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.

Gamified Eating

Unhealthy diet is one the most important lifestyle risk factors for metabolic and physiologic changes predisposing to disease. IBS, for example, can be caused by irregular eating, physical inactivity, and quality of sleep, even though  IBS subjects usually eat more healthy foods (such as vegetables and legumes) than others. Gamification approaches to nutrition education offer advantages for preventing disease over traditional persuasion methods. Gamification might provide not only positive emotional feelings, but it also increases sense of immersion, facilitating learning. 

Yet, about half of existing apps don't improve health and wellbeing because they are not developed in a skilled way. 

What makes a diet best? What is the best diet for you? Every year US News calls health experts to rank popular diets and every year there are changes in ranking. 10 years ago,  the DASH diet beat out  Atkins, Jenny Craig, Slim-Fast and 15 others to win the crown. It was praised as the best for combating high blood pressure. This year it's number 2, after Mediterranean diet scoring high on weight loss, heart and brain health,  diabetes and cancer prevention. For dropping those extra pounds, 10 years ago Weight Watchers ranked No. 1, followed closely by Jenny Craig and the Raw Food Diet. This year i's the Flexitarean Diet. The database has 39 diets, a small fraction of existing "eating plans" built around various personalities and lifestyles. The EAT-Lancet diet is one of those not included - it tries to balance nutrition with environmental concerns. The FODMAP diet - best for IBS - is not ranked either. 

US News & World Report puts hard numbers on the common-sense belief that no diet is ideal for everybody. But finding out which diet is best for you could be a cumbersome task. Many apps exist but they are not sufficiently engaging or sufficiently good for your health. 

Health gamification research is progressing at a fast pace. Researchers are finding which elements the users of nutrition apps prefer. Food gamers like clear measurable goals, performance graphs, and progress bars, but seem to lack motivating elements found in non-nutrition apps - since digital "rewards",  "levels" and "leaderboards" are not sufficiently appealing.  And neither is counting calories, gameplay narratives and individual competition.  

Gamified nutrition apps show promise. Who'll design the perfect food game?

 

REFERENCES

Johnson D, Deterding S, Kuhn KA, Staneva A, Stoyanov S, Hides L. Gamification for health and wellbeing: A systematic review of the literature. Internet interventions. 2016 Nov 1;6:89-106.

Gabashvili IS. Why Red Beans and Rice Are Good ... But Not with Coffee, Forbes 2012, April 30. Retrieved from https://www.forbes.com/sites/ciocentral/2012/04/30/why-red-beans-and-rice-aregood-but-not-with-coffee DOI: 10.6084/m9.figshare.13600517

Berger, M. and Jung, C., 2021, January. Gamification in Nutrition Apps–Users’ Gamification Element Preferences: A Best-Worst-Scaling Approach. In Proceedings of the 54th Hawaii International Conference on System Sciences (p. 1335).

Guo YB, Zhuang KM, Kuang L, Zhan Q, Wang XF, Liu SD. Association between diet and lifestyle habits and irritable bowel syndrome: a case-control study. Gut and liver. 2015 Sep;9(5):649.

Van Asbroeck S, Matthys C. Use of Different Food Image Recognition Platforms in Dietary Assessment: Comparison Study. JMIR formative research. 2020 Dec 7;4(12):e15602.

Karkar R, Schroeder J, Epstein DA, Pina LR, Scofield J, Fogarty J, Kientz JA, Munson SA, Vilardaga R, Zia J. Tummytrials: a feasibility study of using self-experimentation to detect individualized food triggers. InProceedings of the 2017 CHI conference on human factors in computing systems 2017 May 2 (pp. 6850-6863).

Precision antibiotics

Antibiotics can effectively eliminate infection-causing bacteria, but they also perturb microbial communities in the body and this perturbation can be irreversible, depending on the individual. A new study demonstrates that the pre-treatment baseline gut microbiota is a major determinant of whether there will be complete or partial recovery, 

or whether antibiotics will shift microbiome to completely new states with little resemblance to the baseline community. This is consistent with the role of pre-treatment microbiota in determining response to fecal microbiota transplantation (FMT) and dietary interventions.

New research suggests a strong predictive role for baseline microbiota, especially when antibiotic exposure is less intense. Typically, after antibiotic-induced perturbations, composition of the gut microbiome changes from the baseline (phase 1) followed by post-antibiotic reorganization (phase 2) (original figure) - that will either bring the microbiome back to its initial state, change it slightly or change it dramatically creating a completely new microbiome. The latter is usually called a “regime shift”. A resistant community always resists perturbation, while a resilient community is able to completely recover and stabilize into a fully functional state after antibiotic treatment. 

Principal component mixed effect regression using microbiota and granular antibiotic exposure data showed that microbiota departures from baseline depend on the composition of the pre-treatment microbiota. Penalized generalized estimating equations identified 6 taxa within pre-treatment microbiota that predicted the extent of antibiotic-induced perturbations.

In the final model, 5 baseline taxa (Roseburia, Blautia, Eggerthella, a Lachnospiraceae genus, and a Clostridiales genus) predicted larger microbiota departures from baseline, and one taxon (Bacteroides) predicted larger resistance to perturbations. 

Specific Roseburia species degrade dietary fiber β-mannan, producing short-chain fatty acids such as butyrate, with numerous and profound homeostatic effects. Similarly, certain Eggerthella species have significant metabolic potential, contributing, for example, to the conversion of dietary fiber-derived lignans to bioactive compounds Antimicrobial peptides produced by certain Blautia species have been shown to confer colonization resistance against antibiotic-resistant pathogens Bacteroides might be exhibiting stabilizing effect via quorum sensing or by secreting antimicrobial compounds such as propionate.  Bacteroides fragilis has a protective effect on functional gastrointestinal disorders that are thought of as disorders of homeostatic imbalance

Next-generation precision antibiotics should be specific towards particular pathogens and their genes. They also should be tailored to the baseline host microbiome to prevent the development of functional gastrointestinal disorders. 

REFERENCES

Rashidi, A., Ebadi, M., Rehman, T.U. et al. Gut microbiota response to antibiotics is personalized and depends on baseline microbiota. Microbiome 9, 211 (2021). https://doi.org/10.1186/s40168-021-01170-2

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.