how is trehalose listed on food labels
WebTrehalose consists of 2 glucose molecules bound by an ,-1-1 bond. A plus sign next to the number [1+, 2+, etc] means that the information is found within the full scientific study rather than the abstract. In EU, the Scientific Committee on Food (SCF) evaluated trehalose manufactured using the enzymatic technology, declared it safe, and authorized it to be marketed as a novel food/novel food ingredient within the European Community. estimate that trehalose intake from naturally occurring sources is approximately 100 grams per capita annually. Can trehalose be organic? [34], In 1832, H.A.L. I wrote to the UK Food Safety Agency with this question. Moreover, growth in vitro in a laboratory setting does not necessarily generalize to a human gut. Notably in both studies, trehalose metabolism/utilization variants were more widespread than previously thought, suggesting that the ability to utilize low concentrations of trehalose was acquired prior to the recent increase in trehalose production and utilization (Eyre et al. Essentially all international and national food regulatory authorities have evaluated the safety of trehalose and approved it for use. Trehalose aqueous solutions show a concentration-dependent clustering tendency. Zhang Y, Shaikh N., Ferey J.L., Wankhade U.D., Chintapalli S.V., Higgins C.B., Crowley J.R. Heitmeier M.R., Stothard A.I. In the [19] Trehalose has about 45% the sweetness of sucrose at concentrations above 22%, but when the concentration is reduced, its sweetness decreases more quickly than that of sucrose, so that a 2.3% solution tastes 6.5 times less sweet as the equivalent sugar solution. [4][5] Trehalose has high water retention capabilities, and is used in food, cosmetics and as a drug. Trehalose is most often used for Other. People with diabetes and insulin resistance should be extra cautious. 2019 & Saund et al. which enables users to obtain detailed information and reports based on their genome. Tests on 20 volunteers confirmed that trehalose causes a milder increase in blood glucose (38%) and insulin (36%), compared with an equal amount of glucose [40]. Many strains of C. diff carry the genetic mutation to metabolize trehalose, not just epidemic strains. People with diabetes and insulin sensitivity should pay special attention to their daily sugar intake, which includes trehalose. How to minimise exposure to systemic pesticides while eating non-organic fruits and vegetables? This is especially important for people susceptible to C. difficile infections. I wonder if they can just call it sugar? In the A large intake of trehalose at one time may induce laxation. Trehalose, a naturally occurring disaccharide, is used in Taco Bells beef to improve the taste, the chain said. Australia/NZ (FSANZ), Brazil (ANVISA), Canada (Health Canada), China (MOH), India (FSSAI), Trehalose is not associated with the emergence and spread of epidemic, 'Trehalose is not associated with the emergence and spread of epidemic, Advances in Carbohydrate Chemistry and Biochemistry, Trehalase deficiency | Genetic and Rare Diseases Information Center (GARD), http://www.inchem.org/documents/jecfa/jecmono/v46je05.htm#_46052320, http://wayback.archive-it.org/7993/20171031060212/https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/UCM261213.pdf. It is often difficult to tell what is accurate in the media when an entire body of evidence is not reviewed. He points out that while both strains ribotype-027 and 078 existed prior to 2001, that epidemic outbreaks did not occur until 2003, and include major outbreaks in both Quebec, Canada, and Pittsburgh, USA. research claims that trehalose imports have played a significant role in the emergence of epidemic strains of C. diff. On this hypothesis, Prof. Wilcox and his team set out to determine if this mutation was common only to the epidemic strains, conferring a selective advantage as Collins et al. Is it possible for trehalose to be present in an organic certified product? We are dedicated to providing the most scientifically valid, unbiased, and comprehensive information on any given topic. Trehalose - Wikipedia In 2000, FDA approved the sugar as a safe food additive. Trehalose quickly found its way into processed foods in the U.S. and around the world for its mild, flavor-enhancing sweetness and protection of frozen foods. In some store-bought ice creams, its found at concentrations of up to 11 percent. JECFA Report http://www.inchem.org/documents/jecfa/jecmono/v46je05.htm#_46052320. Concluded ADI not specified as a miscellaneous additive by JECFA. In preliminary studies on rats, it prevented ulcers and damage to the stomach lining while maintaining the desired effects [46]. Some bacteria, fungi, plants and invertebrate animals synthesize it as a source of energy, and to survive freezing and lack of water. Why is there a voltage on my HDMI and coaxial cables? [16] In humans, the only known function of trehalose is its ability to activate autophagy inducer. 2018 & Collins et al. 111 4 Beware of supermarket sushi (as in, not prepared fresh to order) - trehalose is commonly used to keep the rice from staling. For example, in Canada, outbreaks of the virulent strains of C. difficile occurred some three years before the approval and expanded use trehalose. Is there a proper earth ground point in this switch box? A large intake of trehalose at one time may induce laxation. The change in the epidemiology of C. diff infection is in part due to emergence of certain strains such as ribotype-027 and 078, which have been associated with increases in morbidity and mortality. However, we cant proclaim S. boulardii effective for trehalose intolerance without valid clinical evidence. Within the fungi, it is prevalent in some mushrooms, such as shiitake (Lentinula edodes), oyster, king oyster, and golden needle. Trehalose A type of sugar, trehalose enhances flavor by adding a mild sweetness to foods (it's about half as sweet as sugar). When it is consumed, it is broken down by the The contents are prepared with the support of Andrea Hardy, Registered Dietitian in Calgary, Canada, in response to the following articles: Nature 553, 285-286 (2018) DOI: https://10.1038/d41586-017-08775-4 EBioMedicine 43 (2019) 347355 DOI: https://doi.org/10.1016/j.ebiom.2019.04.038with the information based on the speech of Prof. Mark H. Wilcox at The 23rd Trehalose Symposium held in Tokyo on 7th November, 2019. I note that some suppliers purport to sell "organic trehalose". 2019). Commonly used as a texturizer, it masks bitterness and food odors, enhances saltiness and highlights fruit flavors. In fact, supplementation with trehalose led to a reduced detection of C. diff toxin to undetectable levels, meaning that trehalose does not appear stimulate C. diff growth in humans. That is, trehalose contains an ,-1,1 glycosidic bond, while maltose contains an -1,4 glycosidic bond. Additional factors that differentiate the two glucose containing disaccharides include the fact that maltose is a reducing sugar, whereas trehalose is not, and trehalose is significantly more stable than maltose under high temperatures and acidic pH (Richards et al.2002). Strains thrived on trehalose, The usually consumed amounts of trehalose are enough to boost their growth, A sharp rise in C. diff. Trehalose The potential health benefits of trehalose discussed below stem from its ability to [14, 8, 15, 16]: Autophagy is a vital defensive mechanism that removes mutated and damaged cells. Moderate amount of trehalose in diet is essential and having low amount of trehalose could result in diarrhea, or other intestinal symptoms. As a result, it slowed down disease progression and extended the animals lifespan [31, 32, 33]. (Especially in the UK.) People who dont tolerate mushrooms probably lack trehalase [57, 58]. Trehalose: Revolutionizing the Food Industry - Mutual Trading HOME trehalose Did a sugar called trehalose contribute to the. [22]:197, Five biosynthesis pathways have been reported for trehalose. "[21], Deficiency of trehalase enzyme is unusual in humans, except in the Greenlandic Inuit, where it occurs in 1015% of the population. Looking online at the ingredients in UK supermarket sushi, I see "sugar" added to the rice, but no mention of trehalose. For this purpose, they make trehalose from corn starch. 2002). It's called trehalose, and even though its presence in the food chain is nothing new, the amount of it in processed foods is. 2019). Owing to their ability to form hydrogen bonds, they self-associate in water to form clusters of various sizes. Because trehalose is contained in marine plants such as hijiki seaweed, it is called seaweed sugar in China.In fact, trehalose is found in dry yeast, accounting for 12% by dry weight of bakers yeast. SelfDecode is a personalized health report service, In this population about 8% had low trehalase enzyme values; however, they are also known to have approximately 60% lactase deficiency, and even sucrase deficiency which is almost unknown in any other ethnic group3. paper, such as inaccurate conclusions about the correlation between trehalose consumption and epidemic strains of C. diff, whether bacteria with variant metabolism of trehalose are only commonly found in virulent strains, and if in fact, trehalose impacts C. diff growth or toxin production in a human gut model. They suggested the role of the gut microbiome in the health effects of trehalose [19]. Investigational drug SLS-005 (Trehalose) enters HEALEY ALS 2002). He found a way to merge his two biggest passionswriting and healthand use them for noble purposes. However, one team of scientists questioned the ability of trehalose to enter the cells and induce autophagy. It now costs $3 per kilo. Outbreaks [52]: In light of the available evidence, trehalose as an added sugar seems to be safe for most healthy people in recommended amounts. Beware of supermarket sushi (as in, not prepared fresh to order) - trehalose is commonly used to keep the rice from staling. Prof. Wilcox and his team found that there is no association between possession of this trehalose mutant gene metabolism, four-gene cluster, and death, likelihood of death, in humans infected with these strains. WebTrehalose is a nonreducing sugar formed from two glucose units joined by a 11 alpha bond, giving it the name -D-glucopyranosyl- (11)--D-glucopyranoside. In test tubes, trehalose induced autophagy in skin tissue. The best answers are voted up and rise to the top, Start here for a quick overview of the site, Detailed answers to any questions you might have, Discuss the workings and policies of this site. Information is shared for educational purposes only. Our team comprises of trained MDs, PhDs, pharmacists, qualified scientists, and certified health and wellness specialists. [36], Trehalose has long been known as an autophagy inducer that acts independently of mTOR. Isotrehalose is also yet to be isolated from a living organism, but was found in starch hydroisolates. Find the summary of the lecture 'Trehalose is not associated with the emergence and spread of epidemic Clostridium difficile strains' here. A place where magic is studied and practiced? Trehalose is freely soluble in water and very slightly soluble in ethanol. Trehalose is a sugar made of two glucose molecules. ), a germ that causes dangerous, hard-to-treat gut infections. [13], Even within the plant kingdom, Selaginella (sometimes called the resurrection plant), which grows in desert and mountainous areas, may be cracked and dried out, but will turn green again and revive after rain because of the function of trehalose. The US Food and Drugs Agency (FDA) labeled trehalose as GRAS (generally recognized as safe) when added to dietary products [48, 49]. Because of its unique culinary properties, it is also a highly desirable disaccharide used in a variety of food service applications to enhance freshness and flavor. A group of scientists found that, In the embryos of diabetic mice, trehalose induced autophagy and prevented neural tube defects [36]. This data, combined with observations that increased production and utilization of trehalose in the food supply coincided with the rise of infections caused by the virulent strains of C. difficile, led to speculation that trehalose caused the epidemic emergence of the virulent strain of C. difficile (Collins et al. Additionally, trehalose is a simple sugar and thus has the potential to impair blood sugar control. After controlling for all clinical factors independently associated with risk for severe infection outcome, the authors found no significant association between the presence of trehalose utilization variants in infectious C. difficile strains and the development of severe infection outcomes. The results of this final experiment showed that in two of the three subjects, there was an increased expression of the treA gene, which is required to metabolize trehalose. For example, you may have seen some criticism of trehalose in recent media reporting based on a recent paper by Collins, It is important to know that because of this paper, the media generated a significant amount of unnecessary fear around trehalose, sensationalizing the small-scale animal study. Did you know? Between 2000 and 2006, imported levels of trehalose were <1 gram per capita per year in the USA and England, not substantially increasing trehalose intake. [23] Second, trehalose synthase (TS) in certain types of bacteria could produce trehalose by using maltose and another disaccharide with two glucose units as substrates. 2020). Trehalose is a naturally occurring disaccharide that has been consumed by humans for centuries and used in food production for decadeslong before the epidemic rise of virulent strains of C. difficile. diff. Read more about serving and portion sizes. See more. Trehalose Assay Kit | Nutritional Analysis [18]:135 It causes less of a spike in blood sugar than glucose. One other final experiment in the Nature paper that is worth noting examined the metabolism of trehalose in the intestines of three human subjects consuming their normal diets (which strangely were never described in the paper). Difference between Organic Bread and Fresh Bread. Trehalose does not stimulate C. diff growth in an infected human model.In fact, supplementation with trehalose in an infected human model suppressed production of C. diff toxin to undetectable levels. Hayashibara Co., Ltd., (Hayashibara) manufactures a trehalose product from starch using enzymatic technology and sells it in many countries under the tradename of TREHA. Stack Exchange network consists of 181 Q&A communities including Stack Overflow, the largest, most trusted online community for developers to learn, share their knowledge, and build their careers. 2019). The only exception is in a specific closely related genetic population, native Greenlanders (Inuits). This can pose serious consequences for patients, including prolonged hospitalization and increased mortality. TREHA trehalose benefits flavor systems by providing off-note masking, saltiness and citrus enhancement, and flavor stability. This high-performance ingredient can now facilitate simplified ingredient statements. TREHA trehalose is recognized as GRAS by the Flavor and Extract Manufacturers Association of the U.S. (FEMA). Because it's naturally occurring, the industry labels it as a natural flavor. WebTrehalose consists of 2 glucose molecules bound by an ,-1-1 bond. In nature, trehalose can be found in plants, and microorganisms. Then, the level of trehalase remained constant in the intestine throughout life. The food industry recognized these unique properties of trehalose and introduced it as an additive in dried and frozen foods. The lack of autophagy lurks behind metabolic disorders, brain damage, cancer, aging, infections, and more [17]. Can I tell police to wait and call a lawyer when served with a search warrant? The most common pathway is TPS/TPP pathway which is used by organisms that synthesize trehalose using the enzyme trehalose-6-phosphate (T6P) synthase (TPS). Or 20 days if it's a hard question. Trehalose is a naturally occurring disaccharide that is found in foods such as mushrooms, shellfish, seaweed (algae) and products made from brewers yeast (e.g., beer and breads). Interestingly, the findings indicated that several carbohydrates and amino acids (not just trehalose) caused a 1.5-fold increase in the virulent strains. 2002). How do I connect these two faces together? The above study suggests its index is surprisingly low (38) while other studies indicate its borderline high (~70) [40, 41]. Please contact us for information on the regulatory status for any countries of interest. https://doi.org/10.1016/j.ebiom.2019.04.038, Trehalose-Induced Remodelling of the Human Microbiota Affects, Is there a causal relationship between trehalose consumption and, Microbial and metabolic impacts of trehalose and trehalose analogues, Genetic determinants of trehalose utilization are not associated with severe, Lactotrehalose, an Analog of Trehalose, Increases Energy Metabolism Without Promoting, Degradation-Resistant Trehalose Analogues Block Utilization of Trehalose by Hypervirulent, Dietary trehalose enhances virulence of epidemic. A small percentage of people lack trehalase, an enzyme that breaks down trehalose. However, the studies listed below should not be interpreted as supportive of any health benefit. WebIn certain circumstances it is necessary to state on the label the quantity, in percentage terms, of an ingredient or category of ingredients used in the manufacture or preparation of a foodstuff. Data are presented supporting safe human consumption of trehalose in doses up to 50 g, and the physiologic ability of humans to digest it. To subscribe to this RSS feed, copy and paste this URL into your RSS reader. For further information on this subject please see the following URL of National Institutes of Health, U.S. Department of Health and Human Services. Trehalose is a naturally occurring glucose found in mushrooms, some seaweed, lobster, shrimp and foods in which bakers or brewers yeast is used. This bond makes trehalose resistant to harsh changes in temperature and acidity [5]. The food industry adds it to dried and frozen food; candy and fruit fillings; chocolate and juices. [9], Trehalose directly interacts with nucleic acids, facilitates melting of double stranded DNA and stabilizes single-stranded nucleic acids. Of course, we would expect to see greater growth of C. difficile on a carbohydrate source compared with water. WebToday, the U.S. Food and Drug Administration issued a draft guidance The Declaration of Allulose and Calories from Allulose on Nutrition and Supplement Facts Labels to provide Trehalose is a sugar which, on a cellular level, appears to have therapeutic mechanisms by regulating protein unfolding. But since it makes C-diff more dangerous, it throws into question its GRAS status. Notably, we have known for many years that C. diff infection, whether it occurs or not, is specific to the animal type.. Trehalose - properties, biosynthesis and applications The digestion and absorption of trehalose in humans is similar to that of other disaccharides. The results make trehalose a promising candidate for sunscreen lotions and other cosmetic products [47]. Clostridium difficile causes a type of hospital-acquired infection that is characterized by diarrhea and inflammation of the colon. Trehalose forms a rhomboid crystal as the dihydrate, and has 90% of the calorific content of sucrose in that form. [28] Trehalase in humans is found only in specific location such as the intestinal mucosa, renal brush-border, liver and blood. As youre about to see in Dangers and Side Effects, its impact on gut bacteria may have a dark side. In animal and cellular research, it showed the potential nerve, heart, skin, and liver benefits, but theres no clinical evidence to back this up. C. diff infections are on the rise in some countries - both the number and severity of cases and can often be difficult to manage. 2018). Trehalose 8%) but rare around the globe [56]. utilized C. diff ribotype-015; some of the strains in this ribotype carry the metabolic mutation for trehalose metabolism and some do not. Aleksa is passionate about herbal pharmacy, nutrition, and functional medicine. rackandboneman Jan 15, 2018 at 19:02 Looking online at the ingredients in UK supermarket sushi, I see "sugar" added to the rice, but no mention of trehalose. [37] In 2017 research was published showing that trehalose induces autophagy by activating TFEB,[38] a protein that acts as a master regulator of the autophagy-lysosome pathway.[39]. An inactive ingredient is any component of a drug product other than the active ingredient. Trehalose quickly found its way into processed foods in the U.S. and around the world for its mild, flavor-enhancing sweetness and protection of frozen foods. In the 1990s, it cost about $7,000 to distill 1 kilogram, or 2.2 pounds. Trehalose shields the cells during freezing (cryoprotection) and thus preserves transplantation organs, stem cells, semen, and different tissue samples [10, 11, 12, 13]. The science around nutrition and food often requires an expert to interpret. Plus, I see that trehalose does not have an E-number, unless it's called something different there. The glycemic index of trehalose how much it spikes glucose levels compared to sugar is still debated. Trehalose occurs naturally in small amounts in a variety of foods most notably mushrooms, honey, lobster, shrimp, certain seaweeds (algae), wine, beer, bread and other foods produced by using bakers or brewers yeast (Richards et al. The product may contain very little whole grains. Besides its physical properties used in technology, trehalose may have certain health benefits. Trehalose Definition & Meaning | Dictionary.com Is it correct to use "the" before "materials used in making buildings are"? Drs. Oz & Roizen: What and where is trehalose? - Online Athens However, recent findings discussed above warrant extra caution until we know more about trehalose safety. The ingredient, which is supplied by Cargill under the As the result of a thorough safety evaluation of trehalose by the Joint WHO/FOA Expert Committee on Food Additive (JECFA), it was concluded that an ADI not specified was appropriate for TREHA, This determination is given to food substances of very low or no toxicity for human consumption as a miscellaneous additive1. Check the ingredients list if whole grains arent in the first three ingredients, the amount is negligible. These strains thrived on trehalose and produced much more toxins [52, 53]. Finally, the majority of existing epidemiological research does not support a valid association between trehalose production/usage and the emergence of resistant strains of C. difficile. Trehalose A popular probiotic yeast, S. boulardii, releases trehalase in the gut. TREHA is a trademark of Hayashibara and a registered trademark of Hayashibara in Japan, the U.S. and other countries. Some microbes use trehalose to make toxins and defensive weapons. More research will be needed to confirm the link. Do foods labeled "non-GMO" only (and not "organic") have more pesticides in them? Neotrehalose has not been isolated from a living organism. And, because of the way they are distributed, we conclude that these mutations are ancient; very old mutations that happened hundreds or thousands of years ago. The metabolism of alpha, alpha-trehalose. rackandboneman. Trehalose is less soluble than sucrose, except at high temperatures (>80C). Is there a causal relationship between trehalose and clostridioides difficile. They are preservative-free and can be used with all types of contact lenses. Extracting trehalose was once a difficult and costly process, but around 2000, the Hayashibara company (Okayama, Japan) discovered an inexpensive extraction technology from starch. R48", "Cloning and sequencing of a cluster of genes encoding novel enzymes of trehalose biosynthesis from thermophilic archaebacterium Sulfolobus acidocaldarius", "TreT, a Novel Trehalose Glycosyltransferring Synthase of the Hyperthermophilic Archaeon Thermococcus litoralis*", "Gene expression and molecular characterization of a thermostable trehalose phosphorylase fromThermoanaerobacter tengcongensis", "The Metabolism of ,-Trehalose**The work cited from the author's laboratory was supported by grants from the Robert A. Welch Foundation and the National Institutes of Health (AI 09402). Sucrose, or common table sugar, is also a non-reducing sugar. All-atom molecular dynamics simulations showed that concentrations of 1.52.2 molar allow trehalose molecular clusters to percolate and form large and continuous aggregates. It is found in nature as a disaccharide and also as a monomer in some polymers. Caution: Just like with other simple sugars, you may want to go slow with trehalose because the gut quickly breaks it into 2 glucose molecules. In medicine, trehalose is used in dry eye drops and advanced drug formulations. Joe Cohen flipped the script on conventional and alternative medicine and it worked. Scientists were skeptical of the claims, and sought to clarify this important scientific question: is trehalose the cause of increasing C. diff virulence? 2019) examined the potential for trehalose metabolism variants to confer a select advantage for the virulent strains of C. difficile by evaluating how common these variants are within the total genetic diversity of clinical C. difficile using previously sequenced isolates. And that if it can do that, the C. diff strain will be able to outcompete potentially, other C. diff strains and maybe other bacteria if we find C. diff in the human gut.. Article 2 The designation "trehalose" shall be displayed on the labelling of the product as such or in the list of ingredients of foodstuffs containing it. Lastly, Prof. Wilcox and his team set out to describe how C. diff would grow in a human gut model (a triple phase chemostat gut model) when trehalose is administered (as a potential food for the bacteria) in comparison to controls. WebTrehalose is a non-reducing sugar formed from two glucose units joined by a 1-1 alpha bond giving it the name of -D-glucopyranosyl- (11)--D-glucopyranoside. Bacteria, plants, fungi, and insects use it as an energy source and a guard against extreme conditions. How to store organic cold press sunflower oil for long term usage? Unfortunately, we often see the media provide alarmist reporting on the latest research around food in attempts to gain attention and share news without confirming proper interpretation of scientific evidence first. They suggest limiting the intake of trehalose to 50 g daily, or 10% of total calories [50]. Trehalose induced autophagy in blood vessel cells and inhibited a virus linked to clogged blood vessels (the human cytomegalovirus or HCMV), but this doesnt tell us much about its potential effects in living organisms [34]. Do I need a thermal expansion tank if I already have a pressure tank? Nonetheless, the researchers chose only to focus on trehalose, allegedly because unlike some of the other carbon sources studied, trehalose supported growth even at relatively low concentrations. 2022 Oct 6. doi: 10.1111/1541-4337.13048. [11], Trehalose is the major carbohydrate energy storage molecule used by insects for flight. It is important to know that correlation does not equal causation, and in fact, when you look closer at trehalose importation and virulent C. diff out breaks, they do not correlate at all. It also improves the taste while causing slightly milder blood glucose spikes. Buckley A.M., Moura I.B., Arai N., Spittal W., Clark E., Nishida Y., Harris H.C., Bentley K., Davis G., Wang D., Mitra S., Higashiyama T., Wilcox M.H. how is trehalose listed on food labels Is that true? diff., trehalose increased the death rate 3 times. Thealoz Duo are over-the-counter drops for dry eye containing a combination of trehalose and hyaluronic acid. To stay on the safe side, avoid trehalose if you have any digestive issues, especially hospital-acquired gut infections. Most of them preferred trehalose over standard eye drops [20, 21]. While the oft-cited association between trehalose production/utilization and C. difficile proliferation may seem compelling, other epidemiological observations suggest that factors besides trehalose consumption may be contributing to the increase in virulent strains of C. difficile (Buckley et al. Please see Table 15 in the U.S. GRAS Notice of trehalose (GRN 00045) which shows the portion of people with trehalase deficiency in the U.S. and EU countries4. Note that each number in parentheses [1, 2, 3, etc.] Dr. Oz: What and where is trehalose? - The Oklahoman U.S. GRAS Notice http://wayback.archive-it.org/7993/20171031060212/https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/UCM261213.pdf, During the 23rd Trehalose Symposium held in Tokyo on November 7, 2019, Professor Mark Wilcox of the University of Leeds (UK), gave a lecture titled Trehalose is not associated with the emergence and spread of epidemic Clostridium difficile strains and explained the contents of his co-authored paper, Clostridium difficile trehalose metabolism variants are common and not associated with adverse patient outcomes when variably present in the same lineage.