Circulating and Salivary Antibodies to Fusobacterium nucleatum Are Associated With Cystic Pancreatic Neoplasm Malignancy

Abstract

Objectives Intraductal papillary mucinous neoplasms (IPMNs) are cystic precursor lesions to pancreatic cancer. The presence of oral microbes in pancreatic tissue or cyst fluid has been associated with high-grade dysplasia (HGD) and cancer. The present study aims at investigating if humoral immunity to pancreas-associated oral microbes reflects IPMN severity. Design Paired plasma ( n = 109) and saliva ( n = 65) samples were obtained from IPMN pancreatic cystic tumor cases and controls, for anti-bacterial antibody analysis and DNA quantification by enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. Tumor severity was graded by histopathology, laboratory, and clinical data. Circulating plasma and salivary antibody reactivity to a pancreas-associated oral microbe panel were measured by ELISA and correlated to tumor severity. Results The patient group with high-risk cystic tumors (HGD and/or associated invasive cancer) shows ample circulating IgG reactivity to Fusobacterium nucleatum ( F. nucleatum ) but not to Granulicatella adiacens ( G. adiacens ), which is independent of the salivary bacteria DNA levels. This group also shows higher salivary IgA reactivity to F. nucleatum , Fap2 of F. nucleatum , and Streptococcus gordonii ( S. gordonii ) compared to low-risk IPMN and controls. The salivary antibody reactivity to F. nucleatum and Fap2 are found to be highly correlated, and cross-competition assays further confirm that these antibodies appear cross-reactive. Conclusion Our findings indicate that humoral reactivity against pancreas-associated oral microbes may reflect IPMN severity. These findings are beneficial for biomarker development.

Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development

“…While the carrier-status related to these taxa was described by some groups to be associated with a decreased risk of developing PDAC [ 15 , 19 , 20 ], others found a positive correlation [ 18 , 21 ]. Interestingly, one study showed higher serum and salivary antibodies against F. nucleatum in patients with high-grade dysplasia intraductal papillary mucinous neoplasms (IPMN) or IPMN with associated invasive cancer compared to patients bearing a low-risk IPMN [ 22 ]. However, other studies could not confirm these differences [ 23 ].…”

Microbial Associations with Pancreatic Cancer: A New Frontier in Biomarkers

“…On account of this, the authors suggest that screening for F. nucleatum in tumor samples may hold prognostic value, with patients positive for this species having a worse prognosis. More recently, Alkhaaran et al demonstrated that patients with severe intraductal papillary mucinous neoplasm (IPMN) have higher levels of circulating IgG and salivary IgA reactive to F. nucleatum [42]. The positive correlation (r = 0.685, p < 0.0001) between F. nucleatum and Fap2 IgA antibodies is interesting on account of the fact that Fap2 is an important adhesin used by F. nucleatum to bind targets in the pancreatic TME [42,51,52].…”

“…More recently, Alkhaaran et al demonstrated that patients with severe intraductal papillary mucinous neoplasm (IPMN) have higher levels of circulating IgG and salivary IgA reactive to F. nucleatum [42]. The positive correlation (r = 0.685, p < 0.0001) between F. nucleatum and Fap2 IgA antibodies is interesting on account of the fact that Fap2 is an important adhesin used by F. nucleatum to bind targets in the pancreatic TME [42,51,52]. A 2018 paper by del Castillo et al likewise reported that a higher relative abundance of Fusobacterium spp.…”

The Multifaceted Roles of Diet, Microbes, and Metabolites in Cancer

“…Fusobacterium nucleatum [77] High-fat (keto) diet [58,77,131] B-glucuronidase [64] SCFA [132,133] Sodium phenylbutyrate [107,108,110] Colorectal Fusobacterium nucleatum [58] Clostridium butyricum, Butyricicoccus pullicaecorum Akkermansia, Barnesiella, Coprococcus, Lachnoclostridium, and Ruminococcus [53,85,99] High-fat (keto) diet [58,60,73] Red meat [21] B-glucuronidase [65] SCFA [70,72,99] Probiotics [85,86] Decursin [50] Sodium butyrate [85,99,[102][103][104][105][106] Sodium phenylbutyrate [107,108,110] Vitamin D [35] Vitamin A [37,39] Nitrates [46] Oat flakes [52] Adaptogenic flower buds [53] n-3 PUFAs [91] Polyphenols [76,78]…”

“…The oral microbe Fusobacterium nucleatum is increased in patients with periodontitis, which is also associated with an increased risk of colorectal cancer [ 75 , 76 ]. In addition, a recent study showed that individuals with pancreatic cancer have higher circulating and salivary antibodies against F. nucleatum , suggesting a link between oral microbiota and pancreatic cancer [ 77 ]. Polyphenols are first metabolized in the oral cavity, modulating inflammatory responses as well as eliciting antimicrobial activity, inhibiting the growth of F. nucleatum [ 76 ].…”