Lactobacillus Attenuate the Progression of Pancreatic Cancer Promoted by Porphyromonas Gingivalis in K-rasG12D Transgenic Mice

Abstract

Accumulating evidence suggests that there is a link between the host microbiome and pancreatic carcinogenesis, and that Porphyromonas gingivalis (P. gingivalis) increases the risk of developing pancreatic cancer. The aim of the current study was to clarify the role of P. gingivalis in the pathogenesis of pancreatic cancer and the potential immune modulatory effects of probiotics. The six-week-old LSL-K-rasG12D; Pdx-1-cre (KC) mice smeared P. gingivalis on the gums, causing pancreatic intraepithelial neoplasia (PanIN) after four weeks to be similar to the extent of lesions in untreated KC mice at 24 weeks. The oral inoculation of P. gingivalis of six-week-old LSL-K-rasG12D; Pdx-1-cre (KC) mice caused significantly pancreatic intraepithelial neoplasia (PanIN) after treatment four weeks is similar to the extent of lesions in untreated KC mice at 24 weeks. The pancreas weights of P. gingivalis plus probiotic-treated mice were significantly lower than the mice treated with P. gingivalis alone (P = 0.0028). The histological expressions of Snail-1, ZEB-1, collagen fibers, Galectin-3, and PD-L1 staining in the pancreas were also notably lower. In addition, probiotic administration reduced the histological expression of Smad3 and phosphorylated Smad3 in P. gingivalis treated KC mice. We demonstrated that oral exposure to P. gingivalis can accelerate the development of PanIN lesions. Probiotics are likely to have a beneficial effect by reducing cancer cell proliferation and viability, inhibiting PanIN progression, and cancer cell metastasis (Epithelial–mesenchymal transition, EMT). The transforming growth factor-β signaling pathway may be involved in the tumor suppressive effects of probiotics.

Oral–Gut Microbiome Axis in Gastrointestinal Disease and Cancer

“…In consistent, carriage of its key pathogen, P. gingivalis, positively correlates to higher risk and mortality in PDAC patients [ 145 , 195 , 196 ]. In a mouse PDAC model, oral administration of P. gingivalis accelerated cell proliferation and epithelial–mesenchymal transition, finally promoting PDAC progression [ 197 ]. Interestingly, intracellular P. gingivalis directly promoted tumor cell growth in human pancreatic cancer cell lines [ 198 ].…”

“…Collectively, the bidirectional crosstalk between oral and gut microbiomes can develop the oral-gut microbiome axis, which plays a crucial role in regulating pathogenesis of various human diseases, primarily in the GI system (see Tables 1-3). [85,188,190,191] Gut-pancreatic microbiome axis • Concomitant shifts in the gut, pancreatic, and tumor microbiomes of PDAC patients [188,190,191] • Overlap between gut and pancreatic microbiomes [85] Association with oral microbiome • Altered oral microbiome in PDAC patients [196,199] • Concomitant shifts in the oral, gut, and pancreatic microbiomes of PDAC patients [76] • Periodontitis was associated with increased PDAC risk and mortality [193,194] • Carriage of P. gingivalis was associated with increased PDAC risk and mortality [145,195,196] • Oral administration of P. gingivalis accelerated progression of PDAC in mice [197] Prevalence of oral microbiota • Fusobacterium in the gut, pancreatic, and tumor microbiomes of PDAC patients [85,196,200] It is noteworthy that the oral-gut microbiome axis improves prediction of pathogenesis and prognosis in the GI system. The meta-analysis has shown that oral microbiome changes are associated with the risk of GI cancer, including CRC, PDAC, and HCC, which can be a potential index for early detection [203].…”

The Landscape of Microbial Composition and Associated Factors in Pancreatic Ductal Adenocarcinoma Using RNA-Seq Data

“…The coexistence of these pathogens or opportunistic pathogen suggests an infected state of PDAC tissue and a potential anti-infection treatment for PDAC. Lactobacillus was reported to attenuate the progression of pancreatic cancer promoted by porphyromonas gingivalis in Kras G12D transgenic mice ( 31 ). Ralstonia is one of the emerging pathogens prevalent in the airways of individuals and keeps an increasing trend ( 32 ).…”

An Update on the Effectiveness of Probiotics in the Prevention and Treatment of Cancer

“…Li et al observed a significant upregulation in E-cadherin levels in HeLa cells and the inhibition of cancer cell migration in response to probiotic treatment [119]. Additionally, probiotic treatment lowered the expression of EMT-related markers (Snail-1 and ZEB-1) in pancreatic cancer mouse models [120]. Kefir, a probiotic fermented food, showed antimetastatic and antiangiogenic effects in murine breast cancer cells, leading to the upregulation of tissue inhibitors of MMPs (TIMPs) [121].…”