Winnie-APCMin/+ Mice: A Spontaneous Model of Colitis-Associated Colorectal Cancer Combining Genetics and Inflammation

Santis, Stefania De; Verna, Giulio; Serino, Grazia; Armentano, Ricardo L.; Cavalcanti, Elisabetta; Liso, Marina; Dicarlo, Manuela; Coletta, Sergio; Mastronardi, Mauro; Lippolis, Antonio; Tafaro, Angela; Santino, Angelo; Pinto, Aldo; Campiglia, Pietro; Huang, Alex Y.; Cominelli, Fabio; Pizarro, Theresa T.; Chieppa, Marcello

doi:10.3390/ijms21082972

Cited by 9 publications

(14 citation statements)

References 27 publications

(31 reference statements)

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“…Both Control and Bronze tomato enriched diets did not affect mice weight, independently from the genotype. However, in line with our models ( De Santis et al., 2017 ; Liso et al., 2019 ; De Santis et al., 2020b ), Winnie mice showed a reduced body weight as compared to C57BL/6 littermates ( Figure 1D ). As expected, the majority of premature deaths were from mice carrying the Winnie allele (in homo- or heterozygosity), regardless of maternal diet.…”

Section: Resultssupporting

confidence: 84%

Polyphenol Enriched Diet Administration During Pregnancy and Lactation Prevents Dysbiosis in Ulcerative Colitis Predisposed Littermates

Santis

Scarano

Liso

et al. 2021

Front. Cell. Infect. Microbiol.

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Neonatal colonization of the gastrointestinal tract depends on mother microbiome, thus mother microbiota dysbiosis is transmitted to the offspring during the delivery and shaped by breastmilk characteristics. Here we used a murine model of UC predisposition (Winnie-/-) to evaluate the effects of maternal diet during pregnancy and lactation. Using heterozygous breeders, we obtained both Winnie-/- and C57BL/6 littermates from the same mother and compared their microbiota at weaning and adult age, using a diet enriched with 1% tomato fruit of a line – named Bronze – highly enriched in bioactive polyphenols, or Control tomato. Females received enriched diets two weeks before the beginning of the breeding and never stopped for the following six months. No significant effect was observed in regard to the percentage of Winnie-/- offspring, as with both diets the percentage was about 25% as expected. Winnie littermates from breeders fed with the Bronze-enriched diet showed reduced dysbiosis at 4 weeks of age if compared with Winnie under the Control tomato diet. This effect was then reduced when mice reached adult age. Conversely, the microbiota of C57BL/6 does not change significantly, indicating that fortified mothers-diet significantly contribute to preventing dysbiosis in genetically predisposed offspring, but has mild effects on healthy littermates and adult mice. An overall tendency towards reduced inflammation was underlined by the colon weight and the percentage of Foxp3+ cells reduction in Winnie mice fed with Bronze diet. Control diet did not show similar tendency.

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Section: Resultssupporting

confidence: 84%

Polyphenol Enriched Diet Administration During Pregnancy and Lactation Prevents Dysbiosis in Ulcerative Colitis Predisposed Littermates

Santis

Scarano

Liso

et al. 2021

Front. Cell. Infect. Microbiol.

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“…Even if APC Min/+ mice mainly developed small intestinal tumors and had a low rate of tumor incidence in the large intestine (as also demonstrated for mice housed in our animal facility) [ 43 , 44 ], we noticed an increased incidence of ACF in the distal colon of APC Min/+ mice born from heterozygous breeders for the Winnie mutation [ 40 ]. Thus, we decided to investigate the role of breeding couple genetics in ACF development.…”

Section: Resultsmentioning

confidence: 56%

“…To identify the microbial profiling promoting CRC development, we evaluated the microbiota of Winnie-APC Min/+ mice and their littermates obtained from breeders in a heterozygous state for the Winnie mutation (for male and female) plus the APC Min/+ mutation (only for male) [ 40 ]. Gene amplicon sequencing analysis of fecal material collected from 8-week-old mice reported 28,301.18 ± 17,409.02 number of reads per sample.…”

Section: Resultsmentioning

confidence: 99%

“…We firstly performed a histological analysis on the large intestine of 8-week-old APC Min/+ mice born from WT female and APC Min/+ male breeders. Table 3 shows the absence of dysplastic ACF incidence in the distal colon of APC Min/+ mice born from WT breeders as compared to those born from heterozygous breeders for the Winnie mutation [ 40 ]. However, occasional non dysplastic and dysplastic ACF in the form of unicryptic lesions and microadenoma > 5 crypts low-grade (LG) were detected in the medial colon of APC Min/+ mice born from WT breeders ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…For this reason, taking advantage of our recently established mouse model (the Winnie-APC Min/+ model) [ 40 ] that combines both an inflammatory background (Winnie mice) [ 41 ] and a genetic predisposition to develop small intestinal polyposis (APC Min/+ mice), in the present study we performed gut microbiota profiling to identify bacterial patterns supporting CRC tumorigenesis in genetically predisposed mice. In fact, Winnie mice, due to a single missense mutation (G9492A, GenBank accession no.…”

Section: Introductionmentioning

confidence: 99%

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Dysbiosis Triggers ACF Development in Genetically Predisposed Subjects

Santis

Liso

Vacca

et al. 2021

Cancers

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Background: Colorectal cancer (CRC) is the third most common cancer worldwide, characterized by a multifactorial etiology including genetics, lifestyle, and environmental factors including microbiota composition. To address the role of microbial modulation in CRC, we used our recently established mouse model (the Winnie-APCMin/+) combining inflammation and genetics. Methods: Gut microbiota profiling was performed on 8-week-old Winnie-APCMin/+ mice and their littermates by 16S rDNA gene amplicon sequencing. Moreover, to study the impact of dysbiosis induced by the mother’s genetics in ACF development, the large intestines of APCMin/+ mice born from wild type mice were investigated by histological analysis at 8 weeks. Results: ACF development in 8-week-old Winnie-APCMin/+ mice was triggered by dysbiosis. Specifically, the onset of ACF in genetically predisposed mice may result from dysbiotic signatures in the gastrointestinal tract of the breeders. Additionally, fecal transplant from Winnie donors to APCMin/+ hosts leads to an increased rate of ACF development. Conclusions: The characterization of microbiota profiling supporting CRC development in genetically predisposed mice could help to design therapeutic strategies to prevent dysbiosis. The application of these strategies in mothers during pregnancy and lactation could also reduce the CRC risk in the offspring.

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Mouse models in colon cancer, inferences, and implications

Kucherlapati

2023

iScience

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Winnie-APCMin/+ Mice: A Spontaneous Model of Colitis-Associated Colorectal Cancer Combining Genetics and Inflammation

Cited by 9 publications

References 27 publications

Polyphenol Enriched Diet Administration During Pregnancy and Lactation Prevents Dysbiosis in Ulcerative Colitis Predisposed Littermates

Polyphenol Enriched Diet Administration During Pregnancy and Lactation Prevents Dysbiosis in Ulcerative Colitis Predisposed Littermates

Dysbiosis Triggers ACF Development in Genetically Predisposed Subjects

Mouse models in colon cancer, inferences, and implications

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