Many intestinal bacteria are believed to be involved in various inflammatory and immune processes that influence tumor etiology because of their metabolic properties and their ability to alter the microbiota homeostasis. Although many functions of the microbiota are still unclear, there is compelling experimental evidence showing that the intestinal microbiota is able to modulate carcinogenesis and the response to anticancer therapies, both in the intestinal tract and other body sites. Among the wide variety of gut-colonizing microorganisms, various species belonging to the Bifidobacterium genus are believed to elicit beneficial effects on human physiology and on the host-immune system. Recent findings, based on preclinical mouse models and on human clinical trials, have demonstrated the impact of gut commensals including bifidobacteria on the efficacy of tumor-targeting immunotherapy. Although the underlying molecular mechanisms remain obscure, bifidobacteria and other microorganisms have become a promising aid to immunotherapeutic procedures that are currently applied to treat cancer. The present review focuses on strategies to recruit the microbiome in order to enhance anticancer responses and develop therapies aimed at fighting the onset and progression of malignancies.
Keywords: microbiota, cancer, Bifidobacterium, microbial biomarker, probiotics
GENERAL FEATURES OF THE GUT MICROBIOTA
The definition of microbiome and microbiota is rather complex and often these two terms are used interchangeably. The microbiota represents the entire population of microorganisms colonizing a specific ecological niche, whereas the microbiome encompasses the full genetic complement of an entire microbiota (Ursell et al., 2012b). In recent years, many studies have focused on the analysis of the bacterial composition that inhabits various sites of the human body. In particular, the Human Microbiome Project (HMP), based on the concept that we are organisms made up of a large number of human and bacterial cells, aims to define the microbiome that consists and/or influences our metabolism, our physiology and any predispositions to diseases (Turnbaugh et al., 2007). The currently employed molecular techniques applied to the microbiota analysis, including the recently emerged metagenomic technology, are based on culture-independent methods. Their application have been made possible due to the advancement of next-generation sequencing methods (NGS),
The human microbiota comprises trillions of symbiotic microbial cells, present in different areas of the body. The majority of these are located in the intestine where they are involved in various functions including nutrient assimilation, vitamin synthesis, bile acid/salt and sterol metabolism, immune stimulation, and maintenance of intestinal homeostasis. Given the variety and importance of such functions, the intestinal microbiota operates as a separate organ of the human and animal superorganism (Brestoff and Artis, 2013; Guinane and Cotter, 2013; Molinero et al., 2019; Illiano et al., 2020).
The differences in bacterial composition in each microbial habitat are due to different environmental conditions such as pH, oxygen levels/redox state, availability of nutrients, humidity and temperature. All these environmental features allow various populations to thrive and exert different activities, while interac- ting with the (human) host environment (Ursell et al., 2012b).
The composition of the human intestinal microbiota is very complex and includes bacteria, archaea, fungi and viruses that have adapted to live on the mucous surface of the intestine or in its lumen (Nuriel-Ohayon et al., 2016), developing immediately after birth and varying between different gut locations, between individuals and over time. Until today, it has been assumed that the neonatal gut intestine was a sterile niche up until birth (Putignani et al., 2014), though various scientific reports have questioned this notion, claiming that bacteria are present in the gut before birth (Nuriel-Ohayon et al., 2016). However, a growing number of scientific publications have argued against such a possibility and most evidence currently favors the idea of a sterile placenta (Lauder et al., 2016). The period immediately following birth is deemed to be crucial for the appropriate development of the gut microbiota (Turroni et al., 2020). Vaginal delivery and breastfeeding are the main defining factors that favor efficient and correct microbial colonization events of the neonatal gastrointestinal tract (Milani et al., 2017a). Among the first colonizers of the infant gut microbiota are bifidobacteria (Turroni et al., 2012), rapidly populating the infant gut within the first weeks following birth. This remarkable phenomenon of gut colonization is believed to be at least partially dependent on the bifidogenic activities of specific mother milk- derived oligosaccharides, commonly referred to as human milk oligosaccharides (HMOs) (Turroni et al., 2019). Recent studies have shown that the bifidobacteria present in the mother’s gut microbiota strongly correlates with that of her baby, indicative of vertical transmission of bacteria from mother to baby (Rautava et al., 2012; Nuriel-Ohayon et al., 2016).
The transition to complementary feeding, and therefore the introduction of solid foods, favors the differentiation of the intestinal microbiota and increases microorganisms belonging to the families of Lachnospiraceae, Ruminococcaceae, Eubacteriaceae, Rikenellaceae, and Sutterellaceae (Laursen et al., 2016). During subsequent years, the microbiota develops to form its adult state and tends to maintain this homeostasis (Underhill and Iliev, 2014), which means that the microbiota
composition of a healthy adult gut is stable (Rodriguez et al., 2015). The intestinal bacterial profile in adulthood displays a high level of inter-individual variability, being influenced by a wide range of factors such as health status, dietary habits, use of antibiotics or other drugs, age, genetics, ethnicity and geography (Ursell et al., 2012b; Yatsunenko et al., 2012). The main bacterial phyla of the human gut microbiota encompass members of the Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Tenericutes, and Fusobacteria. Notably, the gut microbiota of adults are dominated by Firmicutes and Bacteroidetes, which together make up 90% of the human gut microbiota (Rajilic- Stojanovic et al., 2007). The adult gut microbiota composition is radically different from that of the infant’s intestine, in which Actinobacteria, and in particular bifidobacteria, are commonly the most numerous microorganisms (Turroni et al., 2012). In addition, the adult microbiota has proven to be more complex than that of infants in terms of the total number of bacteria and microbial diversity (Eckburg et al., 2005). The microbiota composition changes with aging and becomes less complex in terms of number of species and relative abundance in the elderly population (Claesson et al., 2011). Throughout life, diet influences bacterial colonization and persistence in the intestine, thus shaping the gut microbiota composition (Fuentes and de Vos, 2016). In this context, butyrogenic bacteria such as members of the genus Clostridium cluster XIVa, responsible of butyrate production, are more abundant in the fecal microbiota of omnivores than in the vegetarian microbiota, including humans. However, in response to a Western-based diet, which is characterized by the presence of low fiber levels and high fat intake, the bacteria responsible for fiber degradation, such as Prevotella, Succinivibrio, Treponema, and Bifidobacterium, are reduced in abundance. Conversely, a diet mainly based on meat causes an increase of bile-tolerant bacteria (e.g., Alistipes, Bilophila) to the detriment of the microorganisms involved in the metabolism of plant polysaccharides (Firmicutes) (Milani et al., 2016).
Gut microbiota plays a key role in maintaining and supporting human health. Any deviation from its “normal” composition, a condition for which the generic term dysbiosis was coined (Tamboli et al., 2004), is believed to herald the onset or the worsening of certain diseases, including autoimmunity, colorectal cancer, metabolic diseases, and bacterial infections (Prakash et al., 2011). Indeed, recent work has indicated that altered microbial communities and intestinal barrier impairment are associated with the development of a number of chronic inflammatory disorders, including inflammatory bowel disease (IBD), celiac disease, multiple sclerosis, rheumatoid arthritis, psoriasis, type 2 diabetes, allergic diseases, cardiovascular, and neurodegenerative diseases (Yu, 2018), some of which may directly or indirectly lead to cancer (Stidham and Higgins, 2018).
THE ROLE OF MICROBIOTA IN CARCINOGENESIS
Through their metabolic activities, intestinal bacteria are believed to influence various inflammatory and immune processes that are implicated in tumor etiology, such as in colorectal cancer (CRC) (Kinross et al., 2011; Clemente et al., 2012). CRC is one of the major causes of mortality in developing countries (Jemal et al., 2011). Even though it is well-established that a healthy environment and lifestyle reduce the risk of carcinogenesis, it is still extremely difficult to identify the triggering factor(s) of cancer in individuals, due to its multifactorial etiology (Hanahan and Weinberg, 2011). Currently, the incidence of cancer is still increasing, possibly and in part due to cancer-associated lifestyle choices such as smoking, “westernized” diet and physical inactivity. However, increased exposure to known carcinogens or suspected carcinogens may also be a contributing factor (Torre et al., 2015). Cancer may therefore result from the impact of various genetic factors acting in concert with a range of environmental and life-style associated insults (Garrett, 2015). Studies involving germ-free animals, i.e., animals without a resident intestinal microbiota, have provided compelling evidence for tumor-promoting effects of the microbial composition in spontaneous, as well as genetically or carcinogen-induced tumorigenesis in various organs (Schwabe and Jobin, 2013). Germ-free mice exhibit severe defects in their immunity system, with a near-absent mucous layer and altered IgA secretion (Gopalakrishnan et al., 2018a). Similarly, depletion of the intestinal bacterial microbiota in mice by means of antibiotic treatment, reduces the development of cancer in the liver and in the colon (Dapito et al., 2012; Yoshimoto et al., 2013). It has been suggested that common microbial inhabitants of the human gut, such as Escherichia coli, which normally coexist harmoniously with their mammalian host and promote intestinal homeostasis, may sometimes facilitate colorectal carcinogenesis (Cuevas-Ramos et al., 2010). Indeed, some virulent E. coli strains with acquired pathogenicity islands encoding for a multi-enzymatic machinery for the production of a peptide-polyketide hybrid genotoxin named colibactin, can colonize the human gastrointestinal tract and cause gut diseases (Sun and Kato, 2016). These particular E. coli strains are more commonly present in the mucosa of CRC and IBD patients and they induce double-strand DNA breaks, mutations and chromosomal rearrangements. They also modulate the tumor microenvironment favoring the emergence of senescent cells, which may affect tumor promotion and cancer progression via the secretion of growth factors (Dalmasso et al., 2014).
In addition, a recent report has demonstrated that intestinal bacteria belonging to the class of Gammaproteobacteria can influence the efficacy of cancer therapies by metabolizing the chemotherapeutic drug gemcitabine into its inactive form, commonly used to treat pancreatic ductal adenocarcinoma (PDAC) (Geller et al., 2017). Moreover, thanks to the current knowledge on the role of gut microbes in gastrointestinal carcinoma development, novel approaches targeting the gut microbiota represent a promising way to prevent cancer or at least to delay cancer cell proliferation (Brennan and Garrett, 2016). Therefore, the gastrointestinal microbiota appears to play opposing roles in both preventing and promoting carcinogenesis.
One of the main activities of the colonic intestinal microbiota is to acquire energy by fermenting dietary elements (e.g., polysaccharides) that are not metabolized by host enzymes or by the microorganisms residing in the upper gastrointestinal tract (GIT) (Rowland et al., 2018). Many of such indigestible carbohydrates, resistant to human digestion, enter the colon where they are metabolized by resident microbiota into short chain fatty acids (SCFAs) such as butyrate, propionate and acetate, which are in turn absorbed by the intestinal epithelial cells (IECs) through passive diffusion (Pryde et al., 2002). SCFAs, and in particular butyrate, represent the primary energy source for IECs and play an important role in maintaining the integrity of the associated epithelial layer (Lauder et al., 2016).
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