Long COVID: microbiome scents – we smell a skunk!

This is using data from the study being done with BiomeSight. We will only use their samples. After the first review, a z-score of 6.4 or higher (or a lots of items) was set as a cutoff point. The following ignore False Detection Rate.

  • Conclusion: the ENZYME production of the microbiome is by far the strongest indicator.
  • The reference set consists of 1037 heterogenous samples (i.e. no Long COVID, but a variety of medical conditions) and 154 samples with Long COVID

Taxon Patterns

Care needs to be taken with these numbers because the frequency of reporting on a bacteria is a factor that impacts the z-score. The data for this table is available at Citizen Science site and independent analysis is strongly recommended. This table is a simplified view of very complex data.

tax_nametax_rankNo Symptom MeanSymptom MeanZ-ScoreChange
Terrabacteria groupclade71504052088510.473%
Firmicutesphylum6524525028309.077%
Tenericutesphylum25626362-7.9248%
Eubacterialesorder6098884824687.979%
Mollicutesclass25626362-7.9248%
Clostridiaclass6137434877197.879%
Emticicia oligotrophicaspecies7692553-6.8332%
Faecalibacterium prausnitziispecies100292142415-6.7142%

End Product Patterns

End products only had a single item above our 6.3 z-score threshold with a very small shift.

EndProductNo Symptom MeanSymptom MeanNo Symptom StdDevChange
H2132913076.698%

KEGG Enzyme Patterns

This is where we see a massive number of patterns(182!!) with very high z-scores (i.e. 6.4 or higher). This hints that the bacteria associated with these enzymes may be a good target to modify.

EnzymeNameNo Symptom MeanSymptom MeanNo Symptom StdDevChange
dihydrourocanate:acceptor oxidoreductase58562147222-18.2251%
(S)-3-hydroxy-3-methylglutaryl-CoA acetoacetate-lyase (acetyl-CoA-forming)55210142006-18257%
(1->4)-alpha-D-galacturonan reducing-end-disaccharide-lyase54601139740-17.7256%
acetyl-CoA:kanamycin-B N6′-acetyltransferase55382140425-17.7254%
acetyl-CoA:2-deoxystreptamine-antibiotic N3-acetyltransferase56590141511-17.6250%
poly(deoxyribonucleotide)-3′-hydroxyl:5′-phospho-poly(deoxyribonucleotide) ligase (ATP or NAD+)55562141080-17.6254%
D-serine ammonia-lyase (pyruvate-forming)55931140065-17.6250%
poly(deoxyribonucleotide)-3′-hydroxyl:5′-phospho-poly(deoxyribonucleotide) ligase (ATP, ADP or GTP)55562141080-17.6254%
alpha-maltose-6′-phosphate 6-phosphoglucohydrolase57944142024-17.5245%
ATP phosphohydrolase (ABC-type, iron(III) enterobactin-importing)57953141331-17.4244%
protein-Npi-phospho-L-histidine:D-mannose Npi-phosphotransferase66964152717-17.4228%
ATP phosphohydrolase (ABC-type, Fe3+-transporting)68676154113-17.4224%
D-psicose 3-epimerase70754155871-17.2220%
D-tagatose 3-epimerase70754155871-17.2220%
2′-(5-triphosphoribosyl)-3′-dephospho-CoA:apo-[citrate (pro-3S)-lyase] 2′-(5-phosphoribosyl)-3′-dephospho-CoA-transferase77143161549-17.1209%
ATP:3′-dephospho-CoA 5-triphospho-alpha-D-ribosyltransferase78363162298-17207%
2,4,6/3,5-pentahydroxycyclohexanone 2-isomerase75196158863-16.9211%
ATP:[protein]-L-tyrosine O-phosphotransferase (non-specific)60964143510-16.9235%
acetyl-CoA:citrate CoA-transferase79352162680-16.7205%
L-aspartate:tRNAAsx ligase (AMP-forming)63596144560-16.7227%
poly(deoxyribonucleotide)-3′-hydroxyl:5′-phospho-poly(deoxyribonucleotide) ligase (ATP)69642156282-16.7224%
penicillin amidohydrolase69734151011-16.6217%
protein-Npi-phospho-L-histidine:D-mannitol Npi-phosphotransferase57950140690-16.5243%
ATP:D-erythronate 4-phosphotransferase65433145262-16.4222%
acetate:holo-[citrate-(pro-3S)-lyase] ligase (AMP-forming)90668176404-16.4195%
ATP:D-threonate 4-phosphotransferase65433145262-16.4222%
D-aspartate:[beta-GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n ligase (ADP-forming)73487157884-16.4215%
4-phospho-D-erythronate:NAD+ 3-oxidoreductase65773145502-16.3221%
4-phospho-D-threonate:NAD+ 3-oxidoreductase65773145502-16.3221%
nucleoside-triphosphate diphosphohydrolase69217153915-16.2222%
4-amino-5-aminomethyl-2-methylpyrimidine aminohydrolase75806165018-15.7218%
ATP:D-glycero-alpha-D-manno-heptose 7-phosphate 1-phosphotransferase81281169414-15.7208%
aryl-ester hydrolase77314159122-15.6206%
palmitoyl-CoA hydrolase76772157265-15.4205%
UDP-alpha-D-glucose:1,2-diacyl-sn-glycerol 3-alpha-D-glucosyltransferase91112172382-15.4189%
D-tagatose 1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase (glycerone-phosphate-forming)75959152459-15.2201%
ADP-alpha-D-glucose:alpha-D-glucose-1-phosphate 4-alpha-D-glucosyltransferase (configuration-retaining)63077146386-15.1232%
L-glutamate:tRNAGlx ligase (AMP-forming)97313177576-14.5182%
oligosaccharide 6-alpha-glucohydrolase96720174292-14.3180%
S-adenosyl-L-methionine:tRNA (adenine22-N1)-methyltransferase96117168859-13.9176%
alkylated-DNA glycohydrolase (releasing methyladenine and methylguanine)93342182716-13.7196%
sn-glycerol 3-phosphate:quinone oxidoreductase113940189562-13.6166%
L-iditol:NAD+ 2-oxidoreductase113731190510-13.4168%
(3S)-citryl-CoA oxaloacetate-lyase (acetyl-CoA-forming)108775197009-13.3181%
N-succinyl-LL-2,6-diaminoheptanedioate amidohydrolase88237163157-13185%

KEGG Product

Products are the output of enzymes. Various enzymes may produce the same product. Our starting assumption was that products would have stronger association than enzymes. That was not shown in the data.

CompoundNameNo Symptom MeanSymptom MeanNo Symptom StdDevChange
Acetoacetate3787855442-8.1146%
Reduced electron-transferring flavoprotein106971149551-6.9140%
Dialkyl phosphate7732553-6.8330%
Indole-3-acetate7732553-6.8330%
Pseudouridine 5′-phosphate109418150579-6.7138%
3-Hydroxy-3-(methylthio)propanoyl-CoA7582494-6.7329%
3-Oxopropionyl-CoA7582494-6.7329%
N-Acetyl-beta-D-glucosaminylamine7602473-6.7325%
(2E,4Z)-2,4-Dienoyl-CoA6880995899-6.6139%
Short-chain trans-2,3-dehydroacyl-CoA103627144711-6.6140%
(2E,4E)-2,4-Dienoyl-CoA6880995899-6.6139%
4-(4-Deoxy-alpha-D-gluc-4-enuronosyl)-D-galacturonate3396147705-6.6140%
4-Hydroxyphenylglyoxylate113250152269-6.5134%
Oleoyl-[acyl-carrier protein]7352376-6.5323%
(4Z)-Hexadec-4-enoyl-[acyl-carrier protein]7352376-6.5323%
N6′-Acetylkanamycin-B3476248298-6.5139%
(6Z)-Hexadec-6-enoyl-[acyl-carrier protein]7352376-6.5323%
Pyocyanine7512381-6.5317%
(1E,3E)-4-Hydroxybuta-1,3-diene-1,2,4-tricarboxylate14304549-6.5318%
Aldose7642429-6.4318%
Molybdoenzyme molybdenum cofactor119172159672-6.4134%
N3-Acetyl-2-deoxystreptamine antibiotic3593949415-6.4137%

KEGG Substrate

Subtrate are the fuel for enzymes reaction. Various enzymes may consume the same compound. Our starting assumption was that substrate would have stronger association than enzymes. That was not shown in the data.

CompoundNameNo Symptom MeanSymptom MeanNo Symptom StdDevChange
Dihydrourocanate3802655395-7.8146%
(S)-3-Hydroxy-3-methylglutaryl-CoA3482050269-7.4144%
Electron-transferring flavoprotein106880149551-6.9140%
threo-3-Hydroxy-D-aspartate7602532-6.9333%
3-(Methylthio)acryloyl-CoA7572494-6.8329%
3-Hydroxy-3-(methylthio)propanoyl-CoA7572494-6.8329%
3-Oxopropionyl-CoA7572494-6.8329%
ADP-sugar7722553-6.8331%
Aryl dialkyl phosphate7722553-6.8331%
beta-D-Mannose7722553-6.8331%
D-erythro-3-Hydroxyaspartate7612532-6.8333%
Pseudouridine105195147050-6.8140%
N4-(Acetyl-beta-D-glucosaminyl)asparagine7592473-6.7326%
Short-chain acyl-CoA103536144711-6.7140%
(2-Amino-1-hydroxyethyl)phosphonate7522431-6.6323%
trans-2,3-Dehydroacyl-CoA6874595899-6.6140%
(S)-4-Hydroxymandelate113176152269-6.5135%
5-Methylphenazine-1-carboxylate7502381-6.5317%
Hexadecanoyl-[acp]14684753-6.5324%
Kanamycin B3472948298-6.5139%
Octadecanoyl-[acyl-carrier protein]7342376-6.5324%
(1E)-4-Oxobut-1-ene-1,2,4-tricarboxylate7392338-6.4316%
2-Deoxystreptamine antibiotic3591649415-6.4138%
Adenylated molybdopterin119083159672-6.4134%
Alditol7632429-6.4318%
beta-Carotene7202314-6.4321%
Molybdate119083159672-6.4134%

Bottom Line

Several years ago, I hypothesized that a symptom or condition is the result of a coming together of many small deviations in individual bacteria representation. There may be 10 different combination of bacteria with none overlapping causing a symptom. The inspiration for this was observing the literature and experience of people with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) — a sibling condition to Long COVID. This model is contrary to the common belief that there is a single or small number of items that is the cause. My looking at Brain fog (using same technique as above Brain Fog: Microbiome scents…) came up with nothing. That was not desired, but almost expected because that population is very heterogenous for cause with a long time since the triggering event for the microbiome to diverge from each other (often treatment attempts would be a factor). With long COVID, we have a short time since the triggering event and the people tend to be treatment naïve, This makes finding patterns a lot easier (when you look under the right rocks!).

Almost everything is overproduction. This may be caused by the immune system ramping up to provide fuel to fight COVID. The microbiome is stuck in an on-state, likely with cross talk between enzymes keeping it stuck on. The term of the Pasteur Institute for Tropical Medicine, “an occult infection” describes the behavior seen nicely.

Addressing the few microbiome shifts is one approach — but the enzymes dominate in both statistical significance and number of items, It is likely the best path to address the enzymes instead of individual bacteria.

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