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. 2022 Oct 21:13:954885.
doi: 10.3389/fimmu.2022.954885. eCollection 2022.

The beneficial effects of Lacticaseibacillus casei on the small intestine and colon of Swiss mice against the deleterious effects of 5-fluorouracil

Stphannie Jamyla de Araújo Barbosa  1 , Maisie Mitchele Barbosa Oliveira  2 , Susana Barbosa Ribeiro  3 , Caroline Addison Carvalho Xavier de Medeiros  2   4 , Maria Laura de Souza Lima  5 , Gerlane Coelho Bernardo Guerra  1   4 , Raimundo Fernandes de Araújo Júnior  6   7 , Francisco Caninde de Sousa Junior  8 , Agnes Andrade Martins  9 , Daniel Felipe Fernandes Paiva  9 , Raphael Victor Silva Andrade  9 , Conceição S Martins Rebouças  10 , Gerly Anne de Castro Brito  10 , Renata Ferreira de Carvalho Leitâo  10 , Aurigena Antunes de Araújo  1   5
Affiliations

The beneficial effects of Lacticaseibacillus casei on the small intestine and colon of Swiss mice against the deleterious effects of 5-fluorouracil

Stphannie Jamyla de Araújo Barbosa et al. Front Immunol. .

Abstract

Background: Intestinal mucositis is one of the most common and important side effects of 5-fluorouracil (5-FU). Currently, there are still no specific and effective protocols for its prevention and treatment. The aim of the present study was to evaluate the effect of oral administration of Lacticaseibacillus casei (L. casei) on the progression of 5-FU-induced intestinal mucositis. Methods: L. casei (1x109 CFU/ml) or saline was orally administered to Swiss mice, beginning 15 days before intestinal mucositis induction by single intraperitoneal 5-FU administration (450 mg/kg). Body weight, number of peripheral leukocytes and fecal lactic acid bacteria were monitored. After euthanasia, on day 18, tissue samples from colon and each small intestine segment were collected for histopathology. Jejunal tissues were collected and evaluated for iNOS and TNF-alpha immunoexpression, IL-1-beta, IL-6 and TNF-alpha levels, malonaldehyde (MDA) accumulation, invertase activity and factor nuclear kappa B (NFkB-P65) gene expression, toll like receptor-4 (TLR-4), mucin-2 (MUC-2), occludin and zonula occludens-1 (ZO-1).

Results: The positive impact of L. casei on 5-FU-induced leukopenia was observed, but not on 5-FU-induced weight loss in mice. L. casei reduced 5-FU-induced inflammation in the colon and small intestine (p<0.05). Decreased TNF-α, IL-1β, IL-6 (p<0.05) and MDA (p<0.05) levels, as well as decreased iNOS and TNF-alpha protein expressions (p<0.05) were found in the jejunum from L casei group. In addition, L-casei down-regulated NFKB-P65 (p<0.05) and TLR-4 (p<0.05) gene expressions and up-regulated MUC-2 and mucosal barrier proteins occludin and ZO-1 gene expressions (p<0.05). Furthermore, greater lactic acid bacteria population (p<0.05) was found in the L. casei group when compared to control groups.

Conclusion: Oral L. casei administration can protect the intestine of Swiss mice from 5-FU-induced intestinal mucositis, thus contributing to overall health.

Keywords: 5-fluorouracil; Lacticaseibacillus casei; chemotherapy; mucositis; probiotic.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Weight of the animals (1st day and 18th day of treatment) and the leukocyte count (mm³) in the blood after euthanasia. Groups: Saline, 5FU (5-fluorouracil) and L. Casei (Lacticaseibacillus casei). *p < 0.05, ***p < 0.001.
Figure 2
Figure 2
Histophatological analysis. Lacticaseibacillus casei (LC), prevented 5-FU-induced histopathological injuries in duodenum, jejunum, ileum and colon. 5-FU induces villi shortening (black arrows), loss of crypt architecture (green arrows) and intense inflammatory cell infiltrate (red arrows) in the duodenum, jejunum, ileum and colon, and edema (brown arrows) in the colon submucosal layer. H&E; scale bar corresponds to 200 µm.
Figure 3
Figure 3
Invertase activity, Malonaldehyde Dosage (MDA). Groups: Saline, 5FU (5-fluorouracil) and L. Casei (Lacticaseibacillus casei). *p < 0.05, ***p < 0.001.
Figure 4
Figure 4
Representing examples of iNOS immunostaining: Control (Saline; A), 5-FU (B); L. casei (LC; C) and percentage of iNOS immunolabeled cells (D). Values were expressed as mean ± SEM. For statistical analysis, one-way ANOVA was used followed by Tukey's test, where #p < 0.05 vs. control group, *p < 0.05 vs. 5-FU group. Magnification x400.
Figure 5
Figure 5
Representing examples of TNF-α immunostaining: Control (Saline; A), 5-FU (B); L. casei (LC; C) and percentage of TNF-α immunolabeled cells (D). Values were expressed as mean ± SEM. For statistical analysis, one-way ANOVA was used followed by Tukey’s test, where #p < 0.001 vs. control group, **p < 0.01 vs. 5-FU group. Magnification x400.
Figure 6
Figure 6
IL-1 beta, IL-6, TNF-α levels. Groups: Saline, 5FU (5-fluorouracil) and L. Casei (Lacticaseibacillus case). **p < 0.01, ***p < 0.001.
Figure 7
Figure 7
Quantification of gene expression. Beta actin, NFKB-P65, TLR-4, MUC-2 (mucine), OCLN (ocludine), ZO-1 (zonula occluden). Groups: Saline, 5FU (5-fluorouracil) and L. Casei (Lacticaseibacillus casei). *p < 0.05, **p < 0.01, ***p < 0.001.
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