epub 2011 Jan 11

Rangnekar AS, Chey WD. The FODMAP diet for irritable bowel syndrome: food fad or roadmap to a new treatment paradigm? Gastroenterology. 2009 Jul;137(1):383-6. Epub 2009 May 29. 

Other links:

• The FODMAP Theory for IBS
• Does the FODMAP Diet Help IBS?
• IBS and FODMAPs
• Wikipedia article on Fructose malabsorption
• Center of research on FODMAP diet
• A list of individual sensitivities by a sufferer for whom a low FODMAP diet worked
• FODMAP update from Crystal Nelson
• Low Fodmaps discussion on IBSgroup.org
• Foodmap article and discussion on HealthHype.com
• Foodmaps discussion on HealingWell.com
• Foodmap discussion on Celiac Disease forum
• Fodmap questions on Colitis forum 
• Foodmaps discussed on Crohn's forum (J-Pouch group)
• Fodmap diet discussed on Diabetes forum
• Foodmap Diet  discussed by Wedding community
• Low Foodmap diet for IBS on SparkPeople
• Foodmap discussions on Fructose Malabsorption Yahoo forum (subscription required)
• FODMAP diet on Facebook
• FODMAP calculator video
• FODMAP discussions at Aurametrix