Association between Probiotics and Modulation of Gut Microbial Community Composition in Colorectal Cancer Animal Models: A Systematic Review (2010–2021)

Zeighamy Alamdary, Shabnam; Halimi, Shahnaz; Rezaei, Akram; Afifirad, Roghayeh

doi:https://doi.org/10.1155/2023/3571184

Canadian Journal of Infectious Diseases and Medical Microbiology

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Abstract Introduction Methods Results Discussion Conclusion Conflicts of Interest Acknowledgments References Copyright Related Articles

Review Article | Open Access

Volume 2023 | Article ID 3571184 | https://doi.org/10.1155/2023/3571184

Association between Probiotics and Modulation of Gut Microbial Community Composition in Colorectal Cancer Animal Models: A Systematic Review (2010–2021)

Shabnam Zeighamy Alamdary,¹Shahnaz Halimi,¹Akram Rezaei,¹and Roghayeh Afifirad¹

Academic Editor: Tingtao Chen

Received18 Feb 2023

Revised09 Jul 2023

Accepted21 Jul 2023

Published09 Sept 2023

Abstract

Background. Colorectal cancer (CRC) is one of the most prevalent gastrointestinal malignancies and is considered the third major cause of mortality globally. Probiotics have been shown to protect against the CRC cascade in numerous studies. Aims. The goal of this systematic review was to gather the preclinical studies that examined the impact of probiotics on the alteration of gut microbiota profiles (bacterial communities) and their link to colorectal carcinogenesis as well as the potential processes involved. Methods. The search was performed using Scopus, Web of Science, and PubMed databases. Five parameters were used to develop search filters: “probiotics,” “prebiotics,” “synbiotics,” “colorectal cancer,” and “animal model.” Results. Of the 399 full texts that were screened, 33 original articles met the inclusion criteria. According to the current findings, probiotics/synbiotics could significantly attenuate aberrant crypt foci (ACF) formation, restore beneficial bacteria in the microbiota population, increase short-chain fatty acids (SCFAs), and change inflammatory marker expression. Conclusions. The present systematic review results indicate that probiotics could modulate the gut microbial composition and immune regulation to combat/inhibit CRC in preclinical models. However, where the evidence is more limited, it is critical to transfer preclinical research into clinical data.

1. Introduction

Colorectal cancer, a multifactorial gastrointestinal malignancy, is one of the most critical public health issues and the third leading cause of cancer mortality worldwide [1]. In recent years, the global prevalence of CRC has increased worryingly. In 2020, there were expected to be 1.93 million new CRC cases diagnosed and 0.94 million CRC-related deaths worldwide, accounting for 10% of global cancer prevalence (total 19.29 million new cases) and 9.4% of all cancer-related deaths (total 9.96 million deaths) [2]. Today, over 5.25 million (5-year prevalence) people are living with CRC globally. According to GLOBOCAN 2020 [3] estimates, there will be 1.15 million new cases of colon cancer and 0.7 million new cases of rectal cancer in 2020 worldwide. With continued growth, these numbers are expected to rise to 1.92 million and 1.16 million, respectively, in 2040. The gut microflora with bacteria as its predominant inhabitants helps the human immune system mature and maintain the natural barrier’s integrity. In a healthy individual, the structure and immune function of the colorectal epithelium preserve a mutually beneficial relationship between the microbiota and the host [4]. Indeed, a healthy microbiota prevents the proliferation and colonization of pathogenic bacteria by covering intestinal niches and fighting for nutrients. Several factors, including gene mutations, family history, dietary compounds, and microbial dysbiosis, might contribute to the improvement of CRC disease [5]. Among them, increasing research shows that CRC development is strongly correlated with gut microbiota dysbiosis. Microbial dysbiosis is linked to the production of carcinogenic agents, as well as inducing inflammatory responses, secondary bile acid synthesis, and metabolic signals that lead to malignant alterations in epithelial cells and, eventually, the prevalence of CRC [6, 7]. CRC patients have considerably reduced intestinal microbiota diversity and clearly altered microbial abundance compared to healthy people [8]. These days, the advancement of next-generation sequencing technologies has made it easier to analyze microbial composition and diversity. In a healthy and normal gut, the most prevalent bacteria mainly are two phyla, Firmicutes and Bacteroidetes, which account for approximately 90% of the microbial system [9]. Currently, specific species such as Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis, Peptostreptococcus stomatis, Parvimonas micra, and Campylobacter jejuni are enriched in CRC [10], in contrast to some beneficial species such as Bifidobacterium breve, Lactobacillus rhamnosus, and Akkermansia muciniphila which are poor in CRC subjects. Furthermore, the metagenome sequencing and metabolomics combination demonstrated that the CRC-associated microbiome can be a source of harmful metabolites (e.g., L-2 hydroxyglutarate, succinate, and fumarate). For example, B. fragilis, F. nucleatum, and some Prevotellaceae family have been reported to produce succinate [11, 12]. Several attempts have been made to fight and suppress colon cancer through dietary modifications by some nutritional alternatives in the colon lumen, mainly probiotics (live valuable microorganisms with the potential to enhance microbial balance in the host), prebiotics (nondigestible oligosaccharides), and synbiotics (probiotics and prebiotics combination). Different in vitro, animal, and clinical trials have indicated that probiotics as microbiota modulators and immune response regulators have antitumor efficacy with diverse mechanisms such as the competitive removal of pathogenic intestinal bacteria, enzyme activity alteration of intestinal microflora, decrease in carcinogenic secondary bile acids, attenuation of carcinogens and mutagens binding, and increasing SCFAs production [13–16]. In addition, reduced DNA damage and suppression of ACF development have been thoroughly demonstrated as direct and ideal anti-CRC effects of probiotics in the intestinal mucosa [7, 17].

Therefore, the goal of this study is to evaluate and collect high-quality preclinical studies through a systematic assessment to determine the safety and effectiveness of pro/synbiotics in CRC animal models. Indeed, we performed this systematic review on the studies that explicitly assessed the efficacy of probiotics on gut microbial (bacterial) community composition in CRC animal models and the effectiveness of probiotic supplements on proinflammatory marker alteration and SCFAs production was evaluated.

2. Methods

2.1. Guidelines

The guidelines defined by PRISMA were followed for this systematic review (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) [18].

2.2. Literature Search Strategy

A systematic search was conducted to evaluate the efficacy of probiotics in the CRC animal models with a focus on microbiota bacterial population. Original research papers were searched in three electronic databases (Scopus, Web of Science, and PubMed) up to December 22, 2021, by two researchers independently. Also, a search was undertaken for grey literature in Google Scholar. Besides, reference lists of all related systematic reviews and articles were monitored to eliminate any potential flaws in online databases and search engines. Initial searches were conducted using terms chosen from our research questions. The terms were “probiotics,” “prebiotics,” “synbiotics,” “colorectal cancer,” “colon cancer,” “CRC,” and also “mice,” “rat,” and “animal model” were searched to improve the results. The search strategy of each database was matched to its particularities. The reference lists of all articles included in this study were also checked for any relevant or ignored studies. After the initial search, two investigators screened the titles and abstracts and excluded articles that did not meet the inclusion criteria. If duplication of the same study was found, its data were included just once. And also, by manually searching Iranian medical laboratory websites, additional relevant papers were discovered and included in a standardized data extraction form. A third investigator double-checked the results to ensure that all eligible articles were considered. Eventually, an alert was set up based on our research keywords in all databases. The flow diagram of the article selection process is represented in Figure 1.

2.3. Eligibility Criteria

Studies included in the study met the criteria of being original studies in the animal CRC models, published in English and concerning the administration of probiotics and synbiotics in animal models with CRC. Non-English papers and nonoriginal articles (reviews, editorials, letters, congress papers, comments, abstracts without full text, and book chapters) were excluded. We had limited access to the Embase database, as well as studies that did not meet the eligibility criteria, i.e., (a) studies that used only prebiotics agents; (b) in vitro assays; and (c) clinical studies; and after excluding these items, specifically, studies evaluating microbiota populations were finalized. So, 33 studies that assessed bacterial microbiome compositions by three methods, including high-throughput sequencing, the PCR-denaturing gradient gel electrophoresis (DGGE) fingerprint method, and real-time PCR, were reviewed.

2.4. Data Extraction

Two reviewers independently coded and extracted the data from the 33 selected studies. Again, this process was supervised by a third researcher. The data extracted included the following: first author (year of publication), location, animals, number of animals (age range), probiotic types (strain type, doses), interventions, cancer agent and study duration, number of ACF, bacterial profile in gut microbiota, inflammatory markers, SCFAs, and fecal enzymes.

2.5. Risk of Bias Assessment

The risk of bias (RoB) in animal studies was assessed using the SYRCLE’s (Systematic Review Center for Laboratory animal Experimentation) tool [19]. This instrument is based on the Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials and is modified for biases specific to animal intervention studies [19]. The following methodological parameters were evaluated using standardized questions to guide the researcher’s judgment: Selection bias: “Sequence generation,” “Baseline characteristics,” “Allocation concealment”; Performance bias: “random housing” and “blinding of investigators regarding the intervention that each animal received during the experiment?”; Detection bias: “random outcome assessment,” “Was the outcome evaluator-blinded?”; Attrition bias: “Incomplete Outcome Data”; Reporting bias: “Is there any selective outcome reporting in the study’s reports?”; Other biases: “Other potential sources of bias that could lead to a high risk of bias.” The items in the RoB tool were graded with “Yes” (low risk of bias); “No” (high risk of bias); or “Unclear” (the item was not reported and or insufficient information and methodology; consequently, the risk of bias was unknown) (Figure 2).

3. Results

3.1. Literature Search and Study Selection

The search strategy submitted a total of 744 papers in the following databases: Scopus, Web of Science, PubMed, and Google Scholar. The process of study selection is shown in the PRISMA flowchart (Figure 1). In the second screening phase, 345 duplicate publications were removed, and 399 articles were retained for detailed full-text evaluation. Three hundred and seventy articles were excluded for the following reasons: articles were not original studies (comments, books, editorials, and reviews), there were no English language papers, studies of microbiome compositions were not evaluated; prebiotics were employed alone against CRC, unrelated cancers, and in vitro models alone. Four out of the 29 studies were removed due to the lack of full text (2 articles), and in two articles, there was no mention of the bacterial profile composition in probiotic groups. On the other hand, eight papers were added to our study by hand searching. Eventually, 33 articles describing the efficacy of the probiotics on CRC treatment in animal models, especially based on evaluating the microbiome population, were included in our analysis.

3.2. Characteristics of the Included Studies

The summarized characteristics of 33 studies are presented in Table 1. These studies were published from 1/1/2010 to 12/14/2021. The selected studies were performed in 13 different countries. The majority of the studies were conducted in China (16 out of 33 studies) [20–30]. Among the 33 studies, 28 trials used only probiotics (single or in combination with other probiotics) to investigate their impact on colon cancer [20, 21, 23–48]. Five trials used prebiotics as an intervention agent in combination with probiotics [22, 49–52]. Besides, as shown in Table 1, among the 33 studies, 8 studies used a combination of multistrain probiotic bacteria [22, 26, 28, 30, 37, 44, 46, 52]. In these 8 studies, L. acidophilus (4 studies) showed the highest number of combinations with other bacteria [22, 26, 37, 46]. Probiotic administration in a total of 33 studies was oral because it is safer, cheaper, and more controllable.

A total of 19 different probiotic species were administered daily at doses of 1 × 10⁷ to 6.4 × 10¹¹ colony forming units (CFU) alone and/or in combination with each other. Based on Figure 3, L. acidophilus, L. casei, and L. rhamnosus (18.2%) were the most common probiotics used by the included studies.

In these studies, some unique probiotics such as C. butyricum (2 trials) [20, 23], E. fecalis (1 study) [26], P. pentosaceus (1 trial) [40], and Kefir (1 trial) [43] were used as probiotic agents in CRC models. In 33 included preclinical studies, the major models used were mice (25 studies) [20, 23–31, 33, 35, 36, 38–40, 42, 45–52], the age of the animals ranged from 3 to 16 weeks, and the duration of the study was 28 days to 32 weeks. Among 33 articles included, the most prominent cancer agent was azoxymethane/dextran sodium sulfate (AOM/DSS) (14 studies) [23, 25–29, 33, 35, 36, 39, 40, 45, 46, 48]. The second most commonly used cancer agent was 1,2-dimethylhydrazine (DMH) as the inducing agent of preneoplastic lesions and tumors were induced, and the doses varied from 10 to 40 mg/kg (11 studies) [21, 22, 32, 34, 37, 41–43, 49–51]. In 3 studies, genetically modified animals, in which disease developed spontaneously, were used [20, 24, 31]. In addition, in 2 studies, CT-26 cell lines were used as cancer causes [30, 38]. In 2 trials, colorectal tumors were induced in animals by cyclic treatment with dextran sulfate sodium (DSS) [44, 52]. Finally, one study did not mention cancer agents [47].

3.3. Effects of Probiotics on Histopathological Characteristics

3.3.1. Analysis of Aberrant Crypt Foci (ACF) in Dealing with Probiotics

Five studies presented the results of the development of ACF after the animals were exposed to the carcinogen, and ACF was identified and analyzed by methylene blue staining in all studies [21, 34, 43, 49, 50]. ACF is recognized as a precancerous lesion of CRC (preneoplastic lesions) that persists, grows in the distal colon, and has the potential to progress to cancerous tissue. In these five references, probiotics alone or combined with prebiotics effectively reduced colon ACF incidence and multiplicity in the CRC models. In 2 studies [21, 34], L. salivarius [34] and L. rhamnosus [21] treatments showed a significant decrease in total ACF number compared with DMH-treated rats. Ali et al. [49] demonstrated the administration of L. casei, inulin, and synbiotic (L. casei + inulin) significantly decreased the number of ACF by three, five, and six times, respectively, compared to the DMH-treated group (). Besides, Cruz et al. [50] demonstrated synbiotic (yacon diet + VSL#3) consumption reduced the incidence of total ACF by 38.1% compared to the DMH group (). Interestingly, de Almeida Brasiel et al. [43] reported that intake of Kefir as potential probiotic fermented milk had no significant effect on the number of ACF between cancerous groups and Kefir-treated cancerous groups.

3.3.2. Epithelial Proliferation Changes in Probiotic Treated Animals

In six studies [20, 23, 25, 38, 45, 48], epithelial proliferation was assessed by Ki67 staining as a cell proliferation marker protein. The proliferation index was determined by counting the number of Ki67-positive cells per crypt. In 5 studies [20, 23, 25, 45, 48], probiotics significantly suppressed the proliferating cells per crypt in the colons of probiotic-treated mice. In one study by Chang et al. [38], Lactobacillus casei variety rhamnosus (Lcr35) supplementation did not affect intestinal crypt proliferative activity. Besides, Zhu et al. [34] evaluated colonic cell proliferation in rats by PCNA staining. They showed that Lactobacillus salivarius Ren suppressed the cell proliferation of colonic mucosa in cancerous rats.

3.3.3. Effect of Probiotic Treatment on Goblet Cell Percentages

In four studies [28, 29, 38, 49], the number of goblet cells was analyzed. In 3 studies, probiotics [28, 29] and synbiotic [49] administration prevented AOM/DSS and DMH-induced goblet cell loss in CRC models. On the other hand, Chang et al. demonstrated that Lcr35 at the highest dose did not significantly reduce goblet cell damage in the cancerous group [38].

3.3.4. Effects of Probiotics on Gut Barrier Integrity in CRC Models

The integrity of the gut mucosa and the intestinal epithelial barrier was examined by mucin-2(MUC2), adherence junction protein-1 (ZO-1), and tight junction (occludin) proteins in 4 studies [22, 28, 29, 51]. They found that the expression of these proteins declined significantly in the AOM/DSS [28, 29] and DMH [22, 51]-induced mice, and these alterations were dramatically reversed in cancerous animals treated with probiotics and synbiotics.

3.3.5. Effect of Probiotics on Inflammatory Cell Infiltration in the Colon

Hematoxylin and Eosin (H & E) staining results from 8 studies [23, 28, 29, 31, 43, 44, 46, 52] revealed that probiotics and synbiotics administration significantly reduced the degree of inflammatory cell infiltration and crypt damage in CRC animal models.

Altogether, the major effects of various probiotics on the development of histopathological parameters in CRC models were collected in this study including (1) Probiotic application alone or with prebiotics limited the development and incidence of ACF as preneoplastic lesions. (2) Probiotics suppressed the proliferation of intestinal tumor cells and upregulated their apoptosis. (3) Probiotics alone or in combination with prebiotics could help to recover and prevent goblet cell loss caused by CRC. (4) Probiotic and synbiotic administration ameliorated intestinal gut barrier integrity by enhancing some related proteins in CRC cancerous models. (5) Probiotic alone or with prebiotics moderated inflammatory cell infiltration in CRC animals.

3.4. Efficacy of Probiotics on Shifts in Fecal Microbiota Compositions

In Table 2, we summarized and identified the impact of probiotics and synbiotics on the relative distribution of bacterial communities in the gut microbiome at the phylum, family, genus, and species levels between cancer groups and probiotic/synbiotic-treated cancer groups.

3.4.1. Phylum Level

Based on Table 2, among 33 reviewed studies, the major predominant phyla were Bacteroidetes (10 studies), Firmicutes (9 studies), Proteobacteria (8 studies), Verrucomicrobia (5 studies), Actinobacteria (4 studies), and Deferribacteres (3 studies), respectively. The abundance of phylum Bacteroidetes decreased in 7 studies: 3 studies by synbiotics [22, 50, 51] and 4 studies by probiotics [27, 36, 39, 47]. Bacteroidetes increased in 3 studies [23, 33, 38] (2 studies by probiotics [23, 33], and one study by synbiotic [38]). And also, Firmicutes were assessed in 9 studies (out of the 33 studies) [20, 23, 27, 31, 38, 45, 47, 50, 51]. In 4 studies (4 out of the 33) [23, 38, 50, 51], Firmicutes declined significantly in treated CRC animals (2 studies by probiotics [23, 38] and 2 studies by synbiotics [50, 51]). But in 3 other studies, the Firmicutes level had an increasing trend by probiotic agents alone [31, 45, 47]. In Chen et al.’s study [20], Firmicutes/Bacteroides ratio was insignificant by C. butyricum in Apc^min/+ mice. Interestingly, in Cruz et al.’s study [50], Firmicutes level was increased by VSL#3 while it had a declining trend in the synbiotic + DMH animal group.

In 24% of studies (8 out of the 33 studies) that detected Proteobacteria in phylum level [22, 27, 28, 35, 36, 47, 50, 51], four studies identified an increment in treated CRC models (3 studies by probiotics (27, 28, 36) and one study by synbiotic [51]). In contrast, four articles showed a significant decreasing trend in the phylum of Proteobacteria in probiotics (2 studies [35, 47]) and synbiotics (2 studies [22, 50]) treated CRC animals. In addition, Verrucomicrobia as one of the most prevalent phyla in the gut microbiome was shown in 15% of studies (5 out of the 33 studies) [27, 33, 36, 47, 49]. In 3 studies, the prevalence of this phylum decreased notably in probiotic-treated cancerous models [33, 36, 47], While it developed in 2 studies by B. bifidum [27] and synbiotic [49]. Finally, Actinobacteria in 12% of studies (4 out of the 33 studies) [27, 31, 46, 51] and Deferribacteres in 9% of studies (3 out of 33 studies) [25, 26, 33] were identified in the phylum level.

3.4.2. Family Level

At the family level, Lachnospiraceae and Ruminococcaceae (in 5 studies) [20, 23, 27, 40, 50, 51] were reported as the main families among 33 included studies. In 2 studies by Wang et al. [27] and Chung et al. [40], the abundance of these two bacteria simultaneously in the family level increased dramatically by probiotic agents in cancer groups. Interestingly, dos Santos Cruz et al. [51] determined that Lachnospiraceae and Ruminococcaceae declined together by synbiotic (VSL#3 + PBY) intervention in CRC animals. In another study by Cruz et al. [50], the abundance of Lachnospiraceae at the family stage was raised in CRC models that received VSL#3 + Yacon as synbiotic agent. Surprisingly, C. butyricum had different effects on the abundance of the two families mentioned above. Liu et al. [23] showed that Lachnospiraceae decreased in C. butyricum-treated cancerous animals. On the other hand, in Chen et al.’s study [20], Ruminococcaceae were increased by treatment with C. butyricum in CRC groups. Furthermore, Lactobacillaceae had significant expansion in 3 studies [21, 40, 50] by P. pentosaceus [40], VSL#3 + Yacon [50], and LGG [21] in cancer groups. And also, Prevotellaceae were reported in 3 studies [21, 25, 33], with an increment in 2 studies by L. casei [33] and LGG [21] and a reduction by L. helveticus [25] in cancerous animals. Besides, the Porphyromonadaceae level was reduced in 2 studies by L. helveticus [25] and VSL# [36] in CRC involving animals. Moreover, Bacteriodaceae [21, 25] and Clostridiaceae [21, 50] were reported in two studies with an increasing trend in probiotic and synbiotic-treated CRC models. Eventually, in one study, Akkermansiaceae, as essential beneficial probiotic bacteria, were significantly enriched in response to the treatment of P. pentosaceus in CRC models [40].

3.4.3. Genus Level

At the genus level, in 13 out of 33 studies [21–23, 26–28, 39, 43–47, 50], Lactobacillus was the most predominant genus reported among included studies and improved notably by probiotic and synbiotic agents in CRC animal groups, and then Akkermansia as one of the main genera was discovered in 7 studies (7 out of 33 studies) [24, 27, 29, 39, 46, 48, 49]. Five out of 7 studies showed that this genus increased remarkably in probiotics-treated cancerous animal groups. But, in 2 studies, the Akkermansia genus declined in L. fermentum [39] and LGG [24] in groups challenged with CRC. Besides, Prevotella as butyric acid-producing bacteria at the genus level had a remarkable increase in 3 studies in probiotics-treated CRC-models [23, 30, 45]. But Rong et al. [25] and de Almeida Brasiel et al. [43] reported that the shifts towards the increased abundance of Prevotella in mice with colitis and tumors were lowered by L. helveticus NS8 and Kefir as probiotic agents. And also, Turicibacteria was shown in 5 studies [23, 27, 28, 42, 49]. In 4 studies [23, 27, 42, 49], it was increased notably by probiotics and synbiotics. In contrast, in one study by Wang et al. [28], the abundance of these bacteria decreased with a mixture of probiotics in CRC animal groups. Another dominant genus was Desulfovibrio which was reported in 5 trials [20, 26, 28–30], and in all studies, it was decreased significantly by probiotics agents in CRC groups. As well, the Helicobacter genus (in 4 out of 33 studies) had a contraction trend in probiotic and synbiotic-treated groups [20, 22, 29, 50]. Finally, Roseburia was reported in 4 studies with an increased trend by probiotics and synbiotics in CRC models [24, 28, 30, 50]. Totally at the genus level, probiotics exhibited a superior protective effect against CRC induction agents by enriching beneficial bacteria in the colon, such as Lactobacillus, Akkermansia, Prevotella, Turicibacteria, and Roseburia.

3.4.4. Species Level

Different Bacteroides spp. were identified in 5 studies [25, 30, 32, 33, 37]. According to Rong et al.’s study [25], Bacteroides acidifaciens increased and Bacteroides uniformis decreased by L. helveticus NS8 in groups in which AOM/DSS was inoculated into animals as a carcinogen. In addition, Lactobacillus spp. increased significantly in 5 studies [25, 37, 39, 45, 52] by probiotics alone or a mixture of probiotics. Finally, in 2 studies, different species of Bifidobacterium had an increment trend in Lactobacillus alone or mixed with other probiotics in cancerous models [25, 37].

3.5. Effects of Probiotics and Synbiotics on the Fecal Concentration of SCFA

Based on Table 2, in 10 studies, production of SCFAs along with microbiota composition was assessed [20, 24, 28, 29, 33, 34, 42, 44, 50, 51]. Seven studies showed that high levels of SCFAs secretion were observed in cancer groups receiving different species of Lactobacillus alone or in mixtures with Bifidobacterium [24, 28, 29, 33, 34, 42, 44], and Chen et al. [20] reported that the levels of acetic, propionic, and butyric acid () in the C. butyricum-treated cancerous mice were significantly higher than in cancerous groups. Moreover, two studies by Cruz et al. [50, 51] revealed that synbiotic-treated animals had higher concentrations of acetic, propionic, and butyric acids at all times.

Besides, only in one study [20], the levels of the fecal secondary bile acids (BAs) DCA and LCA were evaluated, and the primary BAs were not affected by C. butyricum treatment. The levels of the fecal secondary BAs DCA and LCA were markedly increased in the HFD-treated mice compared with the control (DCA: ; LCA: ). Surprisingly, the DCA and LCA levels in the C. butyricum group decreased significantly (DCA: ; LCA: ).

3.6. Fecal Enzymes Assay

Fecal enzymes, i.e., β-glucuronidase, azoreductase, and β-glucosidase have been implicated in converting procarcinogens into carcinogens; thus, the activity of these enzymes was assessed to deduce the modulating potential of probiotics in the colonic environment. Only three studies [34, 41, 50] reported changes in fecal enzyme activity in probiotic and synbiotic-treated groups (Table 2). In 2 studies, fecal enzymes were assessed along with bacterial microbiota compositions and SCFAs [34, 50]. Also, Zhu et al. [34] revealed that there was a significant decrease in azoreductase activity in LS-treated + DMH rats when compared to DMH rats, while the activities of β-glucosidase and β-glucuronidase were not significantly affected by LS treatment. Moreover, CRC animals receiving the synbiotic displayed a significant reduction in β-glucuronidase enzyme activity when compared to the control group. In addition, in both studies, SCFAs production was increased notably by probiotics and synbiotics.

3.7. The Effect of Probiotics on Inflammatory Marker Expression

The effects of probiotics on inflammatory marker expression were assessed in 20 studies [21–23, 25, 28, 29, 31, 33, 35, 36, 38–40, 42, 43, 45, 46, 48, 50, 52] (Figure 4). In these studies, 16 cytokines were assessed and quantified by western blotting, real-time PCR, and ELISA methods. Fourteen out of 20 studies (70% of preclinical trials) [23, 28, 29, 31, 35, 36, 38, 42, 43, 45, 46, 48, 50, 52] assessed TNF-α levels in cancer models that received probiotics, and in 57% of the included studies (8 out of 14 studies) [23, 28, 29, 38, 43, 46, 50, 52], TNF-α declined significantly in probiotic-treated groups. Besides, among the 20 preclinical trials, 13 trials (65% of studies) [21, 23, 28, 29, 31, 36, 38, 39, 42, 43, 48, 50, 52] analyzed the effects of probiotics on IL-6 levels. In 9 out of 13 studies (69% studies) [23, 28, 29, 31, 38, 39, 42, 43, 52], IL-6 levels decreased with probiotics treatment in CRC animal groups. While in 30% of studies (4 out of 13 studies) [21, 36, 48, 50], IL-6 changes were nonsignificant. The next prominent marker (INF-ɣ) was investigated in 9 out of 20 studies (45% of studies) [21, 35, 36, 42, 43, 45, 46, 48, 50]. The expression of this marker was nonsignificant in 44% of included studies [21, 36, 48, 50] and increased in 33% of studies [35, 42, 45] by probiotic agents in included studies. In 8 out of 20 studies (40% of trials) [21, 28, 29, 31, 42, 45, 48, 50], IL-17 expression was detected, and 50% of the included studies (4 out of 8 studies) [28, 29, 31, 42] showed a decrease trend in the probiotic-receiving group. But in 50% of studies, this change was unnoticeable [21, 45, 48, 50]. Moreover, the effect of probiotics on IL-1β levels was detected in 6 out of 20 studies (30% of included studies) [25, 28, 29, 36, 40, 43], and in 83% of included studies (5 out of 6 studies) [25, 28, 29, 40, 43], this marker declined significantly by probiotic agents. Finally, each of the following cytokines, including IL-1α [39], IL-13 [46], IL-18 [36], IL-21 [21], and IL-23 [36], was reported only in one study with no significant changes in probiotic treatment groups.

3.8. The Regulation of Signaling Pathways in Dealing with Probiotics

The effects of probiotics/synbiotics on the regulation of apoptotic markers were measured in 11 studies [20–23, 25, 31, 33, 38, 42, 45, 49] (Table 2). In these studies, NF-κB, Cox-2, Bcl-2, and β-catenin expressions were elevated in cancerous groups but depleted in probiotic and synbiotic-treated CRC groups. In two studies, da Silva Daurte et al. [42] and Gamallat et al. [21] found that LGG + DMH-treated animals had higher p53 expression (classic tumor suppressor gene) than DMH-treated animals. In three studies [21, 23, 38], probiotics administration reduced Bcl-2 expression while increasing Bax expression, demonstrating that probiotics could inhibit colorectal cancer development in animals by promoting the expression of proapoptotic genes.

3.9. Risk of Bias Assessment

The SYRCLE’s tool [19] was used to assess the methodological quality and potential risk of bias in the 33 included studies (Figure 2). Compared to randomized clinical trials, poor reporting in preclinical studies is a known issue. In this systematic review, the majority of preclinical trials showed a questionable risk of bias (unclear) in aspects such as describing their randomization, blinding process, and allocation process. Only two studies (6% of studies) mentioned blinding outcome assessors. The highest risk of bias was shown in the incomplete outcome data items (21% of studies). Most articles (88% of studies) were found free of other sources of bias. None of the articles were considered to show selective reporting. Consequently, the majority of assessments were scored as unclear risk of bias (53% of studies) and then low risk of bias (43% of studies) in the current 33 studies.

4. Discussion

CRC is the third most prevalent cancer in both men and women, and most of its environmental etiological factors, such as changes in dietary habits and lifestyles, can be regulated therapeutically to minimize the risk of disease development. Regular intake of probiotics would present a more effective anticarcinogenic effect in the early stages of CRC [53]. In the current systematic review (data analysis from 33 studies), we collected the outcomes of the effect of various probiotic strains alone or in combination with prebiotic supplements (as a synbiotic) on ACF incidence, gut bacterial populations, levels of inflammatory markers, and SCFAs metabolites levels with fecal enzyme secretion in CRC preclinical models (all factors were summarized in Figure 5).

ACF is recognized as a CRC precancerous lesion, and significant numbers of ACF are detected in full-blown CRC models. Increased ACF numbers are associated with a higher risk of CRC [54]. Based on five studies in the current review, the number and percentage of ACF decreased notably in CRC models that received probiotics [21, 34, 43, 49, 50]. And also, Cruz et al. [50] demonstrated that synbiotics administration reduced the percentage of ACF occurrence (38.1%) more than probiotic supplementation (19.8%) compared to the cancer group. Indeed, synbiotics were more effective than probiotics at reducing ACF development. The possible mechanisms of ACF failure by pro/synbiotics in CRC animals can be the following: (a) Prior pro/synbiotics supplementation (before induction of cancer agents) [55]. (b) Preventing DNA damage in the colon through the complex interaction of probiotics or their metabolites with cancer metabolites by increasing the number of fecal lactobacilli in the gut microbiome which may have inactivated some procarcinogenic enzymes such as β-glucuronidase, nitroreductase, and β-glucosidase enzymes, resulting in lower ACF counts [56, 57]. (c) Brief adherence of probiotics to the colonic epithelial cells may protect the epithelial barrier from carcinogens and their metabolites while also reducing the binding and contact time of epithelial cells to carcinogens [58, 59]. (d) A positive correlation between ACF incidence and decreasing fecal pH (acidification of the colonic content) by SCFAs produced by probiotics [50]. (e) High-level secretion of IFN-γ as an antiproliferative and antiangiogenic protein by some probiotics and its noticeable apoptotic activity, which may diminish ACF [21]. It is worth noting that the observed difference in percentages of ACF reduction by different probiotics could be attributed to the fact that probiotic response is species- and strain-specific.

In this systematic review, we have focused on the association between probiotic/synbiotic supplementation and the regulation of gut microbiota bacterial profiles in CRC animal models. Lactobacillus and Bifidobacterium were the most widely investigated probiotic bacteria, followed by C. butyricum (2 studies) and P. pentosaceus (1 study). These reviewed studies have reported that probiotic intervention (single/mix) or along with prebiotics (synbiotic) markedly improved the abundance of microbiome-friendly bacteria such as Lactobacillus, Bifidobacterium, Akkermansia, Romboutsia, and Roseburia in the preclinical CRC context. Besides, based on ten studies [20, 24, 28, 29, 33, 34, 42, 44, 50, 51] in this review that assessed SCFAs along with bacterial communities in microbiota, SCFAs-producing bacteria showed an increasing trend along with higher production of SCFAs in pro/synbiotic-treated groups. These bacteria included the following: (1) Turicibacter has been linked directly to the production of butyric acid, which acts as an immunomodulator with anti-inflammatory activity in Cruz et al. and da Silva Duarte et al.’s studies [42, 50]. (2) Increased abundance of Roseburia as a butyrate and short-chain fatty acid-producing bacteria, along with high butyric acid levels in 3 studies [24, 28, 50]. (3) Increasing prevalence of Clostridium XI and Clostridium XVII (as important butyrate producers) [20] after probiotic/synbiotic supplementation with high levels of butyric acid production in CRC models [34, 50]. (4) High proportion of Lachnospiraceae (SCFAs producing bacteria) in family, genus, and species levels along with an increase in butyrate in Zhu et al. [34], Wang et al. [28], and Cruz et al.’s [50] studies. (5) Greater relative abundance of Prevotella and Alloprevotella from the Prevotellaceae family with higher butyric acid levels [33, 34]. (6) Ruminococcaceae and Eubacterium, which are well known to produce SCFAs, were elevated together with total SCFAs in a study by Chen et al. [20]. (7) Enrichment of Lactobacillus, Bifdobacterium, Akkermansia, and Faecalibaculum that is produced simultaneously by L. coryniformis MXJ32 with high levels of SCFAs [29]. Besides, treatment with a probiotics mixture showed a significant increase in some SCFAs-producing bacteria simultaneously, including Lachnospiraceae_NK4A136_group, Faecalibaculum, Roseburia, and lactobacilli in 2 studies [28, 44]. Indeed, SCFAs as beneficial metabolites of gut microbiota have multiple pathways to ameliorate CRC, including suppressing bacterial pathogens [60], regulating cell proliferation and differentiation [61], preserving colonic epithelial health, reducing inflammation, and inhibiting histone deacetylases[62]. Butyrate-producing bacteria, in particular, are more prominent since butyrate acts as a histone deacetylase inhibitor, modulating the expression of oncogenes and boosting the secretion of anti-inflammatory cytokines [63]. However, it is worth noting that some of these beneficial bacteria in response to probiotics showed contradictory manners in current reviewed studies. For example, at the family level, Lachnospiraceae and Ruminococcaceae as SCFAs producing bacteria decreased dramatically in two studies [23, 51] in response to pro/synbiotics. Besides, Turicibacter, surprisingly, showed a negative correlation with butyrate in Wang et al.’s study [28]. Also, the Akkermensia genus, as a type of Gram-negative bacteria and a promising probiotic candidate, declined in two studies [24, 39] in response to probiotic treatment in cancerous groups.

Furthermore, β-glucuronidase, β-glucosidase, and azoreductase bacterial enzymes are associated with the conversion of procarcinogens to potential carcinogens in the colon by the release of cytotoxic and genotoxic metabolites [14, 64]. Modulating the activity of these bacterial enzymes could be one of the mechanisms by which probiotics could minimize exposure to carcinogenic substances and hence reduce colorectal cancer development. For instance, the genera Bifidobacterium and Lactobacillus displayed minimal β-glucuronidase activity for modifying the microbiota [65]. In addition, based on two studies [41, 50] in our review, β-glucuronidase activity decreased in response to probiotic and synbiotic supplementation. While Zhu et al. [34] identified β-glucosidase and β-glucuronidase showed no alterations in L. salivarius-treated cancerous animals, still azoreductase activity was reduced in this group, indicating a possible protective effect against carcinogenesis by decreasing levels of carcinogen activation and DNA mutation.

Based on 33 reviewed papers, it was demonstrated that many immune pathways inhibit carcinogens by probiotics in animal CRC models that these potential and diverse pathways briefly include the following:(1)Protective effects of pro/synbiotic against colon cancer through increasing the phosphorylated JNK-1 expression as well as boosting beneficial bacteria in the colon such as Akkermansia and Turicibacter while decreasing the expression of phosphorylated GSK3b and β-catenin [49].(2)Probiotics might be able to suppress inflammation and improve mucositis in the intestine by inhibiting NF-B activity (which upregulates proinflammatory cytokines TNF-, IL-1, and IL-6), and TNF- and IL-6 proinflammatory effects could be reduced by taking probiotics [38].(3)Reducing pathogenic bacteria and infiltration of CD68⁺ macrophages (limiting macrophages recruitment) and then a significant reduction in proinflammatory markers such as IL-1α, IL-1β, and IL-6 by probiotics [39].(4)A marked increase in IL-2 and IL-4 by probiotic and synbiotic in CRC models which results in the regulation of immune cells and antitumor defense [50, 66].(5)The increased IFN-γ protein secretion by LGG (probiotic) in CRC animals is consistent with the considerable apoptotic activity, immune-regulatory function, antiproliferative, and anticancer strategies of IFN-γ [21].(6)Probiotics induce apoptosis in CRC tumors by significantly decreasing Bcl-2 levels while increasing Bax, caspase-3, and p53 expression. In addition, probiotics block Cox-2, which activates the downstream target proapoptotic protein p53, which links to tumor suppression [21, 67, 68].(7)Inhibitory effect of probiotics on Bacteroides that releases metalloprotease and fragilysin toxins which help CRC promotion through boosting IL-17a production and inducing E-cadherin cleavage [21, 69].(8)Beneficial effects of a strain of Lactobacillus reuteri in a model of CRC by a histidine decarboxylase (HDC), which downregulated IL-22 expression levels that were enhanced in tumor tissues [45, 70].(9)Attenuating the over-activation of TLR4/NF-κB in the CRC models by probiotics and inhibiting inflammation by preventing the release of certain reinflammatory cytokines (TNF-α, IL-1β, and IL-6) and CXCR2 ligand chemokines (CXCL1, CXCL2, CXCL3, CXCL5, and CCL7) [29].(10)Great probiotic potential and anti-inflammatory effect of Lactobacillus by downregulating proinflammatory markers such as IL-6, IL-17 F, and IL-22 [31, 71, 72].

It is worth mentioning that none of the concluded studies reported a reverse or negative effect of probiotics against CRC in animal models except the Arthur et al.’s study [36]. In this study, an unexpected result of consuming VSL#3 probiotic was the lack of an inhibitory effect on tumorigenesis and the tendency to enhance tumor invasion in AOM/Il10^−/− mice. They have previously shown that inflammation affected the composition of the intestinal microbiota in Il10^−/− mice, leading to an increase in Proteobacteria, which influenced CRC formation. In the current study [36], they demonstrated that VSL#3 administration after the initiation of inflammation and dysbiosis can boost tumorigenesis and primarily induce the elimination of beneficial bacteria such as Clostridium.

Together, these 33 studies have revealed that the anti-CRC effects of probiotics arise through alteration of the composition of the microbiota by various mechanisms, including (i) probiotics promote microbiota hemostasis by competing with putrefactive and harmful bacteria, reducing their abundance while increasing the number of LAB bacteria. (ii) In spite of their strong adhesion to the intestinal epithelium, probiotics are noninvasive and inhibit pathogen adhesion to the intestine [22, 73]. (iii) By lowering the pH of the environment, probiotics inhibit the proliferation of detrimental bacteria, and during this period, beneficial bacteria flourish in the acidic environment, balancing the intestinal microbiota [74]. (iv) Antimicrobial substances produced by probiotics in microbiota include bacteriocins, deconjugated bile acids, reuterin, hydrogen peroxide, and lactic acid, which can be used by probiotic microbiomes as a means of inhibiting pathogenic and carcinogenic bacteria populations [75]. (v) In addition to reestablishing gut microbiota balance, probiotics stimulate the secretion of anti-inflammatory cytokines by regulatory T (Treg) cells and IgA in intestinal epithelial cells and decrease proinflammatory pathways (through decreased levels of IL-1β, IL-6, and TNF-α). A study by Gao et al. found Roy’s Lactobacillus can suppress the incidence of inflammation-related CRC in mice by secreting histamine, and this suppresses tumor growth by producing histamine [70]. (vi) Probiotics improve SCFAs as bioactive metabolites of bacteria, regulating gastrointestinal microecology and energy balance as well as the CRC cell proliferation inhibiting through the Wnt/ß-catenin pathway. (vii) By modulating the activity of fecal bacterial enzymes such as β-glucuronidase, β-glucosidase, and nitroreductase, probiotics can significantly change the metabolism structure of detrimental bacteria in the gut microbiota. (viii) Probiotics increase mucin production and tight junction protein expression to improve gut-barrier function.

4.1. Strengths and Limitations

Taken together, the remarkable strength of this systematic review is that we have presented all the latest preclinical papers that investigated the potential beneficial effects of probiotics in addressing colorectal cancer animal models by focusing on microbiome bacterial populations. In addition, histopathological changes, signaling pathways, inflammatory markers alteration, short-chain fatty acids, and fecal enzyme release were gathered systematically in these studies. Nevertheless, there are some limitations in our study because of the different methodological designs and protocols of the included studies such as the use of diverse ranges of probiotic strains, prebiotics products, and cancer induction agents, as well as the administration of lots of dosages with different duration of treatment and different pathways for the preparation of probiotic supplements in these studies, which prevented us from drawing absolute conclusions and pooling the included studies in a meta-analysis. Despite this heterogeneity, we tried to collect some homogeneous data based on 33 studies; these include (1) the bacteria which are the most beneficial? Based on Figure 1 and Table 1, 85% of studies used members of the genus Lactobacillus alone or in a mixture with other probiotics with strong positive effects on modulation of gut microbiota composition by enriching beneficial bacteria, especially Lactobacillus, Akkermansia, Prevotella, Turicibacteria, Roseburia, and other markers. (2) the dose of which probiotics administration is the most effective? The analysis of probiotic dosage revealed significant differences among the 33 studies. A total of 19 different probiotic species were administered daily orally at doses of 1 × 10⁷ (in mice) to 6.4 × 10¹¹ (in rats) CFU in two best-recommended averages ≥10⁹ and ≥10⁸ CFU, respectively, displaying the best achievement such as improving the abundance of gut microbiota-friendly bacteria. (3) How many weeks was the best time to study? The duration of studies ranged between 4 and 24 weeks in three categories, as follows: (1) study period from 4–10 weeks, (2) 11–20 weeks, and (3) study period more than 20 weeks. Despite the broad study period in 33 studies, the positive effects of probiotic treatment on increasing beneficial bacteria and reducing cancer damage were demonstrated in all study periods, including the lowest and highest study periods. (4) cancer modeling agent with which optimal dosing is best? Since the optimal method and gold standard for tumor induction in CRC animal models have not yet been established, two major classes of cancer agents were discussed in these 33 studies, respectively: (1) AOM with a concentration of 8–12 mg/kg in a period between five days and six weeks, (2) 30 mg/kg and 40 mg/kg DMH used in rats in the induction period (2–10 weeks), as well as 10 mg/kg and 20 mg/kg in mice DMH (6–20 weeks). Since not all probiotics strains exhibit anti-CRC activities, screening the potent strain for the development of a probiotic-based therapeutic agent to control or prevent the incidence of CRC is crucial, and as regards, 85% of these 33 original studies used Lactobacillus species alone or mixed with other probiotics. With superior effects on CRC attenuation and successful modulation of the bacterial population in the microbiota, the Lactobacillus genus can be suggested for comprehensive clinical studies in the treatment of colon cancer and promoting the reproduction of beneficial bacteria in the gut microbiota.

5. Conclusion

Since the precise mechanisms of probiotics for ameliorating human CRC as a multifactorial cancer, and circumstances of rapid shifts of the bacterial microbiota compositions from health to disease are still poorly understood, standard protocols must be applied in preclinical settings in order to ensure reproducibility and generalization of probiotics function results to clinical studies and develop treatment pathways based on a balance in fecal microbial structure. On the other hand, since animal metabolisms differ markedly from those of humans, animal models may not always reflect what occurs in humans. It is suggested to conduct additional studies, particularly long-term, randomized double-blind, placebo-controlled clinical trials to clarify and confirm preclinical findings in dealing with probiotics prior to advising their routine use as an adjunctive therapy for CRC prevention and treatment. Finally, the combination of CRC cell line studies, animal models, and clinical trials will help researchers develop a comprehensive picture of probiotic therapeutic pathways for guiding health care policies in the global fight against CRC.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

This study was financially supported, in part, by TUMS Office of Vice Dean for Medical Research at the Tehran University of Medical Sciences (Grant No. 49528-101-2-99).

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Copyright © 2023 Shabnam Zeighamy Alamdary et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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