From 4R to 5R: The Evolution of Functional Medicine in Gut Health

Functional medicine provides a powerful model known as the 5R Approach (Kim, 2024), which builds on the original 4R framework (Remove, Replace, Reinoculate, and Repair; Liška, 2003)) by adding a crucial final step: Rebalance.

This method is particularly valuable in treating gut dysbiosis, a condition in which the ratio of beneficial and harmful bacteria in the intestine is disrupted, leading to inflammation, poor digestion, and systemic health issues. Research has linked gut dysfunction to chronic conditions such as rheumatoid arthritis, eczema, and neurological disorders (Liška, 2003) as well as nonsyndromic body odor (Gabashvili, 2020)  

1. Remove: Eliminating Triggers of Gut Dysfunction

The first step in healing the gut is removing harmful elements that contribute to dysbiosis and inflammation. These include:

Pathogens – Overgrowth of harmful bacteria, yeast (Candida), or parasites.

Inflammatory Foods – Processed sugars, refined carbohydrates, artificial additives, and common allergens (gluten, dairy, soy).

Toxins & Medications – Overuse of antibiotics, NSAIDs, and environmental toxins disrupt gut flora and damage the mucosal lining.

📌 An elimination diet can help identify specific food triggers. GI map test as well as testing for known gut infections (such as H.pylori, HSV, CMV, giardia or Candida spp.) can also guide targeted interventions.

2. Replace: Supporting Digestive Function

Once harmful elements are removed, the next step is to restore digestive efficiency by supplying essential compounds for proper digestion:

Digestive Enzymes – Help break down food and enhance nutrient absorption.

Stomach Acid (HCl) – Supports protein digestion and prevents bacterial overgrowth.

Bile Salts – Assist in fat digestion and absorption, especially if gallbladder function is compromised.

📌 Consider incorporating enzyme-rich foods like papaya (papain) and pineapple (bromelain) or taking targeted supplements.

3. Reinoculate: Restoring Beneficial Bacteria

A diverse microbiome is essential for digestion, immunity, and gut-brain interactions. Research suggests that early-life gut health, influenced by factors like breastfeeding, can impact long-term microbial balance (Ley et al., 2021).

📌 Aim for a variety of fiber-rich foods, prebiotics (asparagus, bananas, onions) and probiotic-rich fermented foods to support microbiome diversity, rather than relying solely on probiotic supplements. 

4. Repair: Healing the Gut Lining

An increase in harmful bacteria can damage the intestinal mucosal cells, contributing to leaky gut syndrome and systemic inflammation (Kim, 2024). Repairing the gut lining is crucial for long-term resilience.

Key nutrients that aid gut repair include:

L-glutamine – An amino acid essential for intestinal wall regeneration.

Collagen & Bone Broth – Provide glycine and proline, which strengthen the gut barrier.

Zinc & Vitamin A – Promote mucosal healing and immune function.

Omega-3 Fatty Acids – Reduce inflammation and support tissue repair.

5. Rebalance: Addressing Lifestyle Factors

The final and often overlooked step in gut healing is rebalance—restoring the mind-body connection and lifestyle habits that influence digestive health. The gut-brain axis plays a crucial role in regulating digestion, with parasympathetic “Rest and Digest” responses supporting motility and secretions (Gantzer, 2021).

To rebalance:

Stress Management – Chronic stress disrupts gut function and increases inflammation. Practices like meditation, deep breathing, and yoga enhance parasympathetic regulation.

Sleep Quality – Poor sleep affects gut motility and microbiome balance. Aim for 7-9 hours of uninterrupted sleep.

Physical Activity – Moderate exercise supports gut health by improving motility and microbiome diversity.

📌 Engage in mindful eating—slow down, chew thoroughly, and avoid distractions to support optimal digestion.

The 5R Approach offers a structured, evidence-based method for restoring gut health and preventing chronic disease. Whether dealing with digestive disorders, autoimmunity, or general well-being, this framework provides a sustainable path to healing.

By removing harmful triggers, replacing digestive supports, reinoculating the microbiome, repairing the gut lining, and rebalancing lifestyle factors, we can achieve long-term gut resilience and overall health.

REFERENCES

Gabashvili IS Cutaneous Bacteria in the Gut Microbiome as Biomarkers of Systemic Malodor and People Are Allergic to Me (PATM) Conditions: Insights From a Virtually Conducted Clinical Trial JMIR Dermatol 2020;3(1):e10508 doi: 10.2196/10508

김규남. 기능의학적 5R 치료의 근거와 적용. Journal of Korean Institute for Functional Medicine. 2024 May;7(1):1-8: Kyu-Nam Kim  Korean Society of Functional Medicine Journal of Korean Institute for Functional Medicine Vol.7 No. 1 2024.05 1 - 8 (8 pages) DOI : 10.32581/jkifm.2024.7.1.1

Liska DJ, Lukaczer D. Gut dysfunction and chronic disease: the benefits of applying the 4R GI restoration program. ANSR-Appl Nutr Sci Rep. 2003:1-8.

J. Gantzer Acta Supporting Gut Health by Homeostasis and Intrinsic Mechanisms. Scientific Neurology 1 November 2021 https://www.actascientific.com/ASNE/pdf/ASNE-04-0444.pdf

Rare Diseases in the Era of High-Cost Drug Development

We are currently witnessing a remarkable era in medical innovation, marked by rapid advancements and transformative developments. Yet the medical community is often unable to tell what works and what doesn’t. As the complexity of medical treatments increases, the importance of distinguishing reliable therapies from ineffective ones becomes ever more crucial. In this context, robust data collection and sophisticated analysis are indispensable tools.

In recent years, the trend in clinical trials has shifted towards smaller studies focusing on diseases that either attract substantial health insurance reimbursements or predominantly affect affluent populations. This shift is largely driven by the expectation of high drug prices post-development. However, this leaves a significant gap in research and treatment for conditions like Metabolic Body Odor (MEBO) and "People are allergic to me" (PATM). These conditions disproportionately impact individuals who may find it challenging to achieve financial security due to the nature of their ailments.

In 2008, a community survey by pharmacist Arun Nagrath highlighted a lack of confidence in medical advice among patients. Fast forward to the present, and while medical practitioners may exhibit greater confidence, their assurance is not always underpinned by evidence. This is evident in the prescription of costly tests, which clinicians may struggle to interpret or follow up effectively.

The landscape of self-treatment is continuously evolving. Popular remedies change over time, and the effectiveness of these treatments varies widely. In 2008, probiotics and Chlorophyl/Copper Chlorophyllin products were at the forefront. However, some patients reported that their odor issues worsened after using these remedies (as indicated by the red area in the corresponding pie chart, compared to green for effectiveness and gray for uncertainty). Many patients found that perfumed products exacerbated their condition, including about half of reported deodorants, though the other half was suitable types. Remedies once popular, like Mushroom extracts such as ProM and Champex, Activated Charcoal, Baking Soda and Hydrogen Peroxide have faded from the discussion. Vitamin B2, although used by fewer than a quarter of respondents in 2008 and found effective by some, remains a favored treatment. Oldenlandia and Coconut oil were found useful by small fraction of respondents. Somebody even used Bleach to clean themselves and found it to make things worse.  Interestingly, certain drugs intended for other conditions were reported to have secondary effects on odor – beneficial in cases like Prilosec and Probathine, and detrimental with Anxiolytics, Antidepressants, and Antivirals, the latter aligning with recent findings related to the COVID-19 vaccine. Antifungals were used by a few and were never found to worsen condition. Neither did Folic acid, Zinc, Calcium and Magnesium.  There were cases when digestive enzymes, contraceptives, and baking soda treatments made things worse. 

Interest in resveratrol, a compound present in red wine, reached its zenith in the late 2000s and early 2010s. During this period, the MEBO community extensively used and promoted this compound. In the mid-2010s, DMB became a focal point of discussion for many, while Fluxovas entered the scene and began to be mentioned starting in 2020.

While the popularity of probiotics endures, there is a noticeable shift towards personalization. Individuals are increasingly acknowledging the significance of identifying probiotic strains that harmonize with their unique physiology and health objectives. Our microbiome study unveiled that individuals with higher cutaneous bacteria (and total bacteria) abundances in the gut benefited from reducing microbial diversity and overall bacterial counts. In contrast, those with lower abundances found advantages in increasing microbial diversity. This highlights the absence of a universal solution for probiotics.

This evolving self-treatment scenario emphasizes the pivotal role of precision medicine, considering individual genetic, environmental, and lifestyle influences for disease treatment and prevention. Conditions like TMAU, MEBO, and PATM, lacking standardized effective treatments, emphasize the pressing need for more nuanced and targeted approaches.

Precision medicine, gaining popularity, particularly in tandem with Artificial Intelligence approaches this year, marks a departure from one-size-fits-all strategies. It relies extensively on data, specifically genomic, microbiome, and metabolomic data, to tailor treatments to individual patient needs. This patient-centric approach promises to revolutionize treatment strategies, especially for those with previously under-researched and underserved medical conditions.

MEBO's causes remain largely unknown, and without clear diagnostic criteria, it is often referred to as idiopathic malodor. This uncertainty mirrors the earlier challenges in diagnosing conditions like IBS, which was once seen as a diagnosis of exclusion. Today, the importance of ruling out other diagnoses through tests is recognized.

MEBO is a poignant example of a rare condition that can severely impact an individual's ability to pursue a career and achieve financial success. This condition is not only socially debilitating but also lacks effective diagnostic and treatment options. Diagnostic studies for such rare conditions are prohibitively expensive, and the lack of effective therapies exacerbates the problem. Moreover, the large heterogeneity within the patient population makes finding a one-size-fits-all solution particularly challenging.

So, what should be done in this scenario? First and foremost, there's a need for increased funding and research attention towards rare diseases like MEBO. This could be facilitated by incentivizing pharmaceutical companies through tax breaks or grants to undertake research in less profitable but socially significant areas.

Secondly, fostering collaborations between research institutions, pharmaceutical companies, and patient advocacy groups can create a more holistic approach to understanding and treating these conditions. Such collaborations can also help in the collection of more comprehensive and diverse data, and better ways to collect it, which is crucial given the heterogeneity of conditions like MEBO. 

Thirdly, the role of government and healthcare policymakers is critical. They can implement policies that encourage research and development in neglected areas, ensuring that the healthcare system is inclusive and caters to all, regardless of the financial implications or rarity of the condition.

Lastly, leveraging technology and innovation in medical research can also provide new avenues for diagnosis and treatment. For example, artificial intelligence and machine learning could be used to better understand complex conditions like MEBO, potentially leading to more effective and personalized treatments.

So far there’s never been any real emphasis on making clinical trials better or easier to conduct. Our goal, as a society, seems to be to manufacture more and more sports cars and to drive them faster and faster into the mud.

We hope that the healthcare industry and policymakers work together to ensure that all patients, regardless of their financial status or the rarity of their condition, have access to the treatments they need.

REFERENCES

This is biology's century. We're not ready for it (statnews.com)

Better Trials. Someday. | Science | AAAS

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

Gabashvili IS. Cutaneous bacteria in the gut microbiome as biomarkers of systemic malodor and People Are Allergic to Me (PATM) conditions: insights from a virtually conducted clinical trial. JMIR Dermatol. 2020 Nov 4;3(1):e10508. doi: 10.2196/10508. https://derma.jmir.org/2020/1/e10508/ 

Gabashvili IS. Artificial Intelligence in Biomedicine: Systematic Review

medRxiv 2023.07.23.23292672; doi: https://doi.org/10.1101/2023.07.23.23292672

Chronicles of Community-Driven Research: The Evolution of MEBO and PATM Studies

In the ever-evolving landscape of medical science, the untangling of medical mysteries often hinges not just on technological advancements or expert researchers, but on the active involvement of community members. Community efforts have been instrumental in the identification and understanding of elusive conditions MEBO (Metabolic Body Odor) and PATM (People Are Allergic to Me).

Late 1990s - early 2000s: The Dawn of Online Support Forums 

Before the conditions were officially named, online forums like MSN Body Odor Support Forum, ibsgroup.org, Yahoo TMAU group, and Curezone BO & Halitosis and TMAU forums served as early platforms for sufferers to discuss their symptoms. 

At this time, Trimethylaminuria (TMAU) was a scarcely recognized condition, and diagnostic tests were both costly and geographically limited. Trimethylaminuria support group, later established as foundation raises 35K and awards it to Dr. George Preti of Monell Center, the world’s only independent, non-profit scientific institute dedicated to interdisciplinary basic research on the senses of taste and smell.

2006-2007: Birth of MEBO and PATM Communities

In 2006, the acronym "PATM" was first coined by a sufferer, and by 2007, a dedicated PATM community was established on MedHelp. The initial post was reposted in PATM forum and garnered over 8,800 responses, signifying the start of a community-led initiative to explore the condition. While the term FBO (fecal body odor) emerged earlier and is still used on online forums,  it is often avoided due to its less appealing connotation. MEBO was coined by another individual suffering from a similar undiagnosed condition. This further fueled community-driven research and knowledge sharing among those affected.

2008: Broadening the Dialogue

The blog Bloodbornebodyodorandhalitosis.com is launched, later transitioned to meboblog.com. This year also saw more in-person meetups and community surveys, including one by pharmacist Arun Nagrath that received about 100 responses. 95% of responders was trying to seek medical help, over 90% thought that their doctor was not knowledgeable nor confident in their recommendations. 

2009: Formalizing Research Efforts

MEBO Research Charity was founded in both the UK and Florida, spearheaded by Maria de la Torre. The first collaborative study with UK's Biolab was initiated, focusing on blood and urine tests. The results were subsequently published on the MEBO blog and clinicaltrials.gov (NCT02692495, principal investigator: Irene Gabashvili).

2010: Unveiling the Microbiome and Genetic Factors

At MEBO's 1st annual conference, held in Nashville, Dr. Gabashvili presents "Microbes and us," discussing the human microbiome's role in poorly understood conditions like idiopathic malodor and multiple chemical sensitivities (MCS). Previously, MEBO interviewed Metametrix about their GI Effects panel, which measured stool bacteria, fungus, and parasites with DNA analysis.  Metametrix, pioneer in diagnostics of nutritional insufficiencies and metabolic dysfunction,was later acquired by Genova Diagnostics.

Dr. Nigel Manning introduces 12 potential subtypes of TMAU. Out of 1,150 urine samples from 716 individuals collected between 1997 and 2009, 379 (53%) indicate significant TMAU presence. The launch of a new FMO3 genetic testing service promises to provide clearer diagnostic results. Additionally, a TMAU service dog program is initiated.

2011: The Advent of Genomic Data Sharing

Community members begin sharing genomic data, and MEBO critiques the limitations of 23andMe's FMO3 testing in blog posts. Dr. George Preti and his team at the Monell Center publish "Individuals reporting idiopathic malodor production: demographics and incidence of trimethylaminuria", revealing that only one-third of individuals with idiopathic malodor test positive for TMAU. New study from Oxford, proposes two genes coding enzymes, besides FMO3, NAT8 and PYROXD2, both with relatively uncharacterized functional roles, as potentially linked to TMAU. 

The second annual meetup in Washington, DC, focuses on the interplay between genetic mechanisms and holistic health. Skype conference call group is formed. 

2012: Empowering Patients Through Technology

A new MEBO study focusing on alveolar breath is initiated (NCT03451994). Aurametrix health management software is publicly launched, allowing patients to diagnose metabolic inefficiencies through digital food and symptom journaling. Karen James, MEBO UK’s Public Relations Director, publishes an article in the Royal College of General Practitioners (RCGP) journal InnovAiT, describing the life of a TMAU sufferer. For iGEM competition,  student team from Fatih university genetically engineers bacteria producing geraniol and FMO3 to eliminate TMA odors. Their product, FreshEcoli, is supposed to work as a synthetic perfume. 

The Third Annual Meetup in Miami Beach features Dr. Elizabeth Shephard discussing pharmacogenetics and personalized medicine.

2013: Deepening Theoretical Insights

MEBO UK's scientific director, Dr. Colin Harvey-Woodworth, publishes an article proposing that some MEBO symptoms may be secondary to dimethylsulphidemia, a previously unidentified metabolic condition linked to DMGDH gene (missense mutation in DMGDH was known to be associated with fish odor similar to pyridoxine non-responsive homocystinuria). Concurrently, a mediterranean study reveals that individuals carrying FMO3 mutations may not necessarily experience odor issues. The study finds that the TMA/TMAO ratio in urine samples from individuals with 158KK/308EG variants indicates reduced FMO3 activity, yet these individuals do not exhibit the hallmark fish-like odor commonly associated with trimethylaminuria. This data underscores the notion that the expression of trimethylaminuria symptoms is influenced by factors beyond the presence of specific genetic variants.

2014: Therapeutic Innovations

Dr. Jean-François Brugère proposes the therapeutic use of archaea to prevent trimethylaminuria and cardiovascular disease. The technique was patented but not yet tested in humans. MEBO's TMAU urine testing program is initiated, and the results  are discussed. Another student team from Paris University, genetically engineers skin bacteria by introducing a trimethylamine mono-oxygenase from a non-human bacteria Ruegeria pomeroyi, for iGEM competition. Dr. Aydin proposes new definitions for halitosis. Reddit TMAU and PATM groups are created. 

2015: Expanding Testing and new molecular targets

The MEBO Conference in Orlando distributes urine test kits based on choline challenges and discusses emerging trends in testing methodologies.

3,3-Dimethyl-1-butanol (DMB), which is a structural analog of choline found in some foods, such as balsamic vinegars, red wines, some cold-pressed extra virgin olive oils and grapeseed oils is demonstrated to inhibit TMA production by gut bacteria. DMB has potential as a therapeutic approach. Studies also show the inhibitory effects of Resveratrol on TMA production in mice, further expanding the scope of potential small molecule targets. Dr Stanley Hazen files a patent.

2016: Streamlining Diagnostic Approaches

MEBO collaborates with Professor David Wishart on a Urine Metabolomics study, registered as NCT02683876, involving Canadian participants. The study aims to explore simpler, non-challenge-based tests for diagnosis.

Several sufferers in the MEBO community report taking Resveratrol for a few months, with excellent results in decreasing or completely eliminating their odor symptoms while increasing consumption of foods high in choline, carnitine, and lecithin.

2017: Diagnostic Breakthroughs and the Social Media Shift

MEBO's Scientific Director, Irene Gabashvili, publishes the Biolab study on BiorXiv. The study reveals significant differences in intestinal permeability among participants based on body regions responsible for VOC emissions. In addition, the study identifies two subgroups of MEBO/PATM sufferers based on sugar intake. Due to the small sample size of 16 participants, the article remains a preprint. Unfortunately, the current structure and incentives of mainstream academic publishing favor well-funded research on common diseases and are less accommodating to research on overlooked rare conditions. 

A Monell Center Study published in BMC Medical Genetics delves into the genetic complexities of TMAU, revealing that not all cases are linked to the FMO3 gene. Although the choline challenge test confirmed a diagnosis of TMAU by revealing a high level of urinary TMA in all 10 subjects, genetic analyses revealed that the FMO3 gene appeared to be normal in four of the 10. Additional analyses revealed defects in several other genes that could contribute to the inability to metabolize the odorous TMA. No rare variants are found in PYROXD2 and a DMGDH, but there were associations with BHMT2, SARDH and SHMT1 genes, which directly interact with DMGDH in the gene network and may participate in the same pathway. At MEBO conference in Miami Beach, Professor Shephard talks about microbiome and diet. 

Armpit microbiome transplantation shows reduction in odor when performed from one sibling to another. 

Danny Kunz and his Citizen Research Group in Germany initiate a DNA sequencing study. Their simulations backed by large enzyme databases suggest that Thyroid-stimulating hormone (TSH) may play a role. Danny proposes a new name for the condition: Intestinal Metabolic Bromhidrosis Syndrome (IMBS).

TMAU UP Podcast is launched on YouTube. Facebook's "Groups" feature spurs the creation of new private MEBO and PATM communities, marking a new era in community engagement and data sharing.

2018-2020: Advancing Research and Understanding

A Microbiome study of MEBO and PATM communities is initiated, registered as NCT02683876. 

A Japanese paper confirms PATM as a physical condition connected to skin petrochemicals and microbes. Meanwhile a case report entitled "People allergic to me and body dysmorphic disorder" published in Asian Journal of Psychiatry is linking a case to a relatively common psychiatric disorder characterized by preoccupations with perceived defects in physical appearance. The average age of BDD onset was previously estimated as 15 with symptoms lasting 18 years on average without proper treatment. The prevalence of BDD is thought to be 0.7-2.4% in the general population, but the condition remains underdiagnosed and poorly understood.

Results from the MEBO-Wishart study align with previous MEBO/PATM findings but highlight the limitations of morning urine tests. A new PATM survey is conducted by an independent PATM ufferer/researcher. Average age of responders is 28. Mononucleosis due to CMV is proposed as the cause of PATM.

A UC San Diego student team explores the enzymatic breakdown of TMA. New gene SELENBP1 is proposed to explain metabolic halitosis. A patent on using Mikania plant extract to inhibit the conversion of choline to trimethylamine (TMA) is filed and granted, based on an earlier patent for using this plant to suppress body odor. 

RareConnect is established as a platform for those affected by rare diseases, including MEBO Research members. MEBO Research becomes a member. Unfortunately, by the end of 2023 it will be shut down, not being able to compete with Facebook and Reddit. Yahoo Groups shut down on December 15, 2020, for the same reason. New Instagram and WhatsApp groups are created.

New paper "Treatments of trimethylaminuria: where we are and where we might be heading" is published. It reviews Fecal microbial transplantation (FMT) that was not especially successful for reducing TMA or was only transiently effective as the symptoms returned one year after treatment. Antibiotic treatment is also transiently effective in some patients and completely ineffective in others.  Future research directions include gene therapy, enzyme replacement/enhancement therapy and gut microbiome modulation. 

Peer-reviewed paper examining the microbiome traits of individuals self-identifying with PATM and MEBO (NCT02683876) is published in JMIR Dermatology. The study reveals that both MEBO and PATM share increased levels of malodor-associated skin bacteria compared to non-MEBO/non-PATM groups, correlating with severity of self-reported symptoms. However, both populations exhibit significant heterogeneity.

2021-2023: Ongoing Challenges and Future Directions

A COVID study identifies flare-ups in 10-15% of the MEBO population post-infection and vaccination, possibly related to microbiome and hormonal fluctuations (NCT04832932; peer-reviewed paper published in JMIR Formative Research). COVID-19 has led to the emergence of new cases, with individuals developing MEBO/PATM conditions following infection and/or vaccination.

A cysteine challenge test for hydrogen sulfide production is suggested. Florida State University's iGem team proposes a synthetic biology project for TMAU. 

New paper by Chris Callewaert explores various cutting-edge approaches to skin health, including genetically engineered probiotics and microbiome transplantation. While promising, the latter method currently lacks scalability for industrial applications. The paper also delves into skin bacteriotherapy, a technique involving the application of one or multiple pure bacterial cultures with health-promoting properties to cleansed or disinfected skin areas. Additionally, the study examines the use of prebiotics applied directly to the skin to encourage the growth of beneficial microbes. Each of these innovative approaches holds promise but also presents its own set of challenges.

A study by Professor Sekine in Nature Scientific Reports identifies volatile organic compounds as key differentiators between PATM sufferers and controls. These results align with our yet to be published findings from MEBO-Menssana Alveolar Breath Test Study (NCT03451994) and Microbiome study (NCT03582826). 

The FSU team introduces their innovative probiotic, E.esperance, at the iGEM competition in Paris on November 2, 2023.

Despite these advancements, mainstream science remains largely uninterested in community-based research, leaving MEBO, PATM and TMAU without a definitive cure.

Lactobacillus, Bifidobacterium and other emerging probiotics

In the past few decades, Lactobacillus and Bifidobacterium genera were the main bacteria to be used as probiotics. One of the reasons for such attention was that these bacteria have the ability to thrive aerobically and are simple to package for sale. Cass Nelson-Dooley and Tony Hoffman of Metametrix (acquired by Genova Diagnostics in 2012) talked about these probiotics in MEBO interviews in 2009, emphasizing that high levels of Lactobacillus could be bad in some cases. Diets rich in simple carbs, poor absorption and small intestinal pockets can feed and trap excess Lactobacillus. Adding probiotics Bifidobacteria or Saccharomyces boulardii and prebiotic fiber to the diet could, in their opinion, help the MEBO population. D-lactate was one of the tests they offered that measured the level of this byproduct of bacterial fermentation, indicating an overgrowth of bacteria in the small intestine. According to our early clinical studies, D-lactate, however, was elevated in less than 20% of MEBO and PATM populations. 

Even though Lactobacillus is only a minor member of the human colonic microbiota, the proportions of those bacteria and particular strains are frequently either positively or negatively correlated with human disease and chronic conditions. Although it generally is not considered a pathogen, it can cause disease in compromised hosts, including bacterial endocarditis, pleuropulmonary infections, gastrointestinal abscesses, urinary tract infection, conjunctivitis, dental caries, and endometritis. Lactobacillus bacteremia, presumably secondary to bacterial translocation from the gastrointestinal tract, has been reported in a patient with severe intestinal inflammation caused by ulcerative colitis. A decrease in genus Faecalibacterium and increase in Lactobacillaceae has been previously reported in patients with constipation (Lactiplantibacillus plantarum P9 supplementation, on the other hand, helped to increase frequency of bowel movements, while L11 improved gut health and odor in cats). Compared to healthy individuals, pediatric and adult Crohn's disease (CD) patients had an increased relative abundance of Lactobacillus species. In both cases, Lactobacillus enrichment coincided with depletion of F. prausnitzii - that could represent a good candidate as next-generation probiotic. Another study found that Weissella cibaria ZWC030 can inhibit skatole. 

The percentages of Bifidobacterium and the Lactobacillus group presented a decreasing trend in patients with quiescent ulcerative colitis (UC) compared to active UC, although no significant differences were observed. Excessive amounts of Bifidobacteria can have negative effects on the body, such as in the case of Bifidobacterium breve bacteremia caused by excessive probiotic supplementation in infants with gastrointestinal conditions. On the other hand, Lactobacillus, Bifidobacterium and F. prausnitzii are depleted in IBS patients, resulting in lower SCFA concentrations (short-chain fatty acids, which are organic acids produced by gut bacteria during fermentation of indigestible foods) compared with healthy individuals. Maternal prenatal stress could also cause lower levels of Lactobacillus and Bifidobacterium and keep them low even later in life. With lower levels of Bifidobacterium, celiac patients have an imbalance in the intestinal microbiota, regardless of pH, even while on a gluten-free diet. Hormone treatment affects Bifidobacterium longum's ability to produce acids: progesterone reduces lactic acid and acetic acid production, while estradiol and thyroxine increase levels of both lactic acid and acetic acid (ethinyl estradiol) or lactic acid and butyric acid (thyroxine hormone). 

Data from our microbiome study (NCT03582826: Microbial Basis of Systemic Malodor and "People Allergic To Me" Conditions  - ClinicalTrials.gov) show that while there was a general trend of increasing levels of Bifidobacteria and Lactobacillus in individuals who achieve remission, less than 10% of participants needed to boost levels of both species to improve their condition. In line with previous knowledge, in MEBO/PATM population, Bifidobacteria (one of the first microbes to colonize the human gastrointestinal tract) was more common in younger individuals. About one third of the participants experienced lesser symptoms when increasing levels of their gut Bifidobacteria, another third benefited from more Lactobacillus and the remaining third felt better when increasing levels of Faecalibacterium prausnitzii (a butyrate-producing anaerobe typically associated with good health). Changes in the levels of these bacteria corresponding to recovering are overlayed on Figure 5 from our paper published in JMIR dermatology. It was illustrating changes in microbial diversity vs abundances of selected bacterial species associated with odor (CSS) for 12 female (F1-F12) and 10 male (M1-M19) participants who self-reported both flare-ups (beginning of the arrow) and improvements (end of the arrow). We added text boxes showing whether the levels of F. prausnitzii (F), Bifidobacterium (B) and Lactobacillus (L) are increasing (🡹) , decreasing (🡻) or fluctuating (🡺) as symptoms resolve. It is obvious that individuals with the highest bacterial diversity don't benefit from increasing levels of probiotic diversity, while those with low diversity levels do need more probiotic microbes in their system. The figure demonstrates the complexity of these bacterial perturbations and emphasizes the need to consider more than just three species when predicting which treatment will work best for reducing MEBO and PATM symptoms. 

As we mentioned in the previous blog post, Lactobacillus is the main genera responsible for odors of the uncooked food waste and off-flavor pit mud.  Some strains of Lactobacillus produce lactic acid, which can contribute to a more acidic environment in the gut. This can be beneficial for some people, but for others it can exacerbate odor issues. Bifidobacteria could also produce organic acids such as acetic acid and lactic acid in addition to short-chain fatty acids (SCFAs) like butyrate, which can have anti-inflammatory effects and promote gut health, but some people may find it unpleasantly smelling. F. prausnitzii produces a range of metabolites including one of the worst smelling compounds Putrescine. F. prausnitzii  plays important role in balancing immunity. Its butyrate production has been correlated to the capacity to induce IL-10, an anti-inflammatory cytokine, in peripheral blood mononuclear cells (PBMC) but not to the ability to block IL-8 secretion in TNF-α-stimulated HT-29 cells. In COVID-19, Faecalibacterium prausnitzii has been inversely correlated with disease severity. 

Research has shown that the gut microbiome is far more complex than previously thought, with hundreds of bacterial species interacting in a delicate balance.  Therefore, focusing solely on Lactobacillus and Bifidobacterium, or any other bacterium, may not be enough to promote a healthy gut microbiome for everyone. Besides, different strains of bacteria within the same species can have different effects on the body.

After more than a century of research, the following species are identified as the primary probiotic species of Lactobacillus species: L.acidophilus, L.casei, L.fermentum, L.gasseri, L.johnsonii, L.paracasei, L. plantarum, L. rhamnosus, and L. salivarius. For Bifidobacteria these are: B.adolescentis, B.animalis, B.bifidum, B.breve, and B.longum. We are learning more about strains of these species. Novel probiotic strain Bifidobacterium bifidum CECT 7366 is active against the pathogenic bacterium Helicobacter pylori - and so are variations of Saccharomyces Boulardii and Lactobacilli johnsonii. Another strain L. plantarum 299v can directly interfere with E. coli colonization and improve the immunological status of the intestinal mucosa although these results have not yet been confirmed in humans. Lactobacillus GR-1 and B-54 or RC-14 strains in the vagina has been shown to reduce the risk of urinary tract infections. Mileti et al. found that Lactobacillus paracasei displayed a delay in the development of colitis and a decreased severity of disease but that L. plantarum and L. rhamnosus GG exacerbated the development of dextran sodium sulfate (DSS)-induced colitis. 

L. rhamnosus supplementation contributes to higher intestinal absorption of free choline and elevated production of methylamines including TMA, whereas L. paracasei consumption may result in increasing bacterial consumption of choline for cholesterol assimilation and phospholipid metabolism rather than for methylamine metabolism.

Bifidobacterium supplemented with various fiber additives can prevent the growth of Clostridium difficile, while Lactobacillus salivarius protects the broiler chicks from Salmonella infections. Several strains of other species promising as probiotics are from Roseburia spp., Akkermansia spp., and Faecalibacterium spp. Probiotic potential risk score (PPRS) allowed to classify 84 Faecalibacterium prausnitzii strains  into low-, medium-, and high-risk groups. 15 strains identified as low-risk strains are prioritized for clinical application. 

Unfortunately, the extreme oxygen sensitivity of F. prausnitzii imposes practical challenges to the production, transportation, storage, and manufacturing of probiotic products to be evaluated in a clinical setting. Instead, we have to turn to prebiotics - a type of dietary fiber - in our food . F. prausnitzii's growth is promoted by inulin, inositol (vitamin B8) and fructo-oligosaccharides, chicory roots, wheat, onion, banana, garlic, and leek, wheat, rye, rice, barley, oat, and sorghum, and gold kiwifruit. 

Gut microbiota can be also influenced by phytochemicals. In one study, black raspberry (BR) reduced the serum levels of trimethylamine-N-oxide and cholesterol in rats fed excessive choline with a high-fat diet (HFC). The authors hypothesized that since gut microbiota plays a crucial role in the production of trimethylamine and microbial metabolites, BR could influence gut microbial composition. Their study examined microbiomes and metabolomes of rats and showed that the BR supplementation enriched Bifidobacterium and reduced Clostridium cluster XIVa. 

While we have made significant progress in understanding the role of probiotics and prebiotics in supporting our gut health, it's important to recognize that there is still a great deal that we don't know. It's becoming increasingly clear that a personalized approach to prebiotic and probiotic use may be necessary to achieve optimal health outcomes. This approach involves paying attention to how different foods make you feel and adjusting your diet accordingly, while eating a diverse and balanced diet that incorporates a variety of whole foods and phytochemicals, staying hydrated, getting enough sleep and exercise, and managing stress levels. Focusing on overall health and well-being will help to support the body's natural ability to maintain a healthy microbiome and avoid dysbiosis-related health issues.

REFERENCES

Din AU, Hassan A, Zhu Y, Yin T, Gregersen H, Wang G. Amelioration of TMAO through probiotics and its potential role in atherosclerosis. Applied Microbiology and Biotechnology. 2019 Dec;103:9217-28.

Pacifico L, Osborn JF, Bonci E, Romaggioli S, Baldini R, Chiesa C. Probiotics for the treatment of Helicobacter pylori infection in children. World J Gastroenterol 2014; 20(3): 673-683 [PMID: 24574741 DOI: 10.3748/wjg.v20.i3.673] 

Lim T, Lee K, Kim RH, Ryu J, Cha KH, Park SY, Koo SY, Hwang KT. Effects of black raspberry extract on gut microbiota, microbial metabolites, and expressions of the genes involved in cholesterol and bile acid metabolisms in rats fed excessive choline with a high-fat diet. Food Sci Biotechnol. 2023 Feb 13;32(4):577-587. doi: 10.1007/s10068-023-01267-4. PMID: 36911337; PMCID: PMC9992478.

Heeney DD, Gareau MG, Marco ML. Intestinal Lactobacillus in health and disease, a driver or just along for the ride?. Current opinion in biotechnology. 2018 Feb 1;49:140-7.

Martín R, Miquel S, Benevides L, Bridonneau C, Robert V, Hudault S, Chain F, Berteau O, Azevedo V, Chatel JM, Sokol H. Functional characterization of novel Faecalibacterium prausnitzii strains isolated from healthy volunteers: a step forward in the use of F. prausnitzii as a next-generation probiotic. Frontiers in microbiology. 2017 Jun 30;8:1226.

Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, Cook JR, Nordvig AS, Shalev D, Sehrawat TS, Ahluwalia N. Post-acute COVID-19 syndrome. Nature medicine. 2021 Apr;27(4):601-15.

Bai Z, Zhang N, Jin Y, Chen L, Mao Y, Sun L, Fang F, Liu Y, Han M, Li G. Comprehensive analysis of 84 Faecalibacterium prausnitzii strains uncovers their genetic diversity, functional characteristics, and potential risks. Frontiers in Cellular and Infection Microbiology. 2023 Jan 4;12:1924.

Gabashvili I.S. Cutaneous Bacteria in the Gut Microbiome as Biomarkers of Systemic Malodor and People Are Allergic to Me (PATM) Conditions: Insights From a Virtually Conducted Clinical Trial. JMIR Dermatol 2020;3(1):e10508 URL: https://derma.jmir.org/2020/1/e10508 DOI: 10.2196/10508

Rašić, J.L., Vujičić, I.F., Škrinjar, M. et al. Assimilation of cholesterol by some cultures of lactic acid bacteria and bifidobacteria. Biotechnol Lett 14, 39–44 (1992). https://doi.org/10.1007/BF01030911

Viruses and Vaccines

The COVID-19 Back-to-normal study was initiated in January 2021 as an effort of a tight-​knit neighborhood to help each other avoid the virus and vaccinate safely.

Later the research protocol was approved by MEBO Research IRB and the study was open to other communities around the world. 

By now, we have over 600 participants. 

Early results of the study in MEBO/PATM community, based on the replies of the first 26 enrollees, showed that while reactions to vaccine were similar to the general population, experiences with COVID-19 infections were not - 2 individuals were not able to avoid the disease in this group, and both of them experienced long term effects. 

As of today, we have stories from 41 members of MEBO/PATM community and 6 different vaccines: AstraZeneca-Oxford, Johnson & Johnson’s single-shot, Moderna, Pfizer-BioNTech, Sinovac Biotech’s CoronaVac and BBIBP-CorV, also known as the Sinopharm vaccine.

Currently, in various areas of the world, 19 COVID-19 vaccines have been authorized for use. Statistics on short-term effects of these vaccines have been published for different groups. If we compare our data to published data matching by ages and vaccines, short-term effects are very similar. Some of our sub-groups, especially healthy elderly participants, experienced far fewer side effects than reported in the literature. There were slightly fewer common adverse reactions in MEBO Pfizer group, but incidences of fatigue were on a higher side for all vaccines, and there were more reports of fever experienced after Moderna and Astrazeneca, albeit it was not significantly different from the general population. More significant differences were for less common and longer-term effects including fast heartbeat, dry mouth, skin reactions and swollen lymph nodes. The figure below shows common symptoms for Long COVID. Underlined are some of the issues reported after COVID vaccine uptakes in the group. Possible worsening of MEBO/PATM symptoms after vaccinations was reported by 10% of study participants. 

The most significant difference of MEBO group from the general population is the response to COVID-19 infection. 6 people (3 males, 3 females) out of 41 study participants experienced COVID-19 and all of them had long-term reactions. 5 out of 6 considered themselves long-haulers. The 6th person reported persistent MEBO/PATM issues  post-acute COVID-19. That's 80-100% of long-haulers, ~4 times more than researchers estimate! Our rate is closer to some groups with severe genetic conditions - such as individuals with hypohidrotic ectodermal dysplasia  - predisposing to bad smell from nostrils. 

Postinfectious fatigue was the most commonly reported symptom in this group. Long-lasting loss of smell happened in ~16% - as in the general population. MEBO/PATM symptoms were significantly increased, unless well under control before the infection. There's anecdotal evidence, based on posts in social media, that some sufferers of chronic COVID-19 are experiencing more aversive underarm smell. 7% of long-haulers are thought to sense phantom distorted smells. Is it really imagined smells or could it be real change in their odor?

We also had reports of successful management of persistent COVID symptoms with a low histamine, gluten-free, dairy-free and no carb diets.

Why is MEBO/PATM community more susceptible to long COVID? A new study argues that long-haulers might actually be experiencing an attack of fatigue-inducing Epstein-Barr virus (EBV, a member of herpesvirus family HHV-4) that was lying dormant in their bodies.  For this study, Gold and his colleagues analyzed blood of 30 people with chronic COVID (out of 185 COVID survivors). 20 out of these 30 carried high levels of EBV antibodies. Vaccines were shown to reactivate viruses too, in much rarer cases. As was demonstrated for Pfizer vaccine that woke up another herpes virus, chickenpox herpes-zoster (HHV-3), that causes shingles when reactivated (this happened to 1% of patients with autoimmune inflammatory rheumatic diseases). Herpes simplex (HSV-1) can be also kept in remission by a healthy immune system and can be also reactivated by COVID-19.

MEBO and PATM symptoms could arise following an infection. Perhaps SARS-CoV-2 can reactivate the old viruses that caused these symptoms to begin with? 

Community immunity (also known as herd immunity) protects everyone. We hope that MEBO/PATM community stays COVID-free and safe. 

REFERENCES

Gabashvili IS. Community-Based Phenotypic Study of Safety, Tolerability, Reactogenicity and Immunogenicity of Emergency-Use-Authorized Vaccines Against COVID-19 and Viral Shedding Potential of Post-Vaccination Infections: Protocol for a prospective study medRxiv 2021.06.28.21256779; doi: https://doi.org/10.1101/2021.06.28.21256779

McDonald I, Murray SM, Reynolds CJ, Altmann DM, Boyton RJ. Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2. npj Vaccines. 2021 May 13;6(1):1-4.

Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens. 2021 Jun;10(6):763.

COVID-19 and vaccine reactogenicity in MEBO/PATM community

Infections have been shown to alter body odor and so have immunizations. So far, only nonhuman animals were able to detect the subtle changes in chemical makeup after vaccinations and even their sensitive noses were not able to differentiate between different vaccines - such as the rabies virus or the West Nile virus vaccines [Kimball et al, 2014]. However, this was the case of very mild reactions to immunization. Even slightly stronger inflammatory responses, to relatively weak immune challenges, can, indeed, be detected by human noses [Gordon et al, 2018]. Urine and axillary odor are becoming slightly more aversive in healthy humans, as a function of immune activation. But this is not supposed to last too long.

Our preliminary results, based on responses to the survey for 24 members of MEBO community and 6 of their family members show a wide variety of reactions to Astrazeneca, J&J, Moderna, Pfizer and Sinovac/Coronavac vaccines. 

Interestingly, Pfizer vaccine that caused no or very mild reactions in several MEBO participants, was also the vaccine that possibly caused temporary worsening of odor symptoms in one person in the community. Another MEBO participant that reported possible worsening of odor from Moderna vaccine had one thing in common with the other individual - they both had pre-existing conditions related to their upper digestive tract. Some Astrazeneca recipients also reported odor issues but did not think it was worse than usual. 

One of the most interesting observations was that even though only 2 members of MEBO/PATM community reported COVID-19 infection (before or between vaccinations), both of them had long COVID with long-term neurological manifestations such as fatigue, ENT symptoms and loss of smell.

Adverse reactions to COVID-19 vaccines are influenced by a multitude of factors, many of which can be anticipated and alleviated. A certain level of inflammation is needed to trigger an effective adaptive immune response, but both environment and genetic makeup determine who is more likely to experience particular symptoms after infection and from the vaccine.

You can help by telling us about your experiences with COVID-19 and/or vaccinations. These surveys can be used for posting your brief stories - no need to answer all the questions. And you can always add to your story later. Please use your anonymous ID and let us know if you have any questions.

Survey

in English:  https://bit.ly/BTN-eng

en Español: https:/bit.ly/BTN-esp

We'll be posting more observations and comparisons with over 600 participants of our study from other communities. 

REFERENCES

Blumental S, Debré P. Challenges and issues of anti-SARS-CoV-2 vaccines. Frontiers in Medicine. 2021;8.

Gordon AR, Kimball BA, Sorjonen K, Karshikoff B, Axelsson J, Lekander M, Lundström JN, Olsson MJ. Detection of inflammation via volatile cues in human urine. Chemical senses. 2018 Nov 1;43(9):711-9.

Kimball BA, Opiekun M, Yamazaki K, Beauchamp GK. Immunization alters body odor. Physiology & behavior. 2014 Apr 10;128:80-5.

New Paper Reveals Insights into Bacteria that Live on Your Skin and in Your Gut

What do MEBO (metabolic body odor), PATM ("People are Allergic to ME" condition) and TMAU (trimethylaminuria) have in common - beside the obvious:  airborne substances that make people feel uncomfortable?  New paper published in JMIR Dermatology - Cutaneous Bacteria in the Gut Microbiome as Biomarkers of Systemic Malodor and PATM Conditions - demonstrates: it's microorganisms that live on the skin and can be also present in the gut. The results of a clinical trial reported in this paper showed that the same microbes can modulate severity of odor or allergic reactions in others independently of genetics and trimethylamine metabolism. 

Researchers long suspected that there was a link between gut and skin health. Recent studies have confirmed it for a number of inflammatory skin diseases - such as psoriasis, rosacea, acne and atopic dermatitis. Microbes have been also suggested as targets for treating TMAU, a disorder that causes the body to constantly emit foul odor - from the skin, the mouth and the nose - via skin or fecal microbiome transplantation, antibiotics and probiotics. However, existing treatments are too broad, can lead to other health problems and lack understanding of precise targets and mechanisms. 

The paper shows that MEBO and PATM conditions don't always arise because of the decrease in microbial diversity. About half of the people might be lacking in microbial richness, but another half has too many different bacterial species to handle. 

The figure shows results of 22 study volunteers that were able to observe both flare-ups and improvements in their condition. The Y axis shows changes in microbial diversity vs abundances of selected bacterial species (X axis) for 12 female and 10 male participants. The arrows are labeled with 3 or 4 digits - the last digits of MEBO ID. Beginning of the arrow shows participants' microbial diversity and proportion of skin microbes in the gut during flare-ups, the end of the arrow points to improvements. As this figure shows, the only exceptions to the conclusion that the fewer cutaneous bacteria in the gut, the fewer skin emanations were 1214, 1287 and 1307. All of them observed very minor if not negligible (and easy to misinterpret) improvement of their condition (flare-ups happening from “all the time” to “most of the time”). 1214 was seen by a professional dermatologist, who concluded that a diagnosis of bromhidrosis didn’t seem warranted. 1307 had undergone a Botox procedure to treat hyperhidrosis, but was still experiencing symptoms (and, from our results, large fluctuations in odorous skin bacteria). 1287 did not report any skin odors and noted only halitosis. 

Read the paper to learn more and stay tuned for more details as they develop.

REFERENCE

Gabashvili IS  Cutaneous Bacteria in the Gut Microbiome as Biomarkers of Systemic Malodor and People Are Allergic to Me (PATM) Conditions: Insights From a Virtually Conducted Clinical Trial

JMIR Dermatol 2020;3(1):e10508

URL: https://derma.jmir.org/2020/1/e10508

DOI: 10.2196/10508

Microbial diagnostics of MEBO

There are many medical conditions for which there are no standard tests for definite diagnosis and no established cures.  Diagnosing and curing Metabolic Body Odor (MEBO) is even more difficult. Especially because MEBO is an umbrella term for several different conditions.

---------- READ MORE -------

Age and Metabolic Body Odor

MEBO is a complex condition and while some of the cases seem simpler, non-linear analysis approaches are better equipped to handle the task.  And this creates new challenges regarding  the existence of confounding factors.

Concluding the MEBO-uBiome study

We are very close to concluding our clinical trial NCT03582826 ​according to the pre-specified protocol. 

Recruitment for our microbiome study commenced in June 2018 and completed in December 2018. The last batch of raw FASTQ sequences and raw taxonomy-level abundance summaries was received in October 2019. We had to spend more time on collecting and processing annotation data (medical histories, dietary intakes, medications, etc), ensuring quality, completeness, consistency and validity, and defining best approaches of dealing with "missing values".

We have now completed final data collection for the primary and secondary outcome measures.

...  Read more ... 

The Anna Karenina Principle: Alloprevotella

"All happy families are alike; each unhappy family is unhappy in its own way", said the great novelist. The Anna Karenina principle (AKP), in the context of metabolic disorders, would mean that an uncompensated deficiency in any one of important enzymes, or presence of any one of pathogenic microorganisms, dooms the person to having the MEBO/PATM symptoms.

... Read more ...

How do you feed your microbiome?

As we are gearing up for final stage of our clinical study NCT03582826, we are looking at different subgroups of our participants, to find more precise, personalized and powerful solutions for everyone. 

We know, that genes and environment always combine to make us who we are. We already talked about some of those seemingly less important genes - such as ABO blood group. The environmental factors include diet, exercise, social environments (such as social support), varying conditions and situations.   

According to descriptions of diets and lifestyle submitted by our participants, about 25% of them are taking commercial probiotic products, about the same number as those who had chicken as the main staple of their kitchen (see word cloud depiction of diet keywords on the right). About 2% take commercial prebiotics, but many more eat prebiotic foods (such as oats/oatmeal, bananas, apples and nuts shown in green). 4% eats onions and about the same percentage actively avoids it.  Milk, Rice, Bread and Pasta were among the most popular foods, after chicken. 

The world is eating less meat overall, and a few years ago, among the meat eaters, the scale tipped from greater consumption of beef to greater consumption of chicken.
This is even more pronounced in MEBO population. 

Half of MEBO population takes vitamins and  supplements.  The most popular among them is Zinc closely followed by Magnesium and Enzymes. Also popular are multivitamins, Calcium,  Resveratol, Vitamin B12, Charcoal, Chlorophyll, Ashwagandha, Biotin, Primrose oil, Omega 3 and Livercare. Blood pressure drugs are among the most used medications.

This information will be useful in understanding differences in microbiomes of subjects with similar symptoms. We might already be observing interesting trends. Certain supplements, for example, seem to benefit some blood group more than others. Same about foods naturally rich in certain minerals and vitamins.

We'll talk about this next time.

On what's in your head, the downside of diversity and deodorizing bacteria: preliminary results of NCT03582826

Mirrored from Aurametrix, preliminary results of NCT03582826:

By now, 105 uBiome kits were registered in our Quality of Life form (out of 300+ sets sent). 16 volunteers have submitted all 3 samples and 23 registered one or two kits. Over half of our participants have not yet started the study. We hope that this post will answer some of their questions on where to start.

The goal of MEBO Gut Microbiome study is to identify microbial communities associated with flare ups and remission of systematic malodor or PATM conditions.  Participants are asked to answer MEBO Quality of Life (QoL) questionnaire about the last 24 hrs before every sample is taken. The Questionnaire is embedded into English and Spanish posts about the study.  The answers are used to calculate total QoL score that increases with less odor and more wellbeing. The questionnaire evaluates physical health, psychological health, social support and environment such as diet and exercise. A separate score is calculated for MEBO (malodor/PATM) symptoms.

This post is about preliminary results of the first 41 uBiome kits representing samples from 24 participants. Quality of Life scores varied from 55 to 149 (best, "ideal" quality of life would be 150), while MEBO scores ranged from 3 (experienced MEBO/PATM symptoms "all the time" and odor was lingering for hours at 10 feet and farther) to 25 (100% odor free).

The pie chart on the right shows social environment for MEBO volunteers: almost half of study participants had active social lives interacting with over 8 people per day. Almost 20% of social interactions were entirely positive, while 10% were entirely negative. Social support did not correlate with MEBO symptoms and it was not predictor nor protective of malodor.

Graphs of depressive feelings vs odors is another prove that even with stress as a trigger, body odors are not all in your head. Obviously, those free of malodors tend to be happier, but it's possible to control depression even with worst MEBO symptoms and happy mood, alone, does not help to control the symptoms.

uBiome provides a multitude of measurements characterizing gut microbiomes. One of the most widely used metrics is gut diversity metrics.

Microbial diversity is cornerstone of a good health and decreased diversity is likely to be associated with poor wellbeing including malodors. Our data, however, show that most MEBO volunteers have healthy diversity scores that do not correlate with incidence of odors. Correlation is observed only for  cases of very low, unhealthy diversity, especially for total quality of life scores as opposed to just malodor symptoms. Even more so, MEBO volunteers in remission, completely free of odors, had healthy,  but not the very best diversity scores.

In extremely diverse communities, people may be less inclined to trust each other, vote and volunteer for activities. In people not suffering from uncontrollable odors, microbes and hosts have a balanced dialogue, and form symbiotic relationships beneficial for both parties.

Could it be that MEBO sufferers have more "smelly" bacteria and less bacteria neutralizing the smell?  Levels of traditional probiotic strains in the study participants do not seem to correlate with their odor levels. As more data is accumulated, interesting patterns are emerging for less common bacteria. An example is Anaerovorax, bacterium that processes putrid-smelling compounds produced by clostridia, pseudomonads, lactic acid and other bacteria from amino acids in food. Anaerovorax is observed in only 3% of uBiome samples, but it is present in a quarter of MEBO participants. Plotting its levels in all samples with Anaerovorax present against the scores representing improvement of MEBO symptoms (from worst odor to no odor), shows a clear trendline - the more Anaerovorax, the less odor. We note that this seem to be the case for ONLY a subset of study participants. For example, participants #901298 and #901240 who contributed 2 samples each into the first 41-sample-set, had 0 Anaerovorax on their worse day and over 0.03% Anaerovorax on their better days. # 901240 submitted 2 "bad day" samples (which is perfectly fine - as it still yielded much needed data!) had a little more Anaerovorax on a slightly better day. #90346 had experienced exactly the same MEBO symptoms on both days of sampling, but the result with 0 Anaerovorax corresponded to a worse Quality of Life score. #90365 experienced exactly the same symptoms for days with and without Anaerovorax, and had the same Quality of Life Score, but there was a noticeable difference in diet. This person had more Anaerovorax when consumed more odor triggers in food (onions and vinegar).

There is not much known about the role of Anaerovorax in human gut. It is proposed to increase when adding meat to a usually vegetarian diet and with increased fasting insulin levels. It is also increased in healthy preadolescent children (7 to 12 years old) and by minerals such as Zinc and Manganese.

Levels of TMA-producing bacteria such as Desulfibrio and Bacteroides seem to lower when odor levels are decreasing in most cases, although signal-to-noise ratio is weak and the dependence is very individual (see Figure). The trend is similar for #901214, #90265, #900841 and #901273. #901253 is one of the outliers: MEBO symptoms in this case were improving with higher levels of Bacteroides and lover diversity (and a much stricter diet).

Bacteroides maintain a complex and generally beneficial relationship with the host. The genus Bacteroides makes up to 30% of the bacteria in the human gut. Levels of Bacteroides increase with rapid weight loss. Specific species of Bacteroides, have a role in preventing infection with Clostridium difficile. Level of Bacteroides, however, increase (or significantly decrease) in inflammatory bowel disease and chronic fatigue syndrome.
Lactobacillus and bifidobacteria probiotics, garlic, walnuts and barley could all decrease levels of Bacteroides. Polydextrose (dietary fiber found in traditional bakery items, beverages, dairy products and sauces) not only decreases Bacteroides but also increases probiotic strains of Lactobacillus and Bifidobacterium.

These are only preliminary results. We'll be looking at more complex patterns in bacterial community structures associated with different subgroups of study participants. We'll be posting new findings as we mine more data and get additional results.

If you have not started the study yet, we hope that this post encourages you to start participating. As you see, every data point counts, even if the results of your experimentation and odor reduction approaches are not as good as we wished.


REFERENCES


Vemuri R, Gundamaraju R, Shastri MD, Shukla SD, Kalpurath K, Ball M, Tristram S, Shankar EM, Ahuja K, Eri R. Gut Microbial Changes, Interactions, and Their Implications on Human Lifecycle: An Ageing Perspective. BioMed research international. 2018;2018.

Zhang Q, Xiao X, Li M, Yu M, Ping F, Zheng J, Wang T, Wang X. Vildagliptin increases butyrate-producing bacteria in the gut of diabetic rats. PloS one. 2017 Oct 16;12(10):e0184735.

Roeder J, Schink B. Syntrophic degradation of cadaverine by a defined methanogenic coculture. Applied and environmental microbiology. 2009 Jul 15;75(14):4821-8.

Lau SK, Teng JL, Chiu TH, Chan E, Tsang AK, Panagiotou G, Zhai SL, Woo PC. Differential Microbial Communities of Omnivorous and Herbivorous Cattle in Southern China. Computational and structural biotechnology journal. 2018 Jan 1;16:54-60.

Filocamo A, Nueno-Palop C, Bisignano C, Mandalari G, Narbad A. Effect of garlic powder on the growth of commensal bacteria from the gastrointestinal tract. Phytomedicine. 2012 Jun 15;19(8-9):707-11.

Cruden DL, Galask RP. Reduction of trimethylamine oxide to trimethylamine by Mobiluncus strains isolated from patients with bacterial vaginosis. Microbial Ecology in Health and Disease. 1988 Jan 1;1(2):95-100.

Craciun S, Balskus EP. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proceedings of the National Academy of Sciences. 2012 Dec 26;109(52):21307-12.