Table 1.

Colorectal cancer: Main results of animal studies.

Publication	Berry	Population/Model	Endpoint	Method	Treatment	Effect
Lala et al., 2006 [34] (a)	Bilberry	Fisher 344 male rats treated with azoxymethane n = 10 per group	1. Number and multiplicity of colonic aberrant crypt foci (ACF) 2. Colonic cell proliferation	1. Staining and light microscopy of colons 2. Proliferating cell nuclear antigen immunohistochemistry	AIN-93 powdered diet supplemented with 3.85 g monomeric anthocyanin bilberry ARE/kg for 14 weeks	1. Significantly reduced number of total and large ACF compared to control. Number of large ACF was reduced by 70% 2. Significantly decreased colonic cellular proliferation by nearly 50%
Cooke et al., 2006 [9] (b)	Bilberry	ApcMin/+ mice n = 16 per group	Number, location, and size of adenomas in gastrointestinal tract	Dissection after termination	Standard diet with ARE from bilberry (Mirtoselect): Group 1: 0.03%, Group 2: 0.1%, Group 3: 0.3% w/w of ARE in diet for 12 weeks	Significantly and dose-dependently reduced adenoma load compared to control (number reduced by 30% with highest dose). Reduced particularly the number of small adenomas dose-dependently in the small intestine
Misikangas et al., 2007 [38] (b)	Bilberry and lingonberry	C57BL/6J Min/+ mice, male and female n = 10–12 in group	Sum of adenoma areas	Dissection after termination	10% w/w freeze-dried bilberry or lingonberry in High-fat AIN93 diet for 10 weeks	Both berries significantly inhibited number of adenomas by 15–30% compared to control. Bilberry did not reduce the size of adenomas, but lingonberry reduced adenoma burden by 60%
Lippert et al., 2017 [35] (a)	Bilberry	Female Balb/c mice, Azoxymethane/dextran sodium sulphate mouse model n = 50 mice divided in 3 groups	Tumor growth and number	Colonoscopy at weeks 4 and 9, macroscopic and microscopic analysis after termination at week 9	Bilberry anthocyanin-rich extract 1% or 10% w/w of extract in diet for 10 weeks	Significantly smaller and less (almost no detectable tumors) in 10% ARE fed mice compared to controls or mice fed with 1% extract. Smaller and less tumors also with 1% extract compared to control, but difference not statistically significant
Mudd et al., 2020 [39] (b)	Bilberry	ApcMin/+ mice treated with antibiotics and infected with enterotoxigenic Bacteroides fragilis n = 6 per group	Tumor number	Dissection after termination	Bilberry anthocyanin extract on average 8.6 mg/kg body weight by gavage 3 times a week for 4 weeks	Significantly reduced tumor number approx. 50% compared to control
Wang et al., 2020 [37] (c)	Bilberry	Female C57BL/6 mice subcutaneously inoculated with MC38-OVA cells, receiving immune checkpoint inhibitor injections n = 6 per group	Tumor volume	Measured every 3–4 days with an electronic caliper	Bilberry anthocyanin extract 156 ug of anthocyanins daily for 27 days	Extract alone did not affect tumor volume compared to control, but significantly enhanced the effect of the drug, possibly through modulation of gut microbiota (effect was abolished by antibiotic treatment)
Liu et al., 2020 [36] (c)	Bilberry	Female C57BL/6 mice subcutaneously inoculated with MC38-OVA cells, receiving immune checkpoint inhibitor injections n = 6 per group	Tumor volume	Measured every 3–4 days with an electronic caliper	Standardized bilberry ARE (Mirtoselect, Indena S.p.A. Italy) 25 mg bilberry extract/kg body weight daily for 2 weeks	Extract was not tested alone but enhanced therapeutic effects of the drug. Enhanced tumor immune filtration was associated with improvement of tumor control.

Animal model type used: (a) induced carcinogenesis, (b) genetic model, and (c) xenograft.