Baseline metabolites could predict responders with hepatitis B virus-related liver fibrosis for entecavir or combined with FuzhengHuayu tablet

Table 1 Demographic and clinical data of patients and volunteers in training set and validation set

	Training set (n = 105)					Validation set (n = 45)
	F-R (n = 23)	F-N (n = 23)	E-R (n = 23)	E-N (n = 23)	NOR (n = 13)	F-R (n = 10)	F-N (n = 10)	E-R (n = 10)	E-N (n = 10)	NOR (n = 5)
Male/Female	15/8	15/8	16/7	17/6	9/4	7/3	10/0	6/4	8/2	4/1
Age (yr)	44.17 ± 6.25	42.43 ± 8.36	40.65 ± 7.73	42.22 ± 7.97	36.92 ± 6.18	42.80 ± 5.01	38.10 ± 11.95	45.00 ± 7.93	47.40 ± 10.44	37.80 ± 8.79
BMI (kg/m2)	23.60 ± 2.56	23.64 ± 3.17	23.54 ± 2.06	23.92 ± 2.73	24.20 ± 1.34	23.22 ± 3.30	24.76 ± 1.65	24.61 ± 2.29	23.16 ± 3.86	22.60 ± 1.71
ALT (IU/L)	42.52 ± 29.59	41.03 ± 20.48	68.91 ± 89.81	47.34 ± 27.83	/	49.80 ± 50.83	48.80 ± 33.14	57.08 ± 46.97	58.33 ± 73.02	/
AST (IU/L)	40.50 ± 21.35	41.80 ± 19.41	53.47 ± 51.20	50.53 ± 27.59	/	38.71 ± 16.39	47.75 ± 28.32	77.64 ± 120.70	48.73 ± 35.54	/
ALB (IU/L)	43.84 ± 5.50	41.43 ± 6.07	43.51 ± 5.75	42.22 ± 4.61	/	42.40 ± 5.08	35.70 ± 6.67	39.68 ± 5.95	41.53 ± 4.64	/
TBIL (μmol/L)	16.15 ± 10.88	13.27 ± 6.36	13.36 ± 9.25	14.16 ± 6.51	/	11.98 ± 4.90	24.49 ± 16.83	22.08 ± 13.61	12.18 ± 5.79	/
Cr (μmol/L)	64.43 ± 17.03	66.39 ± 11.99	69.57 ± 16.59	64.57 ± 14.67	/	72.80 ± 18.27	71.10 ± 9.71	65.80 ± 13.70	83.60 ± 25.07	/
PT (S)	13.22 ± 1.48	13.23 ± 1.41	13.31 ± 1.46	13.78 ± 1.52	/	13.21 ± 1.32	14.27 ± 2.90	14.10 ± 1.33	13.88 ± 1.83	/
PLT (× 10 ×9/L)	119.02 ± 49.99	113.47 ± 61.33	131.70 ± 49.26	104.65 ± 41.65	/	145.10 ± 64.42	112.00 ± 36.18	98.88 ± 45.13	106.40 ± 37.97	/
AFP (ng/ml)	23.70 ± 59.55	12.46 ± 13.22	18.63 ± 42.03	14.75 ± 15.56	/	16.73 ± 31.93	54.81 ± 93.15	25.25 ± 41.79	14.86 ± 15.91	/
FIB-4	2.99 ± 2.06	3.31 ± 2.38	2.54 ± 1.62	3.46 ± 1.75	/	2.29 ± 1.95	2.72 ± 1.51	5.63 ± 8.14	3.55 ± 1.89	/
APRI	1.10 ± 0.96	1.23 ± 0.95	1.40 ± 1.60	1.31 ± 0.73	/	0.81 ± 0.54	1.18 ± 0.84	3.17 ± 6.23	1.28 ± 0.92	/
Ishak score	5.48 ± 0.51	5.43 ± 0.51	5.35 ± 0.49	5.39 ± 0.50	/	5.40 ± 0.52	5.40 ± 0.52	5.50 ± 0.53	5.10 ± 0.32	/

BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALB: Albumin; TBIL: Total bilirubin; Cr: Creatinine; PT: Prothrombin time; PLT: Platelet count; AFP: Alpha fetoprotein; FIB-4: Fibrosis index based on the 4 factor; APRI: Aspartate aminotransferase-to-platelet ratio index; E-R: Entecavir responders; E-N: Entecavir no-responders; F-R: FuzhengHuayu tablet + entecavir responders; F-N: FuzhengHuayu tablet + entecavir no-responders; NOR: Normal.

Table 2 The selected potential metabolites in training set and validation set

Class	HMDB	KEGG	Metabolite	Uni_P	Uni_FDR	FC	log2FC	OPLSDA_VIP
Training set
Fatty acids	HMDB0000448	C06104	Adipic acid	0.03	1.00	0.77	-0.37	1.65
Organic acids	HMDB0000176	C01384	Maleic acid	0.04	1.00	0.84	-0.25	1.73
Fatty acids	HMDB0060038	NA	10Z-Heptadecenoic acid	0.01	0.31	3.10	1.63	1.90
	HMDB0002925	C03242	Dihomo-gamma-linolenic acid	0.02	0.32	2.08	1.05	1.60
	HMDB0001043	C00219	Arachidonic acid	0.04	0.44	1.70	0.76	1.79
	HMDB0002183	C06429	DHA	0.02	0.32	1.85	0.89	2.03
	HMDB0006528	C16513	DPA	0.01	0.31	1.55	0.63	1.99
	HMDB0001999	C06428	EPA	0.02	0.32	1.54	0.62	1.70
Organic acids	HMDB0000700	C01013	Hydroxypropionic acid	0.01	0.31	1.27	0.35	1.21
Fatty acids	HMDB0000673	C01595	Linoleic acid	0.05	0.44	1.39	0.47	1.54
Carnitines	HMDB0006469	NA	Linoleylcarnitine	0.01	0.31	1.40	0.49	2.16
Fatty acids	HMDB0000806	C06424	Myristic acid	0.01	0.31	1.61	0.69	1.76
	HMDB0000207	C00712	Oleic acid	0.02	0.32	1.45	0.54	1.86
Carnitines	HMDB0005065	NA	Oleylcarnitine	0.01	0.31	1.21	0.28	2.32
Fatty acids	HMDB0003229	C08362	Palmitoleic acid	0.02	0.31	1.53	0.61	1.62
	HMDB0000826	C16537	Pentadecanoic acid	0.03	0.42	1.51	0.60	1.51
Benzenoids	HMDB0000205	C00166	Phenylpyruvic acid	0.04	0.44	0.86	-0.22	0.85
Carnitines	HMDB0013128	NA	Valerylcarnitine	0.02	0.31	1.21	0.27	1.47
Organic acids	HMDB0000617	C01546	2-Furoic acid	0.00	0.00	148.12	7.21	2.10
Phenylpropanoic acids	HMDB0011743	NA	2-Phenylpropionate	0.01	0.04	2.89	1.53	1.26
Organic acids	HMDB0000357	C01089	3-Hydroxybutyric acid	0.04	0.20	0.56	-0.83	0.59
Fatty acids	HMDB0000555	NA	3-Methyladipic acid	0.05	0.22	0.95	-0.07	2.09
	HMDB0001043	C00219	Arachidonic acid	0.00	0.01	0.66	-0.60	2.11
	HMDB0000784	C08261	Azelaic acid	0.05	0.22	1.07	0.10	0.86
Organic acids	HMDB0001870	C00180	Benzoic acid	0.00	0.00	346.31	8.44	2.42
Bile acids	HMDB0000686	C17662	bUDCA	0.00	0.02	0.64	-0.64	1.37
SCFAs	HMDB0000039	C00246	Butyric acid	0.00	0.00	3.72	1.89	2.54
Carnitines	HMDB0002013	C02862	Butyrylcarnitine	0.00	0.02	0.55	-0.87	1.80
Bile acids	HMDB0000619	C00695	CA	0.02	0.16	1.42	0.51	1.27
Organic acids	HMDB0000072	C02341	Aconitic acid	0.00	0.01	1.37	0.46	0.76
	HMDB0000094	C00158	Citric acid	0.00	0.02	1.21	0.27	1.31
Carbohydrates	HMDB0000122	C00221	Glucose	0.05	0.22	1.10	0.14	0.75
Carnitines	HMDB0000651	NA	Decanoylcarnitine	0.01	0.06	0.52	-0.94	0.55
Amino acids	HMDB0000092	C01026	Dimethylglycine	0.00	0.03	1.27	0.35	0.90
Amino acids	HMDB0000112	C00334	GABA	0.01	0.05	1.17	0.23	0.46
	HMDB0000123	C00037	Glycine	0.04	0.19	1.18	0.23	1.07
Bile acids	HMDB0000637	C05466	GCDCA	0.00	0.00	6.42	2.68	2.30
Organic acids	HMDB0000115	C00160	Glycolic acid	0.03	0.18	1.26	0.33	1.03
Fatty acids	HMDB0000666	C17714	Heptanoic acid	0.03	0.19	1.30	0.38	1.07
Phenols	HMDB0000118	C05582	Homovanillic acid	0.00	0.01	1.26	0.33	2.40
Phenylpropanoic acids	HMDB0000764	C05629	Hydrocinnamic acid	0.00	0.03	2.71	1.44	1.23
	HMDB0000755	C03672	Hydroxyphenyllactic acid	0.00	0.01	1.44	0.53	2.20
Organic acids	HMDB0000193	C00311	Isocitric acid	0.05	0.22	1.39	0.48	0.65
Amino Acids	HMDB0000168	C00152	Asparagine	0.03	0.19	1.07	0.10	1.85
	HMDB0000719	C00263	Homoserine	0.04	0.19	1.20	0.26	1.41
	HMDB0000696	C00073	Methionine	0.00	0.04	1.23	0.30	1.59
	HMDB0000716	C00408	Pipecolic acid	0.02	0.11	1.20	0.26	0.98
	HMDB0000158	C00082	Tyrosine	0.00	0.00	1.54	0.62	2.51
Carnitines	HMDB0000791	C02838	Octanoylcarnitine	0.03	0.19	0.75	-0.42	0.57
Phenylpropanoic acids	HMDB0000779	NA	Phenyllactic acid	0.00	0.04	2.81	1.49	1.44
SCFAs	HMDB0000237	C00163	Propionic acid	0.00	0.00	2.70	1.43	3.00
Bile Acids	HMDB0000951	C05465	TCDCA	0.00	0.00	11.04	3.47	1.80
	HMDB0000036	C05122	TCA	0.00	0.03	13.19	3.72	1.55
Validation set
Carnitines	HMDB0000062	C00318	Carnitine	0.04	0.65	0.80	-0.31	1.73
Fatty acids	HMDB0001976	NA	DPAn-6	0.04	0.65	1.79	0.84	2.00
	HMDB0003073	C06426	gamma-Linolenic acid	0.01	0.59	3.84	1.94	2.54
Amino acids	HMDB0000123	C00037	Glycine	0.03	0.65	0.85	-0.24	1.60
Peptides	HMDB0000721	NA	Glycylproline	0.01	0.59	0.85	-0.24	1.59
Amino acids	HMDB0000168	C00152	Asparagine	0.02	0.65	0.85	-0.24	1.41
	HMDB0000162	C00148	Proline	0.01	0.59	0.52	-0.94	1.53
Fatty acids	HMDB0006270	NA	Linoelaidic acid	0.00	0.06	2.15	1.10	2.62
	HMDB0002925	C03242	Dihomo-gamma-linolenic acid	0.04	0.80	1.65	0.72	1.39
	HMDB0001043	C00219	Arachidonic acid	0.05	0.80	1.42	0.51	1.59
Organic acids	HMDB0000700	C01013	Hydroxypropionic acid	0.04	0.80	0.47	-1.08	2.07
Amino acids	HMDB0000168	C00152	Asparagine	0.02	0.80	0.81	-0.31	2.66
	HMDB0000191	C00049	Aspartic acid	0.01	0.80	1.55	0.63	2.29
	HMDB0000158	C00082	Tyrosine	0.03	0.80	0.72	-0.47	2.51
Phenylpropanoic acids	HMDB0000779	NA	Phenyllactic acid	0.03	0.80	0.60	-0.75	2.14
Organic acids	HMDB0000617	C01546	2-Furoic acid	0.00	0.02	148.81	7.22	1.66
Phenylpropanoic acids	HMDB0011743	NA	2-Phenylpropionate	0.00	0.02	13.73	3.78	1.90
Fatty acids	HMDB0001043	C00219	Arachidonic acid	0.02	0.17	0.69	-0.53	1.88
Organic acids	HMDB0001870	C00180	Benzoic acid	0.00	0.02	715.57	9.48	1.71
SCFAs	HMDB0000039	C00246	Butyric acid	0.00	0.05	7.84	2.97	1.80
Organic acids	HMDB0000072	C02341	Aconitic acid	0.00	0.06	1.60	0.68	1.90
	HMDB0000094	C00158	Citric acid	0.00	0.02	1.54	0.62	2.32
Amino acids	HMDB0000092	C01026	Dimethylglycine	0.00	0.02	1.65	0.72	0.97
Bile acids	HMDB0000637	C05466	GCDCA	0.00	0.02	12.69	3.67	1.53
Phenols	HMDB0000118	C05582	Homovanillic acid	0.00	0.03	1.51	0.59	2.32
Phenylpropanoic acids	HMDB0000764	C05629	Hydrocinnamic acid	0.00	0.03	7.97	2.99	1.88
	HMDB0000755	C03672	Hydroxyphenyllactic acid	0.03	0.25	1.63	0.70	2.10
Organic acids	HMDB0000193	C00311	Isocitric acid	0.00	0.06	2.32	1.21	1.29
Amino acids	HMDB0000641	C00064	Glutamine	0.04	0.27	1.26	0.33	1.85
	HMDB0000684	C00328	Kynurenine	0.02	0.15	1.53	0.61	0.95
	HMDB0000158	C00082	Tyrosine	0.00	0.01	1.46	0.55	2.23
	HMDB0002931	NA	N-acetylserine	0.03	0.21	1.18	0.24	0.83
Fatty acids	HMDB0003229	C08362	Palmitoleic acid	0.03	0.25	1.60	0.68	1.07
Phenylpropanoic acids	HMDB0000779	NA	Phenyllactic acid	0.03	0.25	20.79	4.38	1.84
Benzoic acids	HMDB0002107	C01606	Phthalic acid	0.01	0.14	1.33	0.41	2.21
SCFAs	HMDB0000237	C00163	Propionic acid	0.01	0.08	4.41	2.14	2.19
Bile acids	HMDB0000951	C05465	TCDCA	0.00	0.00	9.63	3.27	1.75
	HMDB0000036	C05122	TCA	0.01	0.09	9.75	3.28	1.54

GCDCA: Glycochenodeoxycholic acid; TCA: Tricarboxylic acid; TCDCA: Taurochenodeoxycholic acid; NA: Not Applicable; DHA: Docosahexaenoic acid; DPA: Docosapentaenoic acid; EPA: Eicosapentaenoic acid; UDCA: Ursodeoxycholic acid; CA: Citric acid; GABA: Gamma-amino butyric acid.