Increased colon cancer risk after severe Salmonella infection

BACKGROUND: Colon cancer constitutes one of the most frequent malignancies. Previous studies showed that Salmonella manipulates host cell signaling pathways and that Salmonella Typhimurium infection facilitates colon cancer development in genetically predisposed mice. This epidemiological study examined whether severe Salmonella infection, usually acquired from contaminated food, is associated with increased colon cancer risk in humans. METHODS AND FINDINGS: We performed a nationwide registry-based study to assess colon cancer risk after diagnosed Salmonella infection. National infectious disease surveillance records (1999-2015) for Dutch residents aged ≥20 years when diagnosed with salmonellosis (n = 14,264) were linked to the Netherlands Cancer Registry. Salmonella-infected patients were laboratory-confirmed under medical consultation after 1-2 weeks of illness. These datasets also contained information on Salmonella serovar and type of infection. Colon cancer risk (overall and per colon subsite) among patients with a diagnosed Salmonella infection was compared with expected colon cancer risk in the general population. Data from the nationwide registry of histo- and cytopathology (PALGA) and Statistics Netherlands (CBS) allowed assessing potential effects of age, gender, latency, socioeconomic status, genetic predisposition, inflammatory bowel disease (IBD), and tumor features. We found that compared to the general population, colon cancer risk was significantly increased (standardized incidence ratio [SIR] 1.54; 95%CI 1.09-2.10) among patients with Salmonella infection diagnosed <60 years of age. Such increased risk concerned specifically the ascending/transverse colon (SIR 2.12; 95%CI 1.38-3.09) after S. Enteritidis infection (SIR 2.97; 95%CI 1.73-4.76). Salmonellosis occurred more frequently among colon cancer patients with pre-infectious IBD, a known risk factor for colon cancer. Colon tumors of patients with a history of Salmonella infection were mostly of low grade. CONCLUSIONS: Patients diagnosed with severe salmonellosis have an increased risk of developing cancer in the ascending/transverse parts of the colon. This risk concerns particularly S. Enteritidis infection, suggesting a contribution of this major foodborne pathogen to colon cancer development

Single-Cell Analysis of Refractory Celiac Disease Demonstrates Inter- and Intra-Patient Aberrant Cell Heterogeneity

Background & Aims: Refractory celiac disease type II (RCDII) is a rare indolent lymphoma in the small intestine characterized by a clonally expanded intraepithelial intracellular CD3+surfaceCD3-CD7+CD56- aberrant cell population. However, RCDII pathogenesis is ill-defined. Here, we aimed at single-cell characterization of the innate and adaptive immune system in RCDII. Methods: Paired small intestinal and blood samples from 12 RCDII patients and 6 healthy controls were assessed by single-cell mass cytometry with a 39–cell surface marker antibody panel, designed to capture heterogeneity of the innate and adaptive immune system. A second single-cell mass cytometry panel that included transcription factors and immune checkpoints was used for analysis of paired samples from 5 RCDII patients. Single-cell RNA sequencing analysis was performed on duodenal samples from 2 RCDII patients. Finally, we developed a 40-marker imaging mass cytometry antibody panel to evaluate cell–cell interactions in duodenal biopsy specimens of RCDII patients. Results: We provide evidence for intertumoral and intratumoral cell heterogeneity within the duodenal and peripheral aberrant cell population present in RCDII. Phenotypic discrepancy was observed between peripheral and duodenal aberrant cells. In addition, we observed that part of the aberrant cell population proliferated and observed co-localization of aberrant cells with CD163+ antigen-presenting cells (APCs) in situ. In addition, we observed phenotypic discrepancy between peripheral and duodenal aberrant cells. Conclusions: Novel high-dimensional single-cell technologies show substantial intertumoral and intratumoral heterogeneity in the aberrant cell population in RCDII. This may underlie variability in refractory disease status between patients and responsiveness to therapy, pointing to the need for personalized therapy in RCDII based on patient-specific immune profiles

Schematic representation of the data management process.

<p>Number of patients in the two linked databases, as well as the number of patients excluded from further analyses according to each inclusion criterion.</p

Cumulative incidence of colon cancer in patients with <i>Salmonella</i> infection and in the general population.

<p>Cumulative incidence of colon cancer over attained age in patients with a reported history of <i>Salmonella</i> infection and in the general population. Inset: cumulative incidence of colon cancer in patients with any <i>Salmonella</i> serovar infection and in the general population. Main graph: cumulative incidence of colon cancer in patients infected with the two major <i>Salmonella</i> serovars (Enteritidis and Typhimurium), the other less often diagnosed <i>Salmonella</i> serovars combined, and in the general population.</p

Year of diagnosis IBD patients.

<p>Year of diagnosis IBD patients.</p

Colon cancer risk after <i>Salmonella</i> Enteritidis infection.

<p>Colon cancer risk after <i>Salmonella</i> Enteritidis infection.</p

Colon cancer risk by follow-up, <i>Salmonella</i> serovar and infection type.

<p>Colon cancer risk by follow-up, <i>Salmonella</i> serovar and infection type.</p

Increased colon cancer risk after severe Salmonella infection.

Colon cancer constitutes one of the most frequent malignancies. Previous studies showed that Salmonella manipulates host cell signaling pathways and that Salmonella Typhimurium infection facilitates colon cancer development in genetically predisposed mice. This epidemiological study examined whether severe Salmonella infection, usually acquired from contaminated food, is associated with increased colon cancer risk in humans

Cumulative incidence of cancer in the ascending and transverse parts of the colon.

<p>Cumulative incidence of cancer in the ascending/transverse colon over attained age in patients with a reported history of <i>Salmonella</i> infection and in the general population. Inset: cumulative incidence of cancer in the ascending/transverse colon in patients with any <i>Salmonella</i> serovar infection and in the general population. Main graph: cumulative incidence of cancer in the ascending/transverse colon in patients infected with the two major <i>Salmonella</i> serovars (Enteritidis and Typhimurium), the other less often diagnosed <i>Salmonella</i> serovars combined, and in the general population.</p