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

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

Current Trends in Deodorization

In the Victorian era, people would wash off with a sponge soaked in cool water and vinegar, use sweat-absorbing pads in armpit areas and overwhelm unpleasant smells with perfume. The most popular scent was ambergris known for its marine, sweat and earthy scent with a fecal note (if not properly aged). Since energy was obtained from burning of fuels, large amounts of sulfur were always present in the air, covering odors of animal and human waste released into river and streams. 

Engineers eventually designed centralized closed water sewage treatment systems and modern plumbing, enabling rigorous personal hygiene. But in the early 1900s, fear-based marketing convinced people that they smelled bad, and this turned niche deodorant trades into a $22 billion industry. Odorono (from "Odor? Oh No!") was one of the first antiperspirants at the forefront of this transformation. 

The use of antiperspirant deodorants has been declining in recent years due to their potential effect on health and environment, and the availability of more natural and organic alternatives. COVID-19 pandemics has also negatively affected the deodorant market. As a result, the demand for deodorization has decreased during these times. But innovation continues.

Across North America, the deodorants market witnessed growth of few brands creating antiperspirants intended for alternative body parts, such as hands, face, and feet. For example, Gamer Grip Hand Antiperspirant, designed for athletes to improve their grip, has a lasting fragrance for 4 to 6 hours. Neat 3B Face Saver is an antiperspirant gel for the face that can be applied before makeup. Carpe No-Sweat Face is a natural, sweat absorbing gelled lotion created with sweat absorbing ingredients like jojoba esters, vitamin B3, silica microspheres, aloe vera, and colloidal oatmeal.

In the early 2000s, new types of deodorants appeared on the market. Deo Perfume Candy, Swallowable Parfum, and Otoko Kaoru were designed as edibles, and the fragrance was supposed to be released from the user's mouth and nose. However, these products were eventually discontinued due to safety concerns, as well as their lack of popularity. 

Beginning in the mid-2000s, many clothing companies started incorporating silver nanoparticles into their products including nano-engineered anti-odor textiles. While the technology was initially developed for use in the medical industry (antimicrobial wound dressings), nano-porous materials in clothing presented another way to manage body odor. These materials offered the potential to make traditional deodorants old-fashioned or even obsolete. 

Ag nanoparticles, for example, are effective at slowing the growth of bacteria that cause body odor and itchiness. Nano-silver socks help in preventing bacterial and fungal growth. Haojey creates textiles comprising a TiO2 particle core to provide UV resistance, silver nanoparticles for antibacterial textiles, and nanobamboo for odor adsorption. Cotton treated with pomegranate and galnut extract showed excellent deodorizing performance against trimethylamine. Odor-free medical masks are fabricated using Polyvinyl Butyral and Eucalyptus Anti Odor Agent. Aloe Vera and Polyvinyl Alcohol (AV/PVA) electrospun nanofibers show excellent results suppressing growth of S. aureus bacteria (by ~25%) although not E. coli. A team from UC Berkeley introduced a way to reduce underarm sweating and odor by using a cross-linked microporous copolymer containing methacrylate and acrylate units. 

Unfortunately, many of nano-infused textile products are investigated as skin irritants. Besides, considerable amounts of Ag nanoparticles were found to be released on washing Ag nanoparticle integrated fabrics, which is highly toxic to aquatic life. 

Another trend in the world of skincare that started in the late 2000s was topically applied probiotics. 

Although the idea is not new, as research into the human microbiome began to uncover the role that probiotics could play in improving health, the use of probiotics, prebiotics and postbiotics to help combat odor-causing bacteria began to gain traction. Oral deodorizers with probiotics are already commonly found in the market in the form of chewing tablets, lozenges, and capsules. Topical probiotic formulations could exert anti-inflammatory effects by stimulating regulatory T-cells and release of anti-inflammatory cytokines such as IL-10, within the immune system, competing with odor-causing microbes for nutrients, and aggregating and displacing them. When applied to the skin, Lactobacilli, for example, exhibits antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, and Cutibacterium (formerly Propionibacterium) acnes. Topical microbiome transplantation (Roseomonas mucosa lysate cultured from healthy volunteers) is believed to improve atopic dermatitis by restoring epithelial barrier function and innate/adaptive immune balance as well as via inhibition of S. aureus growth. Nitrosomonas eutropha improves appearance of skin. Transplantation of microbiome enriched in S. epidermidis helped to reduce axillary malodor in siblings or other matching individuals. Bacteria responsible for odor emitted from the skin is known and is common for individuals suffering from a variety of odor disorders, including those with genetic variations in ABCC11, FMO3 and those with idiopathic malodor. The presence of these bacteria in the gut microbiome correlates with the intensity of malodor. Balancing composition of gut microbes will definitely help to improve the odor but may take a long time and require tailor-made diets. And it is not clear if "suicide substrate inhibitors" such as iodomethylcholine are sufficiently safe to use.

More than a dozen topical probiotic species have been found to have a unique spectrum of characteristics, including keratin adhesion, inhibitory action, organic acid production, and inhibition of biofilm formation, skin whitening, moisturizing, anti-aging, anti-wrinkle and removing body odor. A new bilayer vaginal tablet of Lactococcus lactis has been designed for the treatment of vaginal bacterial infections and could also help to combat unpleasant odors. And so could Nitrosomonas eutropha, although so far it was only proven to help with acne. Genetically modified bacteria are also being investigated as topical therapeutics. Candidate genes are Fillaggrin, LEKTI, IL-10, genes encoding growth factors and hormones. Studies of safety and efficiency are still, however, in very early stages. The application of high amounts of bacteria, could, for example, lead to a skin immune reaction with irritation and side effects as a result. It could also lead to infection. 

The skin microbiome is relatively stable and quickly restores after washing and skincare product application, even if they contain antimicrobials. The reason is, skin microbiome is actually derived from within the skin, the deeper stratum corneum layers, skin hair follicles and is connected to the gut microbiome. Skin microbiome transplantation methods are currently being investigated and showed some promising results although many challenges remain that need to be overcome. 

Probiotic-infused products and skin transplants are gaining popularity due to their ability to promote healthy bacteria growth on the skin, which can, for example, help reduce body odor. However, there is still a lack of strong scientific evidence of effectiveness and a lack of thorough understanding of side effects.  Probiotics are living microorganisms, which means that they are sensitive to environmental conditions and can be difficult to work with. This can make it challenging to incorporate probiotics into skincare products in a way that preserves their effectiveness and stability. Finally, there are regulatory issues to consider when it comes to introducing new probiotic-based skincare products to the market. In order to be sold as a cosmetic product, a skincare product must be safe and effective, and the manufacturer must provide evidence to support these claims. This process can be time-consuming and costly and may discourage some companies from investing in the development of new probiotic-based skincare products. 

Overall, while there is a growing interest in the potential benefits of probiotics, prebiotics and postbiotics for the skin, the development of new probiotic-infused skincare products is likely to continue to be slow and incremental as researchers and manufacturers work to understand more about how probiotics work and how they can be effectively incorporated into skincare products. 

It is likely that skincare products developed in the future will be tailored to specific genetic profiles, as researchers continue to learn more about the role that genetics plays in skin health and the skincare concerns that people may have. 

One example is a urea-containing moisturizer that could be effective for people with a certain genetic variation in the filaggrin gene, Transient erythema (reddening of skin) is a potential side effect. A number of genes (such as MC1R, ASIP and BNC2) are related to skin conditions including sun sensitivity, skin moisturizing function, oxidative stress, stretch marks, and skin inflammation and are being investigated in personalized skincare R&D. 

Gene therapy and enzyme replacement therapies have achieved some notable successes in recent years. For instance, the US Food and Drug Administration (FDA) approved Luxturna for a rare form of inherited blindness, and Kymriah using genetically modified T cells to attack cancer cells, in 2017. However, the costs of research and development and the risk of side effects are extremely high. 

As a result, it can be difficult to obtain funding for non-fatal conditions like TMAU (trimethylaminuria). Trinzyme, a company focused on enzyme replacement therapies, was founded in 2011 with the goal of developing treatments for TMAU. While the company was able to secure initial funding, it has not yet been able to deliver on its promise of a treatment for this condition. Despite these challenges, the potential for gene therapy and enzyme replacement therapies to revolutionize the way we treat and prevent diseases remains significant, and research and development in these fields continues to advance.

In 2022, several companies started testing their deodorizing cosmetic products intended to block smelly chemical trimethylamine, emitted from the skin if the liver cannot completely break down this product of essential nutrients. Spain-based perfume manufacturer Eurofragance has recently teamed up with a Barcelona Children Hospital on a project to neutralize the strong odor of those who suffer from trimethylaminuria (caused by genetic mutations that affect the FMO3 function of the liver). The hospital's program initially focused on pediatric subjects with primary carnitine deficiency, manifesting as metabolic encephalopathy, lipid storage myopathy, or cardiomyopathy. Since the patients are not able to process long-chain fatty acids to convert them into energy, the accumulation of toxic fatty acyl derivatives impedes gluconeogenesis and urea cycle function which, in turn, causes hypoketotic hypoglycemia, transaminase elevations, and hyperammonemia - hence fishy odor. Eurofragance solution has citrus notes blocking the fish odor receptors in the nose. This way the fishy odor does not disappear, but it is not perceived. Eurofragance designed body cream lotion with 1% fragrance, an eau de toilette with 5% fragrance and a body serum with 2% fragrance. Other businesses designing their own solutions were Nannic "Skin care by science", and stealth-mode teams from British and US companies. 

While there is still a lot more research to be done, the development of these new deodorizing cosmetic products has provided hope for those who struggle with trimethylaminuria and similar conditions.

REFERENCES

Callewaert C, Knödlseder N, Karoglan A, Güell M, Paetzold B. Skin microbiome transplantation and manipulation: Current state of the art. Computational and Structural Biotechnology Journal. 2021 Jan 1;19:624-31.

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

Gabashvili IS. Identifying subtypes of a stigmatized medical condition. medRxiv. 2019 Jan 1:19005223.

Habeebuddin M, Karnati RK, Shiroorkar PN, Nagaraja S, Asdaq SM, Khalid Anwer M, Fattepur S. Topical Probiotics: More Than a Skin Deep. Pharmaceutics. 2022 Mar 3;14(3):557.

Lee GR, Maarouf M, Hendricks AJ, Lee DE, Shi VY. Topical probiotics: the unknowns behind their rising popularity. Dermatology Online Journal. 2019;25(5).

Lee YH, Lee SG, Hwang EK, Baek YM, Cho S, Kim JS, Kim HD. Deodorizing performance and antibacterial properties of fabric treated with pomegranate and gallnut extracts compared with properties of commercial deodorizing and antibacterial agents. Textile Science and Engineering. 2016;53(1):45-54.

Myles IA, Earland NJ, Anderson ED, Moore IN, Kieh MD, Williams KW, Saleem A, Fontecilla NM, Welch PA, Darnell DA, Barnhart LA. First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI insight. 2018 May 5;3(9).

Qadir MB, Jalalah M, Shoukat MU, Ahmad A, Khaliq Z, Nazir A, Anjum MN, Rahman A, Khan MQ, Tahir R, Faisal M. Nonwoven/Nanomembrane Composite Functional Sweat Pads. Membranes. 2022 Dec 5;12(12):1230.

Yang J. Personalized Skin Care Service Based on Genomics. InInternational Conference on Health Information Science 2021 Oct 25 (pp. 104-111). Springer, Cham.

 

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.