Microbiome and pancreatic cancer: A comprehensive topic review of literature

Table 1 Oral microbiome and pancreatic cancer

Ref.	Study design	Case No.	Control No.	Detection	Bacteria association	Outcome	Author conclusion
				Method
Michaud et al[18], 2013, Western Europe	Prospective	405	416	Plasma IgG	Porphyromonas gingivalis ATTC 53978	High titer P. gingivalis (IgG > 200 ng/mL)	Two fold increase in pancreatic cancer among individuals with high titer P. gingivalis
						OR 2.14
						P = 0.05
					High titer, commensal bacteria	OR = 0.55	45% lower risk of pancreatic cancer compared to individuals with lower antibody levels
						95%CI: 0.36-0.83
Farrell et al[12], 2012, United States	Case-control	28	28	Salivary qPCR, Microarray	Neisseria elongata and Streptococcus mitis	N. elongata and S. mitis significantly decreased	N. elongate and S. mitis combination ROC plot AUC 0.90 serves as 96% sensitive, 82% specific biomarker for pancreatic ca vs. healthy subjects
						ROC-plot AUC 0.90;
						95%CI: 0.78-0.96, P < 0.0001
					Granulicatella adiacens	G. adiacens
						Significantly elevated compared to healthy control
Lin et al[24], 2013, United States	Pilot	13	12	Salivary rRNA	Bacteroides genus	More common pancreatic cancer patient vs healthy subjects	Oral flora alterations in microbiome in pancreatic cancer exist compared to healthy individuals
						P = 0.002
					Corynebacterium genus Aggregatibacter genus	Less common in pancreatic cancer vs healthy subjects P = 0.033 and 0.019
Torres et al[25], 2015 United States	Cross-sectional	8	22	Salivary rRNA, PCR	Higher Leptotrichia and lower Porphyromonas colonization	Lepotrichia:Porphyromonas ratio elevated in pancreatic cancer vs healthy control P = 0.001	L:P ratio may be reliable biomarker for pancreatic cancer diagnosis
Fan et al[26], 2016 United States	Nested Case control	361	371	Salivary rRNA gene sequencing	Oral pathogens	P. gingivalis	Presence of oral pathogens are related to subsequent increased risk of pancreatic cancer. On contrary, Fusobacteria and Leptotrichia are associated with dose or concentration dependent decrease risk of pancreatic cancer
					P. gingivalis,	AOR = 1.60
					A. actinomycetemcomitans	(95%CI: 1.15-2.22)
						A. actinomycetes
						OR = 2.20
						(95%CI: 1.16-4.18)
					Fusobacteria and Leptotrichia	Fusobacteria
						decreased risk
						OR per percent increase of relative
						Abundance
						OR = 0.94
						(95%CI: 0.89-0.99)
						Lepotrichia
						OR = 0.87
						(95%CI: 0.79-0.95)

Table 2 Helicobacter pylori and pancreatic cancer

Ref.	Study Design	Case No.	Control No.	Detection	Bacteria association	Outcome	Author conclusion
				Method
Raderer et al[33], 1998, Austria	Case-control	92	27	Plasma IgG ELISA	H. pylori	OR = 2.1	H. pylori seropositivity prominent in pancreatic cancer patients compared with colorectal cancer combined with normal controls
						95%CI: 1.1-4.1
						P = 0.035
Stolzenberg-Solomon et al[34] 2001, Finland	Nested case-control	121	226	Plasma IgG ELISA	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	H. pylori	Male smokers seropositive for H. pylori were nearly twice as likely to develop pancreatic cancer compared to seronegative. Stronger influence adjusting for years of smoking
						OR = 1.87;
						95%CI: 1.05-3.34
						CagA+ strains
						OR = 2.01;
						95%CI: 1.09-3.70
de Martel et al[35], 2008, United States	Nested Case-control	104	262	Plasma IgG ELISA	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	H. pylori	H. pylori infection is not associated with development of pancreatic cancer
						OR = 0.85;
						95%CI: 0.49-1.48
						CagA+
						OR = 0.96;
						95%CI: 0.48-1.92
Lindkvist et al[36], 2008, Sweden	Nested Case-control	87	263	Plasma IgG ELISA	H. pylori	H. pylori overall	Adjusted risk for development of pancreatic cancer highly increased in never-smokers seropositive for H. pylori
						OR = 1.25
						95%CI: 0.75-2.09
						H. pylori in Never smokers
						AOR = 3.81
						95%CI: 1.06-13.63
Risch et al[37] 2010, United States	Case-control	373	690	Plasma IgG ELISA	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	CagA negative H. pylori non-O blood group	CagA-negative H. pylori seropositivity is a risk factor for pancreatic cancer among individuals with non–O blood type
						OR = 2.78,
						95%CI: 1.49-5.20,
						P = 0.0014;
						CagA negative H. pylori O-blood group
						OR = 1.28,
						95%CI: 0.62-2.64,
						P = 0.51
Trikudanathan et al[11], 2011	Meta-analysis	822	1513	meta-analysis of 6 case control studies	H. pylori	AOR = 1.38,	Significant positive association between the presence of H. pylori infection and pancreatic cancer.
						95%CI: 1.08-1.75
Gawin et al[38], 2012, Poland	Case-control	139	177	Plasma IGg, ELISA, western blot	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	H. pylori	No association between seropositivity of H. pylori or CagA with development of pancreatic cancer
						OR = 1.27;
						95%CI: 0.64-2.61
						P = 0.514
						CagA+
						OR = 0.90;
						95%CI: 0.46-1.73,
						P = 0.744
Xiao et al[39], 2013	Meta-analysis	1083	1950	meta-analysis of 9 case-control studies	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	H. pylori Overall	Borderline positive association H. pylori seropositivity overall. Adjusted risk for high quality studies revealed a significant, but modest association. CagA virulence seropositivity was not associated with pancreatic cancer
						OR = 1.47
						95%CI: 1.22-1.77
						Adjusted for “High quality” studies
						AOR = 1.28;
						95%CI: 1.01-1.63
						Adjusted for CagA positive
						AOR = 1.47;
						95%CI: 0.79-2.57
Yu et al[40], 2013, Finland	Case-control	353	353	multiplex serology to 4 H. pylori antigens	H. pylori	OR = 0.85;	No association between seropositivity of H. pylori with development of pancreatic cancer
						95%CI: 0.49 -1.49
Wang et al[41], 2014	Meta-analysis	2049	2861	Meta-analysis of 9 case-control studies (2 non- English language)	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	H. pylori overall	Eastern Asian populations demonstrate significant decreased risk pancreatic cancer associated with H. pylori seropositivity. No association present in Western populations
						OR = 1.06,
						95%CI: 0.74-1.37
						Eastern Asian Population
						H. pylori
						OR = 0.62,
						95%CI: 0.49-0.76
						Cag-A positive
						OR = 0.66,
						95%CI: 0.52-0.80
						Western European population
						H. pylori
						OR = 1.14
						95%CI: 0.89-1.40
						Cag-A positive
						OR = 0.84
						95%CI: 0.63-1.04
Risch et al[42], 2014, Shanghai	Case-control	761	794	Plasma IGg, ELISA	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	Cag-A positive H. pylori	Decreased pancreas-cancer risk was seen for CagA positive H. pylori compared to seronegativity for both H. pylori and CagA. A modest increased risk for CagA-negative H. pylori seropositivity
						AOR = 0.68;
						95%CI: 0.54-0.84
						Cag-A negative H. pylori
						AOR = 1.28;
						95%CI: 0.76-2.13
Chen et al[9], 2015	Meta-analysis	1446	2236	meta-analysis of 5 case control studies	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	Overall	CagA-negative, nonvirulent strains of H. pylori may be a risk factor for pancreatic cancer. No association with seropositivity for H. pylori infection overall, nor when adjusted for CagA or virulent strain infection
						OR = 0.99;
						95%CI: 0.65-1.50
						CagA+
						OR = 0.92;
						95%CI: 0.65 -1.3
						Virulent strain infection
						OR = 0.97
						95%CI: 0.50-1.89
						Nonvirulent infection
						OR = 1.47
						95%CI: 1.11-1.96
Schulte et al[10], 2015	Combination Case-control and meta-analysis	580	626	Plasma IGg, ELISA and meta-analysis of 10 case-control studies	cytotoxin-associated gene-A (CagA) virulence factor and H. pylori	H. pylori overall	No overall association observed for H. pylori seropositivity and risk of pancreatic cancer, but evidence of non-significant CagA strain-specific associations
						OR = 1.00
						95%CI: 0.74-1.35
						Cag-A negative
						AOR = 1.23
						95%CI: 0.83-1.82
						Cag-A positive
						OR = 0.74
						95%CI: 0.48-1.15

Table 3 Tissue microbiome and pancreatic cancer

Ref.	Study design	Case sample size	Detection method and sample	Bacteria association	Outcome	Author conclusion
Nilsson et al[44], 2006, Sweden	Case-control	84	DNA genus specific PCR, surgical specimen	H. pylori	Helicobacter DNA detected in pancreas of 75% patients with adenocarcinoma, but not detected in any control	Helicobacter DNA, mostly H. pylori genus, commonly detected in pancreatic cancer
Takayama et al[45], 2007, Japan	Abstract	-	ELISA and western blot, Pre-clinical cell line	H. pylori	IL-8 and VEGF secretion and proliferation factors NF-kappa-B, AP-1, and serum response element of human pancreatic cells increased by H. pylori infection	H. pylori infection of human pancreatic cells may increase malignant potential of pancreatic cells
Mitsuhashi et al[46], 2015, Japan	Case-control	283	PCR, surgical specimen	Fusobacterium	Detected in 8.8% cases.	significantly shorter survival observed in the Fusobacterium species-positive group
					Median cancer-survival (mo) positive vs negative detection
					17.2 vs 32.5 for
					log-rank P = 0.021