Faecalibacterium ⇒ Faecalibacterium prausnitzii {10000130} Record Keys Parent:Faecalibacterium Definition:Faecalibacterium prausnitzii Details Initialisation date:2020-09-06 LinksSource Meta Information Rank: Species Domain: Bacteria Zone:[ ] Enzyme:[ ] Function:Immunomodulation, Anti fibrosis, Anti-inflammatory , Anti-cancer Notes: - Faecalibacterium prausnitzii was named after the German bacteriologist Otto Prausnitz and was first described in 2002. - - - Since it does not survive contact with oxygen, it went undetected for a long time when trying to cultivate it. It is now well known, but many mechanisms are not yet fully understood. - It became famous for the formation of short-chain fatty acids such as butyrate and acetate. - In fact, F. prausnitzii is the strongest butyrate generator that we have in us. - butyrat as an extremely important fatty acid has shown multiple anti-inflammatory effects by inhibiting pro-inflammatory substances such as IL-8 and helping the immune system to differentiate from regulatory T cells. It also serves as an important source of energy for the cells of the intestinal wall. - The bacterium is also used diagnostically as an indicator for the intestinal barrier. If the concentration is low and additional inflammation values such as zonulin and calprotectin are high, one speaks of leaky gut, the permeable intestinal barrier. - A low F. prausnitzii concentration is associated with more inflammation in the intestine. This behavior was first linked to Crohn’s disease in 2008. The stronger the symptoms of the disease, the lower the frequency of F. prausnitzii and butyrate. One study showed that even in Crohn’s patients in remission (symptoms decreased, but no cure), the number of F. prausnitzii was reduced. - A deficiency of F. prausnitzii can also lead to immune regulation disorders or metabolic diseases. - F. prausnitzii can be supplied well with the fiber inulin which can be found in chicory, artichokes and onions. - Within the gut microbiome, it is particularly well networked with the species A. muciniphila. itssubstrates are an important food source for F. prausnitzii. An assessment of one species is therefore always accompanied by an assessment of the other. - F. prausnitziiis the largest producer of butyrate and the largest consumer of acetate and is the most important species inhabiting the intestine. Its depletion along with the reduction of Bifidobacterium (which is more reduced in patients with kidney stones) leads to a reduction in the intestinal butyrate levels, which thence leads to a functional instability in the gastrointestinal tract and urothelium thereby resulting in an inflammatory pattern. (1) - F. prausnitziiis which is often diminished in patients with Crohn’s disease, appear to exert many of their protective effects through the release of a fatty acid called butyrate. - F. prausnitziiis modulates immune system. - F. prausnitziiis modulates is the indicator for leaky gut.Shared Reference Notes [1.1] - Certain Faecalibacterium prausnitzii strains possess some ability to utilise apple pectin. - F. prausnitzii strains in common with E. eligens can utilise the galacturonide oligosaccharides DP4 and DP5 derived from sugar beet pectin. [1.2] [#Crohn’s disease] [#Escherichia coli] [#Fecal Microbiota Transplantation] - Comprehensive overview of functional dysbiosis in the gut microbiome during IBD activity showed increases in facultative anaerobes, such as E. coli which correlates with inflammation status, and decreases in obligate anaerobes, such as Faecalibacterium prausnitzii and #Roseburia hominis -The results of the present study confirmed decreases in the abundance of Firmicutes and Bacteroidetes, increases in Enterobacteriaceae, Pasteurellaceae, and Veillonellaceae and the presence of Fusobacterium in stool samples of CD patients. - #Butyrate-producing bacteria are depleted in IBD patients, and probiotic treatment with these bacteria has therapeutic potential. - A higher proportion of #Lachnospiraceae in donor stool was associated with a higher success rate of FMT, and recipients that responded to FMT exhibited increases in #Butyrate-producing #Lachnospiraceae and Ruminococcaceae. - The reduced SCFA levels in patients with IBD result from lower abundance of SCFA-producing bacteria, especially those of the phylum Firmicutes. - #Butyrate can act as an energy source for normal colon epithelial cells, promoting their proliferation, but can also inhibit proliferation and induce apoptosis. [1.3] [#Cancer] [#Plant-based diet] - High levels of plant dietary fibers in the gut resulted in proliferation of Faecalibacterium prausnitzii with anti-inflammatory and anti-tumor effects. [1.4] [#Crohn’s disease] - Gut species found to be significantly depleted in CD compared to control include: Faecalibacterium prausnitzii , #Roseburia inulinivorans and #Alistipes senegalensis. - While #Clostridium nexile and #Ruminococcus gnavus were found to be enriched. [1.5] [#Non-industrialized envirounment] - Non-industrialized countries > increased #Prevotella copri, Faecalibacterium prausnitzii and #Prevotella stercorea in #Infants. [#Prevotella stercorea] [#Aging] - P. stercorea or F. prausnitzii > develop steadily with age [1.6] [#Inflamatory bowel disease] - #Exclusive Enteral Nutrition > reduce microbial diversity > lower SCFA concentrations (including #Butyrate) & reduce Faecalibacterium prausnitzii, which is usually considered beneficial in IBD. - Responders to EEN showed lower bacterial richness than nonresponders. - EEN > showed a decrease in Shannon diversity with EEN, but this returned to pretreatment levels two months after EEN was stopped, as did decreases in Bifidobacterium, Ruminococcus, and Faecalibacterium. - It is hypothesized that some of these decreases in specific taxa and diversity are simply due to the lack of fibre in EEN. [1.7] - Members of the genera #Oscillospira and #Coprococcus in the cecum, as well as Faecalibacterium prausnitzii and members of the genus #Bacteroides in the ileum > negatively correlated with #Fibrosis. [1.8] - #Butyrate plays a role in regulating immune response via expansion of Treg cell populations, which is suggestive of a role for SCFA in ameliorating pro-inflammatory responses of immune cells to antigenic stimuli. - Faecalibacterium prausnitzii, help maintain homeostasis through production of SCFAs (#Butyrate) and modulation of downstream inflammatory pathways through potential induction of a tolerogenic cytokine profile (e.g., low secretion of proinflammatory and elevated secretion of anti-inflammatory cytokines) [1.9] - The most prominent butyrogenic bacteria groups are Faecalibacterium prausnitzii, #Butyrivibriocrossotus and #Roseburia intestinalis which several studies have reported the depletion of these bacteria in atherosclerosis - the tested consortium was composed of four butyrate producers (Faecalibacterium prausnitzii, #Butyricicoccus pullicaecorum, #Roseburia inulinivorans, and #Anaerostipes caccae) and five propionate producers (#Roseburia inulinivorans, #Akkermansia muciniphila, #Bacteroides vulgatus, #Veillonella parvula, and #Blautia obeum) [1.11] [#Butyrate] - Faecalibacterium prausnitzii, member of Clostridium leptum subgroup, representing more than 5% of the total gut microbiota in healthy humans, is one of the most abundant #Butyric acid producing bacteria of the gut microbiome. It favorably modulates intestinal immune system, oxidative stress and colonocyte metabolism. - it reduces intestinal inflammatory processes with inhibition of the pro-inflammatory interleukin 8. [1.12] [#Depression] [#Dark chocolate] - #Blautia obeum levels were significantly elevated and Faecalibacterium prausnitzii levels were reduced in DC85 compared to CON (P<.05). - Mood states were measured using the Positive and Negative Affect Schedule (PANAS) - the observed changes in negative affect scores were negatively correlated with diversity and relative abundance of #Blautia obeum. [1.13] [#Ulcerative Colitis] [#Primary bile acids, #Secondary bile acids] - colonic CD displayed a disease-severity-related association with #Bacteroides vulgatus. - Compared to colonic CD, ileal CD profiles displayed increased primary and secondary bile acid levels and concomitant shifts in taxa with noted sensitivities such as Faecalibacterium prausnitzii or affinities for bile acid-rich environments, including #Gammaproteobacteria and #Blautia sp. [1.14] - GutAlive maintained extremely #Oxygen sensitive (EOS) populations that were lost in conventional stool containers, and thus viability of species such as as #Akkermansia muciniphila, Faecalibacterium prausnitzii and a novel member of the #Clostridiales order was kept. [1.15] [#Multiple Sclerosis] - six species are significantly lower in abundance in MS patients than in controls, three of which have known immunomodulatory properties (#Bifidobacterium longum, #Clostridium leptum, Faecalibacterium prausnitzii) [1.16] [#Multiple Sclerosis] [#Urolithins] - in non-disease-active cases, Faecalibacterium prausnitzii and #Gordonibacter urolithinfaciens, whose absolute abundance was enriched. - These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. [1.17] [#Diabetes Type 2] [#Coprococcus etes] - There are 36 different strains of #Butyrate-producing bacteria, and five of them are associated with increased insulin sensitivity: #Coprococcus etes, #Oscillibacter sp. CAG 241, #Alistipes finegoldi and Faecalibacterium prausnitzii. - The genus #Coprococcus was associated with higher insulin sensitivity and disposition index and a lower rate of dysglycemia. [1.18] [#CVD] [#Short Chain Fatty Acid] [#Probiotic, #Probiotic (Bifidobacter and Lactobacilus)] - Short-chain fatty acids and secondary #Bile Acids can decrease #Cholesterol levels by regulating #Cholesterol metabolism. - Microbial #Bile Salt hydrolases can increase #Cholesterol disposal rates by accelerating its conversion to #Bile Acids. - Probiotics from the genera Lactobacillus and Bifidobacterium are efficient reducers of #Cholesterol levels in clinical studies. - Several candidate next-generation probiotics, including #Akkermansia muciniphila, #Bacteroides spp., #Clostridium spp., #Christensenella minuta, Eubacterium spp., and Faecalibacterium prausnitzii, have been shown to decrease #Cholesterol levels in human or animal studies. [1.19] [#Bacteroides massiliensis] - #Prostate cancer > a higher relative abundance of Bacteriodes massiliensis as well as decreased relative abundances of Faecalibacterium prausnitzii and #Eubacterium rectale in the stool from men with PCa compared to the controls. [#Prostate cancer] - fecal abundances of F. prausnitzii observed in benign as compared to malignant patient samples. - F. prausnitzii is generally considered to have anti-inflammatory properties with its ability to produce butyrate and induce secretion of anti-inflammatory cytokines. [#Chronic fatigue syndrome] - Faecalibacterium prausnitzii and #Eubacterium rectale, which are both recognized as abundant, health-promoting #Butyrate producers in the human gut, were reduced in ME/CFS. - deficient microbial capacity for #Butyrate synthesis. - The abundance of Faecalibacterium prausnitzii was inversely associated with fatigue severity. [1.21] [#Chronic fatigue syndrome, #Irritable bowel syndrome] [#Alistipes putredinis, #Anaerotruncus colihominis, #Clostridium asparagiforme, #Coprococcus catus, #Dorea formicigenerans] - Nine bacterial species were selected to predict ME/CFS + IBS: F. prausnitzii, #Bacteroides vulgatus, A. putredinis, C. catus, #Anaerostipes caccae, D. formicigenerans, A. colihominis and C. asparagiforme. [#Chronic fatigue syndrome] [#Alistipes putredinis, #Anaerotruncus colihominis, #Clostridium asparagiforme, #Coprococcus catus, #Dorea formicigenerans, #Pseudoflavonifractor capillosus, #Sutterella wadsworthensis] - Eight bacterial species were found to predict ME/CFS : Coprococcus (C.) catus, Pseudoflavonifractor (P.) capillosus, Dorea (D.) formicigenerans, Faecalibacterium (F.) prausnitzii, Clostridium (C.) asparigiforme, Sutterella (S.) wadsworthensis, Alistipes (A.) putredinis and Anaerotruncus (A.) colihominis. [1.22] [#Crohn’s disease] - a reduction of a major member of Firmicutes, Faecalibacterium prausnitzii, is associated with a higher risk of postoperative recurrence of ileal CD. - A lower proportion of F. prausnitzii on resected ileal Crohn mucosa also was associated with endoscopic recurrence at 6 months. - Oral administration of either live F. prausnitzii or its supernatant markedly reduced the severity of TNBS colitis and tended to correct the dysbiosis associated with TNBS colitis - F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-κB activation and IL-8 production. - F. prausnitzii had an anti-inflammatory profile because it induced very low secretion levels of IL-12 and IFN-γ and high secretion levels of IL-10. [1.23] [#Bipolar disorder] - Levels of Faecalibacterium prausnitzii, #Bacteroides–#Prevotella group, #Atopobium Cluster, #Enterobacter spp. and #Clostridium cluster IV were higher in BD patients than healthy subjects along with a reduced #Bifidobacteria to #Enterobacteriaceae ratio, having these changes a possible impact on brain function in these patients. [1.24] [#Pancreatic Cancer] - Stool from patients cured from PCa has more relative abundance of Faecalibacterium prausnitzii and #Akkermansia muciniphila. [1.25] [#Crohn’s disease] - Patients with CD that previously underwent ileocecal valve resection showed a decline in fecal abundance of Faecalibacterium prausnitzii and #Butyrate [1.26] [#Physical activity] - in males with normal BMI, a stronger grip strength was associated with a higher relative abundance of #Faecalibacterium and F. prausnitzii compared with lower grip strength. [1.27] [#Actinomyces massiliensis] - #Athletes from 16 different sports > dominated by a single or a combination of five species, namely #Eubacterium rectale, Polynucleobacter necessarius, Faecalibacterium prausnitzii, #Bacteroides vulgatus, and #Gordonibacter massiliensis. - Species such as #Bifidobacterium animalis, #Lactobacillus acidophilus, #Prevotella intermedia, and F. prausnitzii were associated with #Athletes participating in high dynamic component sports. [1.28] [#Acute lymphoblastic leukemia] [#Bacteroides ovatus, #Pseudomonas aurantiaca, #Roseburia intestinalis, #Roseburia inulinivorans] - #Children with ALL exhibit reduced relative abundance of both #Butyrate-producing species (#Roseburia faecis, R. intestinalis, R. inulinivorans, #Anaerostipes hardus, Faecalibacterium prausnitzii, #Eubacterium ramulus) and #Acetate-producing species (#Prevotella maculosa, P. aurantiaca, #Bacteroides uniformis, B. ovatus) [1.29] - specific strains of F. prausnitzii from healthy participants reduced #Cognitive impairment in a murine model of brain amyloidosis. [#Bacteroides vulgatus] [#carrot-derived rhamnogalacturonan I] [#Carrot] - cRG-I supplementation (already at an HED of 0.3 g/d) lowered interpersonal compositional differences due to the selective stimulation of taxa that were consistently present among human adults, including OTUs related to #Bacteroides dorei/vulgatus and #Bifidobacterium longum (suspected keystone species), #Bacteroides thetaiotaomicron, #Bifidobacterium adolescentis and #Butyrate-producing taxa such as #Blautia sp., #Anaerobutyricum hallii, and Faecalibacterium prausnitzii. [1.31] [#Infantile eczema] - #Faecalibacterium is significantly increased in the microbiota of patients with #Atopic Dermatitis and eczema, and this genus represents only a single known species, F prausnitzii. [1.32] [#Akkermansia muciniphila] - in #Colorectal cancer > the relative abundances of #Fusobacterium, #Porphyromonas and A. muciniphila are increased, and F. prausnitzii is decreased compared to healthy controls. [#Aging] - older subjects with physical #Frailty and #Sarcopenia > Lower abundance of F. prausnitzii, as well as members of the #Clostridiales class including #Eubacterium and #Roseburia genera. [#Actinomyces odontolyticus] - In #Hepatobiliary cancers and metastatic #Melanoma, #Actinomyces genus and members (e.g., #Actinomyces odontolyticus) are consistently enriched in non-responders, whereas Faecalibacterium prausnitzii is increased in responders. - F. prausnitzii abundance is greater in subjects with lower BMI in comparison to subjects with #Obesity [#Obesity] - Abundance of #Faecalibacterium genus members (i.e., F. prausnitzii) is greater in both women and men with higher skeletal muscle mass. - increases in both lean mass and #Faecalibacterium relative abundance are observed in normal weight subjects after #Exercise training. [1.33] [#Colorectal cancer] [#Carnobacterium maltaromaticum] - F. prausnitzii, converts C. maltaromaticum-derived 7-DHC into downstream #Vitamin D metabolites for mediating the anti-CRC effect. [1.34] [#Diabetes Type 2] [#Oral administration of Metformin] - Faecalibacterium prausnitzii > significant decrease in patients with T2DM treated with #Metformin alone, while no significant decrease was observed in patients treated with #Metformin combined with #Benaglutide. [1.35] [#Eubacterium hallii, #Eubacterium ramulus, #Fusicatenibacter saccharivorans] [#Probiotic] -supplementation with F. prausnitzii, F. saccharivorans, E. ramulus, and E. hallii, or other species both enriched and identified here as major taxonomic drivers of amino acid biosynthesis in the responder group, should be explored as a way to restore the metabolic flexibility required prior to microbiome-targeted lifestyle interventions. [#Eubacterium hallii, #Fusicatenibacter saccharivorans] [#Exercise training] - F. prausnitzii, F. saccharivorans, and E. hallii were reported to be enriched after exercise and diet intervention across multiple studies [1.36] [#Inflamatory bowel disease] - Decreased abundance on #Firmicutes bacteria belonging to the #Ruminococcaceae spp., #Lachnospiraceae spp, F. prausnitzii and #Roseburia spp. families is a signature of microbial dysbiosis in IBD. [1.37] - all #Oat bran treatments were able to decrease the abundance of #Escherichia–#Shigella and increase Faecalibacterium prausnitzii in the gut microbiota [1.38] [#Bacteroides caccae, #Prevotella copri, #Streptococcus parasanguinis] [#Immune checkpoint inhibitor] - The most distinctive species associated with ICI treatment response were F. prausnitzii, S. parasanguinis, B. caccae, and P. copri, [1.39] - #Inulin as a #Prebiotic > increased #Bifidobacterium and Faecalibacterium prausnitzii, and decreased #Bilophila after #Inulin digestion by human volunteers [#Plant-based diet] - species Faecalibacterium prausnitzii and strains within the genus #Oscillospira were increased with the number of plant species consumed [#Bifidobacterium infantis, #Bifidobacterium longum, #Clostridioides difficile, #Kingella denitrificans, #Propionibacterium freudenreichii] - #Vitamin B12 producer are > #Pseudomonas denitrificans, #Bacillus megaterium, and Propionibacterium freudenreichi, #Bacteroides fragilis, #Prevotella copri, #Clostridium difficile, Faecalibacterium prausnitzii, #Ruminococcus lactaris, #Bifidobacterium animalis, B.infantis, B.longum, and #Fusobacterium varium - #Riboflavin supplementation increased the abundance of bacteria that cannot synthesize #Riboflavin, such as Faecalibacterium prausnitzii and #Roseburia spp. - Higher intake was also associated with an increase in the abundance of #Prevotella spp. - #Riboflavin, act as a redox mediator and stimulate the growth of auxotrophic bacteria such as Faecaibacterium prausnitsii [1.41] [#Attention Deficit Hyperactivity Disorder] - F. prausnitzii may reduce neuroinflammation and alleviate ADHD symptoms. - F. prausnitzii exhibits anti-inflammatory effects by increasing anti-inflammatory cytokines and decreasing inflammatory cytokines that promote neuroinflammation and development of ADHD. [1.42] - #Butyrate is produced by cross-feeding interactions between #Acetate-producing #Bifidobacterium spp. and #Acetate-utilizing Faecalibacterium prausnitzii [#Clostridium cluster IV, #Clostridium clusters XIVa] [#Butyrate] - The predominant butyrogenic bacterial species, including Faecalibacterium prausnitzii, #Clostridium spp., #Eubacterium spp., and #Roseburia spp., are from two clusters (#Clostridium clusters IV and XIVa) in the #Firmicutes phylum and the #Clostridiales order [1.43] [#Multiple Sclerosis] - Ms > The clinically nonactive (nonrelapsing) patients showed an enrichment of Faecalibacterium prausnitzii, #Gordonibacter urolithinfaciens, #Anaerostipes hadrus, #Gemmiger formicilis, and #Roseburia inulinivorans compared to clinically active patients [1.44] [#Immune checkpoint inhibitor] - patients receiving ICIs who developed #Colitis had a lower abundance of F. prausnitzii. - F. prausnitzii administration mitigated the exacerbated #Colitis induced by ICIs. - F. prausnitzii enhanced the anti-tumor immunity elicited by ICIs in tumor-bearing mice while abrogating #Colitis. - administration of F. prausnitzii increased gut microbial alpha diversity and modulated the microbial composition, increasing a subset of gut probiotics and decreasing potential gut pathogens. - F. prausnitzii abundance was reduced in mice that developed ICI-associated #Colitis. [1.45] [#Diabetes Type 2] - in T2DM patients > #Bifidobacterium, #Lactobacillus, Faecalibacterium prausnitzii, and #Butyrate-creating bacteria such as #Roseburia intestinalis and F. prausnitzii abundance decreased [1.46] - SEP #Faecalibacticin-3 from the gut microbiome (produced by Faecalibacterium prausnitzii, of the phylum #Firmicutes) displayed cross-phylum antagonism targeting several specific organisms from the phylum #Bacteroidetes. - the five most promising smORF-encoded peptides (SEPs) were encoded by diverse phyla from oral, skin, and gut body sites: #Faecalibacticin-3 (Faecalibacterium prausnitzii), #Fusobacticin-2 (#Fusobacterium nucleatum), #Keratinobacin-1 (#Keratinibaculum paraultunense), #Staphylococcin-2 (#Staphylococcus capitis), and #Prevotellin-2 (#Prevotella copri). [1.47] [#Exercise training] - Chronic exercisers have a greater abundance of the #Lachnospiraceae and Faecalibacterium prausnitzii, major #Butyrate producers. [1.48] - F. prausnitzii is a well-known microbiomarker of inflammatory diseases, which has been reported to be reduced in the gut microbiome of #Atopic Dermatitis and #Psoriasis patients. - #Bullous pemphigoid > reduced Faecalibacterium prausnitzii and greater abundance of pathways related to gamma-aminobutyric acid (#GABA) metabolism in BP patients. [1.49] [#Kidney stone] - F. prausnitzii significantly depleted in Stone Formation [#Bilirubin, #Urobilin ] - The majority of bilR genes were identified in #Firmicutes species, including common human gut species such as #Roseburia intestinalis, #Roseburia inulinivorans and Faecalibacterium prausnitzii. [1.51] [#Kidney stone] - the majority of genes significantly enriched in non-stone formers are affiliated with Faecalibacterium prausnitzii, a major #Butyrate producer and the majority of abundant genes mapped back to F. prausnitzii, #Alistipes spp., and #Akkermansia muciniphila. [1.52] [#Chronic fatigue syndrome] - a significant decline in serum #Butyrate levels were found in ME/CFS patients. - decrease in #Butyrate-producing bacteria among ME/CFS patients involving genus/species like #Ruminococcus, Faecalibacterium prausnitzii, and #Eubacterium rectale. - the abundance of these species were negatively correlated with the severity of fatigue symptoms in ME/CFS patients. [1.53] [#Bacteroides uniformis, #Escherichia coli, #Parabacteroides distasonis] [#Fasting] - During IER > the abundance of #Obesity-related probiotics including F. prausnitzii, P. distasonis, and B. uniformis significantly increased compared with that at baseline, whereas the abundance of pathogenic E. coli significantly decreased. - the reduction in E.coli abundance sustained to the endpoint of phase III, whereas the abundance of F. prausnitzii, P. distasonis, and B. uniformis peaked at midpoint of phase II and declined to near baseline levels at endpoint of phase III. [#Bacteroides uniformis, #Parabacteroides distasonis] - F. prausnitzii, P. distasonis, and B. uniformis can reduce #Obesity and alleviate #Obesity-related metabolic and immune disorders [1.54] - In #Gout, #Bacteroides caccae and #Bacteroides xylanisolvens are enriched. - Faecalibacterium prausnitzii and #Bifidobacterium pseudocatenulatum depleted. - The established reference microbial gene catalogue for #Gout revealed disorder in purine degradation and #Butyric acid biosynthesis in #Gout patients. - Intestinal microbiota of #Gout are more similar to those of type-2 diabetes than to liver cirrhosis, whereas depletion of Faecalibacterium prausnitzii and reduced butyrate biosynthesis are shared in each of the metabolic syndromes. - #Bacteroides caccae is one biomarker of IBD. OmpW protein produced by B. caccae is a target of the IBD-associated immune response, thus the enriched intestinal B. caccae in #Gout patients could potentially induce serious inflammatory response. - Faecalibacterium prausnitzii has anti-inflammatory properties and contribute to gut health through butyrate production. for #Gout patients, potentially explaining the decline in #Butyric acid biosynthesis in #Gout patients.References Notes[ ]
