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

Cytochromes P450 and the World of Volatile Organic Compounds

Cytochrome P450, often abbreviated as CYP450 (CYP) or simply P450, is a vital group of enzymes found in the liver, and it plays a fundamental role in detoxifying the body and metabolizing various foreign compounds.

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Metabolic enzymes employ different catalytic mechanisms. FMOs, for instance, directly receive electrons from nictinamide adenine dinucleotide phosphate (NADPH), while CYPs obtain their electrons via an intermediary protein known as CYP reductase. Furthermore, CYPs activate oxygen only after binding to an oxygenatable substrate, adding an extra layer of complexity to the metabolic puzzle. 

In the complex world of enzymatic metabolism, our comprehension of the comparative efficiency of different enzymes remains somewhat limited. The body's selection of which metabolic enzymes to use is governed by several factors such as substrate specificity, enzyme efficiency, temperature and the surrounding environment in the compartment where the enzyme and substrate are in, co-factors and co-enzymes,  concentration of substrates and competition for substrates. 

Cytochrome P-450 (CYP450) enzymes and Flavin-containing monooxygenases (FMOs), such as FMO3, often participate in the metabolic processes of the same compounds. For instance, substances like Nicotine, Caffeine, Tazarotenic acid, Benzydamine, and the antipsychotic drug Perazine (PER) encounter these enzymes during their metabolic journey.

FMO3, in particular, stands out for its remarkable ability to convert trimethylamine (TMA) into trimethylamine N-oxide (TMAO). However, even TMA navigates a maze of metabolic pathways and could encounter cytochromes P-450.

Similar to FMO3, genetic variations in CYP2E1, such as the SNP g.50657948 T>G, have been linked to odor (lamb odor and flavor in sheep), indicating a broader role beyond metabolism, potentially affecting odorant and pheromone clearance. Ubiquitous amino acid derived from food  - tryptophan serves as the precursor for skatole, and the conversion of tryptophan to skatole involves the action of enzymes, including CYP2E1, in a series of metabolic reactions. CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption, diabetes, fasting, and obesity. 

Poor dietary choices, medications, exposure to external factors such as air pollution, cigarette smoke, radiation (e.g., UV radiation from the sun), and certain environmental toxins, inflammatory processes, whether due to infection, injury, or chronic inflammatory conditions, even normal metabolic processes can generate reactive oxygen species (ROS) as byproducts. Examples are superoxide anion (O2·-), hydrogen peroxide (H2O2), hydroxyl radical (·OH), and singlet oxygen (1O2), among others. Excessive production or impaired elimination of ROS can lead to oxidative stress.

To counteract the harmful effects of oxidative stress, the body activates the detoxification process, in which cytochrome P450 takes center stage. Cytochrome P450 catalyzes the addition of an oxygen atom to foreign compounds, making them more water-soluble. This transformation results in the formation of alcohols and, as byproducts, aldehydes. The detoxification process is a critical defense mechanism that helps the body eliminate harmful substances.

High-fat and high-protein diets have gained popularity but can have adverse effects on our health. Research has shown that these diets may induce organ damage, abnormal serum biochemical indexes, and inflammation. Interestingly, the production of malodorous gas compounds in the body because of these diets can be influenced by the interaction between the intestinal microbiota and liver cytochrome P450. 

from Zhang et al, 2022

Chemicals that alter xenobiotic metabolizing enzymes, such as CYPs, may also alter endogenous hormone levels since some of these enzymes control levels of endogenous hormones. Many of the pesticides that caused mammary gland tumors or other mammary effects also alter steroidogenesis in the H295R adrenocortical carcinoma cell line, activate nuclear receptors or CYP enzymes, or are estrogenic.

CYP family of heme monooxygenase enzymes is known for its ability to catalyze enantioselective hydroxylation and epoxidation reactions. Epoxidation reactions have been hypothesized to proceed via multiple mechanisms involving different reactive intermediates. A study of the bacterial enzyme CYP199A4 from Rhodopseudomonas palustris demonstrated a significant reduction in epoxidation activity when the D251N mutation was introduced. Remarkably, despite these mutations, the chemoselectivity and stereoselectivity of the epoxidation reaction remained intact.

Innovations in biotechnology have led to the development of specialized cytochrome P450 enzymes, such as the Cytochrome P450 BM-3 mutant (139-3). This mutant exhibits high activity towards the epoxidation of non-natural substrates, including propylene, which can be converted to propylene oxide. 

In summary, cytochrome P450 is a fascinating and essential component of our body's biochemistry, with implications that extend beyond detoxification. Understanding its functions and interactions can pave the way for advancements in both medicine and biotechnology.

REFERENCES

Zhang T, Xie B, Liu H. High-fat and high-protein diets from different sources induce different intestinal malodorous gases and inflammation. Food Research International. 2022 Apr 1;154:110989.

Padwa A, Murphree SS. Epoxides and aziridines-a mini review. Arkivoc. 2006 Jan 1;3(6).

Störmer E, Brockmöller J, Roots I, Schmider J. Cytochrome P-450 enzymes and FMO3 contribute to the disposition of the antipsychotic drug perazine in vitro. Psychopharmacology. 2000 Sep;151:312-20.

Harahap RS, Noor RR, Gunawan A. Effect of CYP2E1 gene polymorphisms on lamb odor and flavor in Indonesian sheep. InIOP Conference Series: Earth and Environmental Science 2021 Jun 1 (Vol. 788, No. 1, p. 012022). IOP Publishing.

The Power of Scent: Synthetic Odorants and Hair Health

In a study published this month in the Journal of Dermatological Science, Edelkamp and a team of researchers have unveiled a novel approach to managing the human hair follicle microbiome. The key player is a synthetic odorant that mimics the scent of sandalwood, known as Sandalore®.

The study's foundation lies in the discovery that human scalp hair follicles (HFs) possess olfactory receptors, which enable them to engage in chemosensation. Specifically, activation of olfactory receptor family 2 subfamily AT member 4 (OR2AT4). 

One of the findings was the role of Sandalore® in up-regulating the expression of dermcidin (DCD) within the hair follicles. Previously believed to be exclusively produced by sweat and sebaceous glands, DCD is a potent antimicrobial peptide. The study revealed that synthetic odorant treatment triggered the production of DCD within the hair follicles.

To thoroughly understand the implications of this discovery, the researchers compared DCD expression between fresh-frozen scalp biopsies and microdissected, full-length scalp HFs. These HFs were organ-cultured under various conditions, including the presence or absence of Sandalore®, antibiotics, and the competitive OR2AT4 antagonist, Phenirat®.

Sandalore®-conditioned medium, with increased DCD content, was found to favor the growth of beneficial bacteria, such as Staphylococcus epidermidis and Malassezia restricta, while simultaneously exhibiting antimicrobial activity against Cutibacterium acnes. 

The study opens doors for further exploration into using cosmetic odorants in the management of folliculitis and dysbiosis-associated hair diseases.

REFERENCE

Edelkamp J, Lousada MB, Pinto D, Chéret J, Calabrese FM, Jiménez F, Erdmann H, Wessel J, Phillip B, Angelis M, Rinaldi F, Bertolini M, Paus R. Management of the human hair follicle microbiome by a synthetic odorant. J Dermatol Sci. 2023 Oct 17:S0923-1811(23)00221-9. doi: 10.1016/j.jdermsci.2023.09.006. Epub ahead of print. PMID: 37858476.

Methanethiol: The Scent of Disease and Discovery

In a previous blog post, we discussed the role of SELENBP1 in nonosyndromic (monosymptomatic) halitosis. We learned that if this enzyme isn't functioning correctly, it can lead to the release of more Methanethiol, a volatile and rather unpleasant-smelling gas often associated with the aroma of rotten cabbage. 

However, Selenium binding protein 1 (SELENBP1) isn't just a casual bystander in our biological processes. It has been linked to various health conditions and diseases. These include:

Hypermethioninemia: A rare condition that can sometimes come with learning disabilities and neurological issues.

Schizophrenia: a complex mental disorder that challenges our understanding of the human mind

Hypertension and Ischemic Heart Conditions, conditions such as Guillain-Barré syndrome and Infectious Diseases: Dysregulation of SELENBP1 is associated with Zika virus (ZIKV) and dengue infections, as well as COVID-19.

SELENBP1's role in several types of cancer, including its downregulation at the onset of cancer and upregulation in later stages, is a subject of intense research.

Methanethiol contributes to the distinct scent signature linked to cancer, characterized by a combination of volatile organic compounds (VOCs). Researchers are increasingly exploring this intriguing scent profile as a potential tool for non-invasive early cancer diagnosis.

Methanethiol is a testament to the intricate connections between genetics, metabolism, and disease, reminding us that even the smelliest molecules can lead to groundbreaking discoveries.

Methanethiol also contributes to the distinct scent signature associated with cancer, characterized by a combination of volatile organic compounds (VOCs). This intriguing scent profile is increasingly being explored for non-invasive early cancer diagnosis.

In a recent paper titled "Methanethiol: A Scent Mark of Dysregulated Sulfur Metabolism in Cancer,"  researchers unveiled new findings:

Tumor cells undergo metabolic adaptations to meet increased energy demands and enhance stress resilience. This includes dysregulation of sulfur metabolism and elevated levels of volatile sulfur compounds (VSCs) in cancer patients.

Methanethiol stands out as the predominant cancer-associated VSC and is being considered as a potential biomarker for non-invasive cancer diagnosis.

Within the gut microbiome of colorectal carcinoma (CRC) patients, gut bacteria, particularly methanethiol-producing strains like Fusobacterium nucleatum, are a significant source of exposure to methanethiol.

Selenium-binding protein 1 (SELENBP1) plays a crucial role in the rapid degradation of methanethiol through its methanethiol oxidase (MTO) activity.

Odor-based cancer screening methods, such as sniffer dogs and canine scent detection, even human feedback, have shown great promise in identifying lung and colorectal cancer patients, opening doors to non-invasive detection approaches.

The dysregulation of sulfur metabolism and the potential use of methanethiol as a biomarker, coupled with the innovative odor-based cancer screening methods, offer not just promising but transformative avenues for non-invasive cancer detection and cutting-edge research.

REFERENCE

Philipp TM, Scheller AS, Krafczyk N, Klotz LO, Steinbrenner H. Methanethiol: A Scent Mark of Dysregulated Sulfur Metabolism in Cancer. Antioxidants (Basel). 2023 Sep 19;12(9):1780. doi: 10.3390/antiox12091780. PMID: 37760083; PMCID: PMC10525899.

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. 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.

Human Skin Gas Profiles in PATM

People Allergic to Me (PATM) is a perplexing condition that has left both sufferers and medical professionals searching for answers. Thousands of individuals worldwide claim to experience PATM, leading to severe mental health challenges such as depression, anxiety, and suicidal tendencies. Despite its far-reaching impact, the underlying causes remain mysterious, with only a few scientific studies dedicated to understanding this condition. While a small subset of PATM sufferers has been diagnosed with TMAU, the majority remain without a diagnosis. 

A new study lead by Professor Sekine, recently published in Nature Scientific Reports, explores the human skin gas profiles to shed new light on PATM. 

The study included 44 subjects, divided into two groups: 24 without PATM (non-PATM) and 20 with PATM. The non-PATM group involved 13 male and 11 female participants (age: 18–59, 31 ± 13 years old). The PATM group comprised 12 male and 8 female participants (age: 19–53, average 39 ± 12 years old).

The non-PATM group had no known diseases, while the PATM group reported symptoms of PATM without other apparent diseases.

Researchers sought to understand the skin gas profile of people with and without PATM, potentially the source of body odor or other types of emissions. They measured the emission rate of 75 volatile compounds from the skin using a tool called a passive flux sampler (PFS) coupled with gas chromatography/mass spectrometry (GC/MS). PFS was designed to be convenient and unobtrusive, allowing people to use it on the go without any hassle.

Participants in the study were given a PFS device, similar in size to a bottle cap, to collect skin gas samples from their non-dominant forearm. They wore this device for an hour without any restrictions on their activities. The device was easily attached to the skin with a piece of surgical tape and didn't require any special preparation. After collecting the samples, PFS devices were sent to the laboratory and analyzed.

The PATM group exhibited significantly greater emission fluxes for a variety of chemicals, including some with offensive odors, and lower emissions of others, including some with more pleasant or neutralizing smells. 

Among the 75 measured skin gases, the PATM group exhibited significantly greater emission fluxes for chemicals like alcohol 2-ethyl-1-hexanol (2E1H), aldehyde isovaleraldehyde, hexanal, acetone, toluene, m,p-xylene, methyl mercaptan, ethyl mercaptan, and allyl methyl sulphide (AMS). These chemicals often have offensive odors and/or can lead to adverse health effects. The emissions of petrochemical 2E1H, and aromatic hydrocarbons (with benzene ring in their structure): toluene, and m,p-xylene were notably higher in the PATM group, with increases of approximately 12, 39, and four times, respectively.

Volatile organosulfur compounds such as methyl mercaptan (fecal odor, resembling smell of rotten cabbage or decaying vegetables), ethyl mercaptan (rotten fish, garlic, or onions), and Allyl Methyl Sulfide (AMS, garlic- or onion-like odor) were also significant. These compounds have extremely low odor thresholds and could easily alter body odor perception in PATM subjects. Bacteria in the oral cavity, such as Porphyromonas gingivalis and Anaerobic bacteria in the gut, such as Desulfovibrio species are producers of Methanethiol. 

Isovaleraldehyde contributes to body odor with a pungent fruit-like smell that can also contribute to aroma of beer and cheese. It can be sourced from metabolic breakdown of amino acids like leucine and valine, hence dietary intake, and microbial activity in the gut by methylotrophic yeasts. , species of Clostridium, Actinobacteria (Rhodococcus, Mycobacterium and Gordonia), Proteobacteria (Acetobacterium such as Gluconobacter oxydans), Odoribacteraceae, Ruminococcus gnavus, etc. These microbes are capable of producing  Isovaleraldehyde through anaerobic fermentation and the mevalonate-independent glyceraldehyde 3-phosphate/pyruvate pathway. 

Greater emission of acetone might indicate eating disorders in the PATM group, as it is influenced by fasting, starvation, or diet.

The PATM group had less skin release of various substances, including some types of alcohols, smell-related chemicals, and fruity-smelling compounds. Some of these chemicals are used in flavors or fragrances and are known to have a relaxing effect.

For example, α-pinene, β-pinene, and D-limonene have antifungal activities as well as abilities to decrease depression-like behavior and improve memory via an anti-neuroinflammatory mechanism under chronic restraint stress. 

D-limonene can be consumed through the diet by eating citrus fruits or drinking citrus-flavored beverages. Some fruity-smelling compounds are naturally found in fruits like peach and pineapple and contribute to sweet body scents. It can also be absorbed through the skin from personal care products containing citrus oils or inhaled from air.

Acetic acid smells like vinegar and is made by bacteria breaking down certain substances in sweat. It is linked to body odor in young adults. Lower skin emissions of acetic acid in the PATM group showed that sweating may not be the cause of their unique body odor. Acetic Acid is produced by acetic acid bacteria, such as Acetobacter and Gluconobacter species. Certain lactic acid bacteria, such as Lactobacillus, can also produce acetic acid.

The study also looked at benzaldehyde, which might come from toluene. People with PATM had much more skin emission of toluene but less of benzaldehyde.

The presence of benzaldehyde in the human body is typically at low levels, and its occurrence may vary based on factors such as diet, environmental exposure, individual metabolism, and gut microbiome composition. Almonds, apricots, and cherries are examples of foods that contain benzaldehyde or related compounds. Toluene is a common solvent used in various industrial and household products such as paints, glues, nail polish, and cleaning agents. Inhalation of fumes from these products can lead to toluene being present in the blood and tissues.

The ratio of toluene to benzaldehyde was much higher in the PATM group, and this ratio is seen as a key sign of PATM.

Air quality in terms of petrochemicals is worse in urban areas, high traffic areas, industrial workspaces, poorly ventilated interiors, newly constructed or renovated spaces, automotive interiors, salons and beauty parlors, households using cleaning products containing petrochemicals, such as certain detergents, aerosol sprays, and solvents, spaces with indoor smoking and even some healthcare facilities. 

Our previous study on breath VOC profiles in PATM, TMAU and MEBO (Alveolar Breath Test Study registered as NCT03451994) has unveiled intriguing insights into petrochemical metabolism, indicating that non-TMAU MEBO population may have difficulties with metabolizing environmental pollutants, while the Microbiome study (registered as NCT03582826) uncovered possible microbial sources of compounds that differentiate PATM, TMAU and MEBO from non-MEBO & non-PATM populations. Our findings align remarkably with Professor Sekine's work.

The synergy between these discoveries is shedding light on the underlying mechanisms and potential diagnostic markers. We will be publishing these complementary results soon, further contributing to the scientific community's knowledge of PATM, TMAU and MEBO.

Stay tuned for our upcoming publications, as we continue to unravel the mysteries of these conditions, working towards a future where this condition is better understood, diagnosed, and managed. 

REFERENCES

Sekine Y, Oikawa D, Todaka M. Human skin gas profile of individuals with the people allergic to me phenomenon. Sci Rep. 2023 Jun 10;13(1):9471. doi: 10.1038/s41598-023-36615-1. PMID: 37301918; PMCID: PMC10257688.

Mobiluncus and Peptoniphilus

Mobiluncus is one of bacteria reducing trimethylamine oxide to trimethylamine. It was also found to be associated with halitosis and bacterial vaginosis. We documented this bacterium in the gut and vaginal samples of several participants of our microbiome study. A new paper found Mobiluncus in umbilical dirt of the high odor score group. 

Since odor scores did not show a normal distribution, samples were divided into two groups, one with an odor score ≥2.0 and one <2. Well-known resident bacteria of skin, such as Cutibacterium, Staphylococcus, and Corynebacterium, were not detected, whereas some anaerobic bacteria, including Mobiluncus (q-value=2.1E-33), Arcanobacterium (q-value=4.5E-22), and Peptoniphilus (q-value=4.3E-17), were highly abundant in umbilical dirt samples with high odor scores. The same genera were detected when samples were divided into two groups with an odor score ≥1.5 as the criterion.

By a predictive metagenome analysis using Picrust2, the authors identified genes that appeared to be specific to umbilical dirt with high odor scores. Metabolic pathways common to the extracted gene groups were analyzed by GSEA (Gene Set Enrichment Analysis). Anaerobic metabolic pathways, such as methane metabolism and glycolysis/gluconeogenesis, were more abundant in the high odor score group, and secondary metabolite production pathways, such as the biosynthesis of secondary metabolites and quorum sensing, were also identified.

While, Mobiluncus is associated with halitosis and bacterial vaginosis, Peptinophilus contributes to underarm odor by producing chemicals such as butyric acid. Acetobacter is one of species that could be counteracting the undesirable odors in this context. 

REFERENCES

Yano T, Okajima T, Tsuchiya S, Tsujimura H. Microbiota in Umbilical Dirt and Its Relationship with Odor. Microbes Environ. 2023;38(3). doi: 10.1264/jsme2.ME23007. PMID: 37407492.

Valerie M, Milaine T, Aicha N, Roger A, Patrick MJ, Ibrahima D, Nehemie D, Laure N, Angeline B. Survey on Intravaginal Practices among Women of Reproductive Age at the Gynaeco-Obstetric and Pediatric Hospital of Yaounde: Association with Bacterial Vaginosis Caused by Gardnerella Vaginalis and Mobiluncus. International Journal Of Medical Science And Clinical Research Studies. 2023 Jan 30;3(1):121-6.

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

Zhang L, Hong Q, Yu C, Wang R, Li C, Liu S. Acetobacter sp. improves the undesirable odors of fermented noni (Morinda citrifolia L.) juice. Food Chemistry. 2023 Feb 1;401:134126.