The microbiota, secondary metabolites and diseases: a putative role of probiotics in prevention and treatment of cancers

doi:10.21203/rs.3.rs-1707313/v1

Live and nonpathogenic microorganisms are called probiotics which are proved to be beneficial for their host. They play a key role on treatment and inhibition of infectious and non-infectious diseases. Since cancer is considered the main cause of death worldwide, it is important to find some strategies for reducing the side effects of chemotherapy. One of the key characteristics of probiotics is their role in treatment and recovery of different kinds of cancers by secondary metabolites which are produced by them. Up to date, different species of probiotics affecting cancer treatment have been explored. In this review, the relationship between probiotics and treatment of different diseases like cancers are investigated in order to use these crucial microorganisms in treatment of different neoplastic diseases.

Probiotics

Metabolites

Cancer

Therapeutic

Disease

The root of the word ‘probiotic’ is Greek, meaning “for life”. They are nonpathogenic microorganisms which can equilibrate the nutritional and immunological content of the host body, in addition to stop establishment of pathogenic microorganisms [1]. Many different factors like age, diet, pancreatic enzymes, intestinal lumen conditions, stress, drug and life style can influence on the type and amount of probiotics [2]. A number of studies have found the effect of probiotics on controlling allergies, blood cholesterol level as well as modulation of immune system. Also their role in pathological conditions like gastroenteritis, ulcerative colitis, pouchitis, crohn’s disease, urinary tract infections and vaginitis have been proved. Furthermore they appear as a great potential for cancer prevention and treatment [3]. Their metabolic activities are what have a crucial function in this process [4]. And finding the mechanism of their action in cancer prevention is interesting [5]. Some of these mechanisms include: regulation of intestinal microbiota composition and activity, attachment and degradation of carcinogenic compounds in intestinal lumen, production of anticarcinogenic compounds, modulation of immune system, prevention of proliferation; and induction of neoplastic cells’ apoptosis [6].

Considering composition and function of probiotics, there are different types of these bacteria. It is estimated that there are over 1000 species of them and the total number equals 10¹⁴ [7]. Interestingly the majority of strains are normal microbiota [8], So many strains of microbes have been investigated to find that if they have probiotic activities. Some species have been proposed for this activity including Lactobacillus and Bifidobacteria which are existed in probiotic food products and species like Enterococcus, Saccharomyces, Escherichia, Sporolactobacillus, Brevibacillus, and Bacillus[9].

Table 1

bacterial and fungal probiotics and their species
Bacteria	Species	References
Actinomyces	israelii	[10]
Prevotella	nigrescens	[10]
Porphyromonas	gingivalis	[10]
Pseudomonas	aeruginosa	[10]
Lactobacillus	sporogenes acidophilus	[11]
	casei delbreuckii	[12]
	Bulgaricus rhamnosus Paracasei Reuteri	[13]
	plantarum	[8]
	fermentum johnsonii	[10]
	gasseri kefiri crispatus	[14]
	confuses sobrius	[15]
Pediococcus	Pentosaceus freudenreichii	[14]
Pediococcus	acidilactici	[16]
Staphylococcus	aureus	[10]
Propionibacterium	Freudenreichii	[15]
Acetobacter	syzygii	[13]
Bifidobacteria	bifidum	[11]
	animalis	[17]
	longum lactis	[12]
	adolescentis breve infantis	[13]
Bacillus	cereus subtilis licheniformis polyfermenticus clausii coagulans polymyxa pumilus laterosporus	[11]
	velezensis	[18]
	mesentericus	[15]
Lactococcus	lactis	[15]
Brevibacillus	laterosporus agri borstelensis	[11]
Streptococcus	cremoris	[12]
	salivariussubsp .Thermophilus	[13]
	mutans intermedius	[10]
Sporolactobacillus	inulinus kofuensis lactosus nakayamae terrae	[9]
Enterococcus	faecium faecalis	[15]
	durans	[13]
	hirae LD3	[19]
Escherichia	coli strain Nissle 1917	[20]
Butyrivibrio	fibrisolvens	[21]
Clostridium	butyricum	[11]
Streptomyces	hygroscopicus violaceoruber coelicolor	[22]
Fungi	Species	References
Saccharomyces	cerevisiae var. boulardii	[1]
Saccharomyces	kluyveri pastorianus exiguous boulardi	[23]
Candida	pintolopesii Saitoana Tropicalis humilis	[1]
Candida	cleridarum glabrata	[23]
Debaryomyces	hansenii occidentalis	[1]
Kluyveromyces	lactis lodderae marxiamus	[1]
Pichia	kluyveri kudriavzevii	[1]
Pichia	anomala rhodanensis spartinae pastoris philogaea	[23]
Issatchenkia	Orientalis	[1]
Meyerozyma	Caribbica	[1]
Cryptococcus	Albidus	[1]
Torulaspora	Delbrueckii	[1]
Metschnikowia	Gruessii	[23]
Phaffia	rhodozyma	[23]
Xanthophyllomyces	dendrorhous	[23]

Dissolved bioactive compounds produced by probiotics play an important role in growth prevention of tumor cells [13]. Furthermore; gastrointestinal microbial products (e.g. butyrate, indoles, bile acids) regulate the function of host immune system in carcinogenesis [24]. The final product of anaerobic bacteria fermentation of dietary fiber is short chain fatty acids (SCFA) including acetate, n-propionate, and n-butyrate [25]. SCFAs are the connection between diet, host microbiota and energy metabolism. It is suggested that about 10% of our daily energy is provided by SCFAs. Several studies demonstrated that 62% of propionate infused to mice is used for glucose synthesis. This process provides the 69% of needed glucose as well as palmitate and cholesterol synthesis from substrates like butyrate and acetate in the absence of propionate. These results highlight the major role of SCFAs produced by probiotics for metabolism of glucose, cholesterol and lipids[11]. The energy substrate for epithelium and peripheral tissues of colon are butyrate and acetate respectively. The absorption of butyrate occurs via gut and it plays a crucial role in: colon steadiness, prevention of some disorders like cancer and chronic inflammation; and in inhibition of inflammation in diseases like ulcerative colitis and colon cancer [26]. A recent study has suggested that epigenetic modulation of gene expression is done by butyrate via histon deacetylase (HDAC) prevention. These modulations have anticarcinogenic, chemopreventive, neuroprotective, anti-inflammatory impacts. Moreover they are claimed that have effect on obesity, insulin resistance, cardiovascular diseases, immunoregulation and inherited disorders. Transportation of epithelial ions as well as colonic water is affected by butyrate. For instance butyrate can decrease the secretion of Na⁺, K⁺ and Cl⁻; therefore it is effective in treatment of congenital chloride diarrhea. G-protein coupled receptors (GPCR) are regulated and activated by butyrate so that the intestinal immune system is balanced via regulating the tolerance to commensals and immunity to pathogenic bacteria. Cholinergic enteric neurons ratio is raised through epigenetic modulation by butyrate. So that it has an impact on secretion of gut hormone into the enteric nervous system (ENS) and then vagus nerve is stimulated to induce endocrine signaling which can affect brain function [5]. The expression of Also it is indicated that tyrosine tyrosine peptide (YY) can be reverted by propionate and acetate. As a result, the risk of colon cancer decreases. Intestinal pH is decreased via producing SCFA which is harmful for pathogens whereas it increases the absorption of nutrient in intestine. It is claimed that Bifidobacteria can constrain enteropathogens by producing acetate [25]. β-glucuronidase is a faecal enzyme produced by entheropathogens like E. coli and Clostridium perfringens, hydrolyzes glucuronide. Glucuronide is necessary for eliminating external compounds and produces carcinogenic aglycons in intestinal lumen [8]. Moreover, detoxifying carcinogens, decreasing cholesterol serum level and also lactose intolerance, producing vitamins and metabolites like organic acids, bacteriocins and H₂O₂ are some instances of what probiotics play an important role in [27]. Lowering cholesterol level by probiotics like lactic acid bacteria is vital because its higher level results in cardiac diseases [15]. Since lactobacilli and bifidobacteria are including active bile salt hydrolase (BSH), they are claimed to have decreasing effect on cholesterol levels. There are some evidences which confirm they do this process by interaction with host bile salt metabolism. As a substrate of bile acids, cholesterol is changed to bile acids resulted in lower cholesterol serum level[16]. It is also confirmed that lactose intolerance problems can be alleviated by probiotics. The person with lactose intolerance is not able to produce the enzyme named lactase or B-galactosidase. So the person is advised to not take the diet containing milk. This state may resulted in calcium deficiency in lactose intolerance patients. However, fermentation of undigested lactose is done by probiotics in gut which is resulted in lower pH conditions and better calcium absorption. So feeding probiotics could be significantly beneficial for these patients [15]. It has proven that there are lots of different bioactive factors taken from probiotics, besides to SCFAs, which show immune modulation functions, including exopolysaccharides, peptidoglycan, single layer proteins, lipoteichoic acids, conjugated linoleic acids and peptides [26].

Table 2

Secondary metabolites produced by probiotics and their activity in human health
Secondary Metabolites Produced by Probiotics
Short-chain fatty acids (SCFAs)		Types	R	Probiotics	R	Activity	R
		Acetic acid	[1]	Propionibacterium spp Bifidobacterium spp Lactobacillus spp Clostridium spp	[2] [5] [5] [5]	Inhibition of growth of pathogens. Synthesis of palmitate and cholesterol in the liver. Energy substrate for peripheral tissues.	[2] [11] [11]
		Propionic acid	[1]	Propionibacterium spp	[2]	Inhibit the growth of putrefactive bacteria, clostridia, yeasts and fungi. It was used as gluconeogenic substrate in whole body glucose production. Energy substrate for peripheral tissues.	[2] [11] [11]
		Propionic acid	[1]	L. salivarius spp salcinius JCM 1230 L. agilis JCM 1048 L. acidophilus CRL 1014	[11]		[2] [11] [11]
		Butyric acid	[1]	Clostridium spp	[5]	The major energy source for colonocytes, Directly affecting the growth and differentiation of these cells and play an important role in modulating immune and inflammatory responses and intestinal barrier function and in preventing colon cancers. It have beneficial effects on health by decreasing adiposity and improving insulin sensitivity. Synthesis of palmitate and cholesterol in the liver.	[5] [11]
				Butyricicoccus pullicaecorum	[4]
				Faecalibacterium prausnitzii	[3]
				Eubacterium spp	[5]
				Roseburia spp	[3]
				L. salivarius spp salcinius JCM 1230 L. agilis JCM 1048 L. acidophilus CRL 1014	[11]
		Lactic acid	[6]	Lactobacillus spp Bifidobacterium spp	[6]	Lowering the pH, inhibit the growth of bacterial pathogens and sometimes even kill them	[10]
		Formic acid	[6]	Lactobacillus spp Bifidobacterium spp	[7]	Antimicrobial effect: lower microbial proliferation in the gastrointestinal tract, reduces the competition of the microflora with the host for nutrients and improving nutrient absorption	[8]
Vitamins	B-group	Folate (B9)	[11]	Bifidobacterium spp Lactobacillus spp	[11]	Folates represent an essential nutrition component in the human diet. Efficiency of DNA replication, repair and methylation are affected by folate, therefore high amounts of folate are required by fast proliferating cells such as leucocytes, erythrocytes and enterocytes They are cofactors of enzymes that act as catalyzers.	[13]
		Thiamin (B1)	[11]	Bifidobacterium spp Lactobacillus spp	[11]	Thiamin, as thiamine diphosphate (TPP), plays a fundamental role in host energy metabolism since it acts as a co-factor for enzymatic reactions that cleaves α-keto acids such as pyruvic acid.	[11]
		Riboflavin (B2)	[11]	Propionibacterium spp Lactobacillus spp		Riboflavin is phosphorylated into Flavin Adenine Dinucleotide (FAD) and acts as oxidative agents through its capacity to accept a pair of hydrogen atoms.	[11]
		Cobalamin (B12)	[14]	Propionibacterium spp Bifidobacterium spp Lactobacillus spp	[14]	An important cofactor for the metabolism of amino acids, carbohydrates, fatty acids and nucleic acids.	[14]
		K₂	[12]	Lactococcus spp Lactobacillus spp Enterococcus spp Bifidobacterium spp Streptococcus spp	[12] [14]	It is essential for the γ- carboxylation of osteocalcin, a bone matrix protein containing γ-carboxyglutamic acid which is synthesized in osteoblast of bone tissues. Vitamin K is an essential cofactor for the formation of γ-carboxyglutamic acid (Gla) residues in proteins. The Gla- containing proteins bind calcium ions and influence, for example, blood coagulation and tissue calcification	[12]
Antimicrobial metabolites		Diacetyl acetaldehyde acetoin	[7]	Lactococcus spp Lactobacillus spp	[7]	Active against yeasts Gram-positive bacteria Gram-negative bacteria	[7]
		Hydrogen peroxide		Lactic acid bacteria		Strong oxidizing effect on the bacterial celland to the destruction of basic molecular structures of cell proteins. Main metabolite of LAB that could protect against urogenital infections, especially in the case of bacterial vaginosis.
		Reuterin and reutericyclin		Lactobacillus reuteri		Both active towards Gram-positive bacteria. reuterin has a broader spectrum of inhibitory activity, including Gram-negative bacteria, fungi and protozoa.
		Cyclic dipeptides		Lactobacillus plantarum Lactobacillus pentosus		Active against fungi
		3-Phenyllactic acid 4-Hydroxyphenyllactic acid		Lactobacillus spp
		3-Hydroxy fatty acids		Lactobacillus plantarum
		Benzoic acid		Lactobacillus plantarum
Bacteriocin		Nisin	[14]	L. lactis	[14]	They are inhibitors to control undesirable bacteria in many food systems. Abp118 from Lactobacillus salivarius strain UCC118 is active against the food-borne pathogen such as Listeria monocytogenes. Una from Lactobacillus casei L26 LAFTI was shown to significantly inhibit an enterohemorrhagic strain of E.coli and a strain of L. monocytogenes in mice . A BLIS with anti-H. pylori activity was identified in probiotic Lactobacillus johnsonii strain LA1 and Lactobacillus acidophilus strain LB.	[14] [6]
		Plantaricin		L. plantarum
		Lactocin S		L. sake
		Acidocin A		L.acidophilus
		Bifidocin		B. bifidum
		Lactocin		L. casei
		Gassericin A		L.gasseri
		Microcin B17	[6]	E. coli Nissle 1917	[6]
		Colicin E1 and Ib		E. coli H22
		Enterocin		Enterococcus faecium
		Salivaricin		S. salivarius
		Butyricin 7423		Clostridium butyricum
		Bacillocin 22		B. subtilis
		Bovamine™		Lactobacillus acidophilus
Anti-mutagenic (AM) factor			[2]	Propionibacterium spp Lactobacillus delbrueckii ssp. bulgaricus 191R Streptococcus salivarius ssp. thermophilus CH3	[2] [8]	Active gainst the mutations induced by 4-nitro-quinoline and N-nitro- N-nitrosoguanidine (transition mutations), as well as 9-aminoacridine and 2-nitrofluorene (frame-shift mutations). AM activity of CL is caused by the proteinaceous compound. prevent initiation of carcinogenesis by producing antigenotoxic metabolites, which can deactivate and detoxify carcinogenic compounds such as N-methyl-N′-nitro-N-nitrosoguanidine	[2] [8]
Bifidogenic metabolites : 2-Amino-3-carboxy-1,4-naphtoquinone			[2]	P. freudenreichii	[2]	an active bifidogenic stimulator	[2]
Exopolysaccharides (EPS(			[14]	Propionibacterium spp Bifidobacterium spp Lactobacillus spp	[14]	EPS can contribute to the improved stability, rheology and texture of fermented dairy products, and may also offer protection to cells against phage attack, desiccation and osmotic stress. immunostimulatory anti-tumoral and blood cholesterol-lowering effects	[14]

4.1. Viral infections

4.1.1. Rotavirus: Lactobacillus lactis, Lactobacillus paracasei, Lactobacillus rhamnosus, Biﬁdobacterium longum, Biﬁdobacterium infantis, Enterococcus faecalis, as well as Saccharomyces boulardii are the main helpful probiotic strains against Rotavirus which caused to gastroenteritis and death in infants and children under the age of five years old [27].

4.1.2. Human papilloma virus (HPV): There are more than 100 kinds of HPV with the ability to infect skin, respiratory mucosa or the genital tract. It is also the most prevalent viral infection which is transmitted sexually [28]. one previous study has demonstrated that probiotics give the higher chance of HPV infection elimination to women [29]. Another study proved that Lactobacillus rhamnosus and Lactobacillus reuteri significantly decrease the mild cytological cervical abnormalities [30].

4.1.3. Influenza A virus (IAV): It is the main cause of infection in human and many other animal species. As there are some differences between prevalence virus and vaccine strains, the effect of vaccination is reduced. However, increasing the humoral and cellular immune responses against influenza virus by Bifidobacterium bifidum, as a probiotic strain, is proved in mouse models. This treatment enhances the levels of influenza-specific antibodies and IL-4 expression [31].

4.2. Bacterial infections

4.2.1. Staphylococcus aureus disease: The main cause of wide range of infections including pneumonia and sepsis is S. aureus. Several studies demonstrated that Bacillus probiotics and fengycins, which are lipopeptides produced by B. subtilis [17] and could inhibit accessory gene regulator (Agr) auto inducing peptide, can be applied as the treatment of S. aureus infection [32].

4.2.2. Bacterial vaginosis (BV) and urinary tract infections: Women at the age of reproductivity are faced to bacterial vaginosis (BV)[33]. Natural colonization of L. rhamnosus and L. fermentum in vagina could occur via oral taking of these organisms. It lasts one week for these microorganisms to restore normal vaginal flora [34]. It is claimed that this treatment has 61% influence on BV removal and 50% on normal vaginal flora recovering [33].

4.2.3. Helicobacter pylori infections: Peptic ulcer diseases, gastric carcinoma and MALT lymphoma are the main diseases which are produced by this bacterium [35]. It is reported that administration of Lactobacillus reuteri conjugated with a proton pump inhibitor (PPI) could be beneficial for H. pylori infections treatment [36].

4.3. Fungal infections

4.3.1. Mucosal Candidiasis: Mucosal and deep systematic candidiasis is caused by candida which is an opportunistic pathogen. Drug resistance and their side effects are the main limitation for candidal infection treatment. Streptococcus salivarius K12, Lactobacillus rhamnosus GR-1, Lactobacillus reuteri RC-14 and also clinical isolates of Lactobacillus are appeared to be effective for treatment of candidal infection [10].

4.3.2. Uro-genital infections: Use of Lactobacillus reuteri RC14 alone or in combination with Lactobacillus rhamnosus GR1 is confirmed by a study to be advantageous for restoring of yeast population from infected vaginal cells In vitro [37].

4.3.3. Gastrointestinal systems: Inflammatory bowel diseases (IBD) can occur as the result of unbalanced gut microbiota. Some microorganisms are confirmed to increase in IBD including Basidiomycota, Ascomycota, and Candida albicans (fungi). On the other hands Lactobacillus casei, L. delbrueckii subsp. Bulgaricus, L.acidophilus, L. plantarum, Biﬁdobacterium longum, B. infantis, B.breve, and Streptococcus salivarius subsp. Thermophiles and E. coli Nissle are some live freeze-dried bacterial species which could act as anti-inflammation in these patients [38].

As discussed earlier, using probiotics for many diseases could be an effective treatment. Some mechanisms of their action include:

The composition of microbiota could be influenced by them so producing commensal microbes is facilitated [39]; Metabolic phenotype could be improved in aging mice by L. acidophilus DDS-1 through regulating the composition of faecal microbiota. Taking Lactobacillus spp. as supplementation leads to regulation of gut microbiota and SCFA production [40]. Regulation of intestinal microflora through regulation of pH is done by Butyrate [39], and it is highly confirmed that it has a significant effect on distal ulcerative colitis, Crohn’s disease and cancer treatment [40]. Treatment of BV, yeast vaginitis or urinary tract infections is possible by L. fermentum RC-14 producing hydrogen peroxide [34]. Increasing vaginal lactobacilli as well as decreasing yeasts and coliforms occur in women who orally takes Lactobacillus rhamnosus GR-1 and Lactobacillus fermentum RC-14 [33].
Direct killing of pathogens demonstrated that bactriocin production in S. salivarius K12 leads to its antimicrobial activities [41]. The wide variety of bactriocins produced by Lactobacilli and Enterococcus could prevent pathogens growth and as a result have an immunomodulation effect [42].
Direct interaction between probiotics and pathogens such as binding of S. salivarius K12 and candida cells that can protect animal models and in vitro systems against oral candidiasis. This effect could occur in two stages: the formation of germ tube and expansion of mycelial [41].
Inhibiting the growth of pathogens; the growth of gram positive as well as gram negative pathogens like Streptococcus mutans and Escherichia coli are shown that could be inhibited by Lactobacillus species. It is also indicated that probiotic bacteria are able to prevent the growth of Candida species [10].
Competition for host-cell receptors; eradication of S. aureus infection may happen by its competition with live Bacillus as a probiotic [32].
Interference with gene expression of pathogens; secretion of autoinducer-2 which is an immunomodulator produced by E.coli can be decreased by some probiotics. This reduction leads to decrease in expression of genes located in enterocyte effacement (Pathogenicity Island). This location plays an important role in binding the bacteria and surface of host cell called attachment and effacing lesion [39].
Probiotics can prevent or improve some diseases through epigenetic regulation of genes [43]. Histone modification is one of the most important targets for microbial pathogens in order to manipulate host cells. Therefore, for preventing the infection, these epigenetic modifications could be the best target. Some studies have suggested that H3S10, H3 threonine 3 histone dephosphorylation and H3K23 deacetylation can be induced by H. pylori CagPAI in gastric epithelial cells [43]. SCFAs can inhibit histone deacetylation called histone deacetylase inhibitors (HDACi)[44]. Clostridium butyricum MIYAIRI 588 is a probiotic bactruim which produce butyrate and enhance accessibility of butyrate if there is a fibrous diet. The activity of histone deacetylases (HDACs) is prevented by intracellular butyrate and propionate (but not acetate) in colonocytes and immune cells. C. butyricum has been showed significantly affect on treatment of gastric ulcers induced by Helicobacter pylori through reducing proinflammatory cytokines and therefore decreasing mucosal lesions[39].
production of antimicrobial metabolites; specific metabolites secretion is stimulated by antiviral activity [29]. Some probiotics which are antagonists of candidal growth can produce hydrogen peroxide [10]. Filamentation of C. albicans and development of its micelles are important attributions for virulence of this pathogen which are hindered by an active compound produced by Saccharomyces boulardii [10].
Development of gastrointestinal host defenses against infection; Probiotics colonization have been showed effects on different parts of host defenses such as secretion of polymeric IgA. Commensal bacteria can also secrete small molecules that can enter Small molecules released by commensal bacteria can enter the epithelial cells of intestine and prevent activity of NFKB. Moreover, negative ragulators of cell surface and intracellular can be activated through interaction between TLR-2 / TLR-4 and some molecular patterns like peptidoglycan and LPS. This process leads to down-regulation of transcription factors and therefore inflammatory cytokines and chemokines are decresed. It also palys an important role in intestinal host defense as well as gastrointestinal chronic deseases prevention [45].
An adjuvant effect on immunologic responses; It is proved that after Clostridium infection, specific IgG and IgA antibodies of toxin A of Clostridium difﬁcile can be increased by Saccharomyces boulardii which is a fungal probiotic. Lactobacillus rhamnosus strain GG has been showed to enhance IgA response to rotavirus in infants with rotaviral gastroenteritis [45].

6.1- Recurrent abdominal pain (RAP): Some functional gastrointestinal disorders are called recurrent abdominal pain (RAP) while they have no clear cause. Some pharmacological, dietary or psychosocial treatments has been applied for RAP [46]. Lactobacillus rhamnosus GG has been found to show treatment effect on decreasing the pain compared to placebo group in one study [18]. Moreover, in another study it was shown that B coagulans GBI-30, 6086 probiotic can alleviate abdominal pain and bloating in irritable bowel syndrome (IBS) [19].

6.2. Cardiovascular diseases (CVD): Controlling blood pressure (BP) can be perfectly done by gut microbiota through different mechanisms including applying the control at central and autonomic nervous system or supporting the function of endothelial cells. So some diets which can preserve intestinal flora, could be crucial [47]. Kefir is one of the important food which plays an important role in decreasing BP and protecting dysfunction of cardiovascular [48]. Kefir which is produced by bacteria and yeasts symbiotic with kefir grains, is kind of fermented milk beverage. There are special microbiota in a polysaccharide and protein matrix in kefir grains. Because of its combination, there are complicated microbial interactions in kefirs but however there are always some species like L. delbrueckii and L. kefiranofaciensare (20). Some evidences proved that treatment of some cardiovascular deseases can be performed by pribiotics as natural coadjuants. They also have been showed to have effects on lowering abnormal high BP. For instance, systolic/diastolic BP and also heart rate in hypertensive patients can be decreased by Lactobacillus casei [47].

6.3. Allergic disorders: Several studies suggested that the risk of atopy is related to gut microbiome dysbiosis and probiotics are good candidate to reform it. Some probiotics have been proved to be beneficial for allergic diseases like atopic dermatitis in pregnant mothers and also infants [49]. Furthermore, lactobacillus GG showed some impacts on children up to 4 years old with high risk of atopic eczema [50].

Producing some beneficial nutrients and bioactive compounds by probiotics can play an important role in neoplastic disease treatment like cancer. So changing in microbes may lead to change in risk of cancer. It has been proved that substitution of pathogenic bacteria and special probiotic strains can be effective in cancer prevention[51]. Probiotics are demonstrated useful for many types of cancers regards to reducing or preventing side effects of chemotherapy. Here are some mechanisms of decreasing chance of cancer by different probiotics: Bacterial enzymes and intestinal metabolism can be modulated by probiotics. Some pro-carcinogenic compounds are secreted in intestine as a result of some bacterial enzymes stimulation like β-glucuronidase, azoreductase and nitroreductase [21]. Different carcinogens like heterocyclic aromatic amines (HCA) and N-nitroso compounds can bind or be metabolized by LAB and other probiotics. HCA disclosing to some bacterial strains leads to decreasing of mutagenicity. Competition of probiotics and pathogenic intestinal microbiota is effective on neutralization of cancer development. For instance, LAB strains like Bifidobacterium and Lactobacill can reduce the number of Clostridium perfringens in patients with polyp and colon cancer. It is proved that probiotics can regulate multiplication and apoptosis of cells. This mechanism is the most important one for cancer inhibition. NF-κB activation which is induced by TNF can be suppressed by Lactobacillus reuteri if it is used in specific dose and time. It also promotes activated immune cells apoptosis through ubiquitination of IKBa prevention and pro-apoptotic signaling of mitogen activated protein kinase (MAPK). Some receptors and cytoplasmic proteins with tyrosine kinase activity can active signaling pathways which are crucial for cancer development. Probiotics can be considered a great therapeutic candidate for intestinal cancers through suppression of tyrosine kinase signaling. A safe probiotic for treatment of colon cancer is Saccharomyces boulardi which down-regulates MAPK signaling [21]. It is proved hat secondary bile salts which are cytotoxic, mutagenic and antiapoptotic, can be transformed by bile salt hydrolases (BSH) of Lactobacillus and Biﬁdobacterium [15]. One of the mechanisms which can prevent cancer is producing specific and nonspecific immune responses [52]. Probiotics can prevent carcinogenesis through directly inhibition of tumor growth or preventing tumor cells to suppress immune system [53]. Moreover their secondary metabolite, DNA or componenets of cell wall can also affect the immune system [54]. Short chain fatty acids (SCFAs) which are produced by Bifidobacteria and Lactobacilli can apply a trophic impact on mocusa of intestine and decreasing Th17 polarization and inflammatory cytokines leading to tumor genesis inhibition. Probiotics also have shown reduction of angiogenesis and alteration to anaerobic metabolism resulted in tumor hypoxia [55].

7.1. Colorectal cancer (CRC): There are many evidences which prove that imbalance of gut microflora leads to CRC [56]. Many different factors such as lifestyle, diet, infection or environmental factors cause the change in microflora and symbiotic relation between host and its environment related to CRC [57]. However probiotics can make the change in host microflora and play beneficial role for the host[56]. Although there is no evidence for special bacterial strains to be dangerous for CRC, some pathogenic bacteria are proved to be in charge of 15% of CRCs. Increased number of Fusobacterium is seen in microbiota of many CRC patients[57]. Fad A is a virulence factor of Fusobacterium nucleatum which can interact with E-cadherin leading to activation of β-catenin signaling and promoting CRC [58]. Production of useful metabolites, induction of immune tolerance and resistance of pathogens are different mechanisms by which intestinal probiotics can prevent CRC. Expression of some proteins and polyamines which are tumor specific, are inhibited by Lactobacillus. IL-12 cytokine which is a key component of innate immunity activation, can be produced at high levels by different strains of Lactobacillus casei (L. casei, L. rhamnosus and L. zeae) and Lactobacillus fermentumcan. It is also reported that ErbB2 and ErbB3 play critical role in tumor genesis and can be prevented by Bacillus polyfermenticus [21]. Therefore, Bacillus spp. is considered as a clinical treatment for colon cancer. Furthermore some bacteria produce SCFAs through fiber fermentation which can maintain the intestinal microbiota leading to prevention of tumor development and promotion of apoptosis. Butyrate, the main source of energy for intestinal cells, applies its anti-tumor effects through several pathways including: increasing the expression of Bak gene and decreasing the expression of Bcl-XL gene result in apoptosis induction. Butyrate can enhance antioxidant activity leading to Reactive nitrogen fragments (RONS) formation inhibition. RONS play a crucial role in activation of intestinal inflammation and CRC, inducing histone deacetylases (HDACs) activation, proliferating colonic adenocarcinoma cells and preventing cell differentiation and apoptosis [59]. Clostridium, Roseburia, Eubacterium [60] and MDT-1 which is a strain of Butyrivibrio fibrisolven [21] are reported to have abilities to regulate dietary fiber fermentation and producing SCFAs (like butyrate) by which have significant impacts on protecting against CRC.

7.2. Urothelial cell carcinoma (UCC) and bladder cancer: Having milk and dairy diets is proved to be effective on lowering the risk of bladder cancer. Lactobacillus as an oral probiotic is reported to decreasing UCC recurrence. These probiotic bacteria can decrese the cancer risk by binding to compounds which are associated to urinary tract cancers like cadmium and other heavy metals and pesticides [58]. The researchers also found that Lactobacillus species, especially L. casei and L. rhamnosus GG (LGG), inhibit the proliferation of bladder cancer cells by producing cytotoxic effects. They concluded that these probiotic species could increase the secretion of cytokines by neutrophils and induce the maturation of dendritic cells and the production of antigen-specific cytotoxic T cells. moreover In addition to the use of recombinant cytokines, probiotic bacteria can also become an additional treatment option against cancer cells to induce cytokine production. [61].

7.3. Metastatic melanoma: Several studies have demonstrated that commensal bacteria are related to the effectiveness of immunotherapy in mouse melanoma models. Some bacteria like Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium are proved to be beneficial for immunity of patients[62]. The microbiota of skin have a significant impact on host protection against cancer and pathogens. Firmicutes are the main phylum of the skin microbiota which is usually presented with Staphylococcus, Streptococcus and Lactobacillus. 6-HAP protein produced by S. epidermidis shows antiproliferative function on tumor cells resulted in protecting against skin neoplasia tumor growth[63]. Moreover, integrity of skin barrier and pathology can be improved by Lactobacillus plantarum NCIMB8826[64].

7.4. Breast cancer: Useful lactic acid bacteria proliferation during lactation and composition of microbiota can decrease the risk of cancer through responding to carcinogenic species of bacteria. Some quorum sensing peptides producing from bacteria like PhrG from B. subtilis, CSP from S. mitis and EDF from E. coli, together with its tripeptide analogue, are reported to have effects on development of tumor cells and their angiogenesis and metastasis. Bacteria generate these peptides at distant locations or they can move through blood vessels and get to breast tissues [22]. Safe application in humans, helping function of epithelial barrier, antipathogen characteristic expression, ability of degradation detoxification of high risk chemicals are the main factors for choosing the proper probiotic strain[65]. Fermented soy milk beverage has found to prevent tumor cell growth. Bifidobacterium breve can ferment soy milk results in high content of isoflavone aglycone and prevention of rat mammary carcinogenesis. Due to the similarity in structure of estrogen and isoflavone, isoflavone shows anti-estrogenic function by which shows breast anticancer effects[66]. This function can be considered crucial for estrogen-dependent breast cancers which are the major kind of breast cancers [65]. Lactobacillus acidophilus, Lactobacillus bulgaricus, Streptococcus lactis, or Bifidobacteria presenting in fermented soy milk show inhibitory effect on growth of estrogen-receptor positive MCF-7 human breast cancer [66].

7.5. Esophageal cancer (EC) and gastric cancer (GC): EC and GC patients usually have high risk of death because of malnourishment [67]. Nutritional treatments help these patients to reduce the risk of death and other symptoms. Enteral nutrition (EN) using tube feeding is one of the possible ways for this treatment [23]. Diarrhea is the most common symptom in these patients which is related to intestinal flora imbalance and EN. Some studies have found that EN can change the combination of intestinal flora. For instance biﬁdobacteria can change by 1000-fold in EN receiving. In EC and GC patients who have surgery, fiber and probiotic combination can play an important role for diarrhea treatment. Lactobacillus and biﬁdobacteria which are the main normal microbiota of intestine lead to pathogenesis if they are dysbiosis. Fermentation of fiber and production of lactic acid can caused by Lactobacillus while SCFAs production is done by biﬁdobacteria[67]. Better immune function in GC and increased levels of IL-6, IL-8 and TNF-α caused by probiotics and EN combination was proved by other studies [68]. Recent studies have shown that Helicobacter pylori (Hp) can alter the composition of the stomach microbiota, and that changes may increase the incidence of Hp-related diseases. such as gastric cancer. The beneficial effects of probiotics on humans can be related to their role in improving the gastrointestinal microflora and the function of the intestinal immune system.These include the ability of probiotics to compete with intestinal pathogens, increase IgA antibody secretion, regulate cytokine mRNA expression, increase mucin, bacteriocin and lactic acid production, and modulate microbiota growth. [69].

7.6. Head and neck cancers: Chemotherapy due to the attacking intestinal epithelial can cause to dislocation of intestinal bacteria. So using some probiotics like Lactobacillus acidophilus and Bifidobacterium bifidum in head and neck cancer treatment can inhibit radiotherapy and cisplatin to cause toxicity [70]. Research has revealed that candidiasis is most prevalent among patients undergoing head and neck radiotherapy, and due to the side effects of conventional antifungal drugs and resistance of Candida species. to azoles are a matter of concern Probiotics enhance the defense function of oral epithelial cells by inducing cytokine production, recovery and protection of the oral immune system and the microbial flora that is often compromised in patients with head and neck radiotherapy. Therefore, the use of probiotics can have beneficial results in reducing the pathogenic species of oral candida with fewer or no side effects in patients with head and neck radiotherapy [71].

7.7. Hepatocellular carcinoma (HCC): 70% of liver blood stream is supplied from intestine blood. Therefore gut microbiota and their metabolites are presented to the liver and any kind of change in them can have influences on function of liver immune cells. On the other hand metabolism of primary bile acids to the secondary ones can be mediated by commensal bacteria. Enterohepatic circulation can get back these bile acids to the liver which can be effective on development of liver cancer [23]. Furthermore, development and maintenance of inflammation and pro-oncogene environment can occur as a result of translocation of pathogen-associated molecular patterns (PAMPs) like LPS from intestine and interaction of them with Toll-like receptors (TLRs). For instance, TLR4 has been proved to be over expressed in HCC tumor tissues [55]. It was proved that hepatic natural killer T (NKT) can be prevented to be accumulated and inhibited antitumor immune response in liver tumors by Clostridium species. Moreover, changing primary bile acids to the second ones is done by some species of Clostridium like C. scindens leading to reducing NKT cells and enhancing metastases of liver tumor[23]. Neutralization of toxic carcinogens like aflatoxin B1 by probiotics is one of their major roles. It has proved that there is a relation between reducing the aflatoxin-DNA compounds in urine which is a liver cancer biomarker, and some strains of bacteria [55] and also a mixture of Lactobacillus rhamnosus LC705 and Propionibacterium freudenreichii subsp. Shermanii administration. Therefore an effective dose of aflatoxin can be decreased by probiotics. In this way probiotics can play a major role in lowering the liver cancer risk by a useful dietary[24].

7.8. Lung cancer: This cancer can be malignant, proliferative, invasive and metastatic [72]. Although surgery is the first candidate in early stages, many discovered tumors are in advanced stages [73]. Systematic chemptherapy is the most common treatment for these advanced patients because targeted therapies and immunotherapy can’t be effective [74]. Nausea, vomiting and diarrhea are some side effects of systematic chemotherapy which may weaken the patient’s status and decrease the effect of treatment leading to increasing the treatment period and costs. It is suggested that diarrhea which is induced by chemotherapy in lung cancer patients can be alleviated by C. butyricum administration. It can promote the intestinal repairing, homeostasis and inflammation reduction. Butyric acids which are produced by C. butyricum lead to proliferation of Bifidobacteria and Lactobacilli in intestine and maintenance of intestinal microflora. This also results in increasing the useful bacteria like Blautia, Faecalibacterium and Roseburia and decreasing the pathogenic bacteria such as Bacteroides and Escherichia. Moreover increasing the number of CD8+ T cells and NK cells to the cytotoxic pathways by C. butyricum has observed which may have an important effect on lung cancer patients [73].

7.9. Oral cancer: Probiotics are considered as a potential candidate for building up the effectiveness of normal cancer treatments like chemotherapy and immunotherapy. They mainly regulate the mucosal immunity against cancer[54]. Lactobacillus plantarum has been proved to being existed in mouth and having effect on cancer treatment. Moreover some polysaccharides secreted by bacteria can show antitumor effects on Caco-2, BGC-823, and HT-29 cells [49]. It is suggested that L. plantarum can activate some survival and apoptosis pathways by expression of MAPK and PTEN genes. MAPK and PTEN play roles in induction and inhibition of tumors respectively. Several cancers show increased level of MAPK expression. It can be effective in apoptosis regulation and cancer metastasis. The ability of increasing expression of MAPK mRNA and decreasing the expression of PTEN mRAN by L. plantarum has been proved which can be leading to cancer treatment in KB cancer cells co-cultured with L. plantarum[54]. Earlier studies confirmed that over expression of MAPK leads to development of cancer cells by increasing growth factors in number. So it seems that inducing the angiogenesis and inhibition of apoptosis pathways are the most common strategy of MAPK which also have impact on activation of NF-κB pathway. On the other hands MAPK inhibition has been proved to be able to prevent tumor growth which can be a positive complementary factor for cancer treatment by shifting the cancer cells to anti-cancer drugs causing more death in cancer cells [75]. These findings indicate that MAPK and PTEN/AKT pathways can be regulated by probiotics specially commensal bacteria to activate or inhibit these pathways leading to reduction of cell growth in oral cancers. Therefore the product of this bacterium can be used as complementary treatment in oral cancers. Consuming dairy products due to the presence of lactobacillus family in them can be effective in cancer patients via integration of commensal bacteria community [54]. In a number of studies, from L. salivarius REN was mentioned as one of the factors preventing the proliferation of squamous cell carcinoma of the human tongue. L. salivarius REN was identified as an inhibitor of COX-2 gene upregulation encoded by the PTGS2 gene. Increased expression of COX-2 is commonly seen in different types of cancer. This is because the COX-2 product is converted to PGE2, which can cause cancer to develop. Therefore, reducing the expression of COX-2 gene is a useful treatment method in preventing oral cancer [76].

7.10. Gynecologic cancers: The relation between microbiome and gynecological cancers has been confirmed by many studies [77]. So many different gynecologic cancers like cervical cancer, uterine cancer, and ovarian cancer may be related to gut and vaginal microbiomes. Firmicutes phylum particularly Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii are normally present in healthy vaginal microbiome which can be different in numbers over time [78]. Different types of gynecologic cancers have different causes but probiotics are showed to affect the treatment. The impacts of probiotics on these types of cancers are outlined below:

7.10.1. Cervical cancer: Cervical cancer is mainly caused by human papillomavirus (HPV) and it is showed that it can be improved by domination of L. gasseri in microbiota. On the other hand, some studies proved that low range of L. gasseri and high range of Atopobium can decrease HPV improvement rate. As a result, vaginal microbiota (VBM) significantly affects the HPV condition [79]. In advanced stages of cervical cancers, the most common treatment is radiotherapy, may combined with surgery or chemotherapy which can have side effects on bowel. Abdominal pain, urgency, diarrhea, fecal incontinence, and bloating are some examples of bowel symptoms which have been seen in 80% of patients during radiotherapy. GI microbiome is a good alternative. Studies showed that GI microbiota in patients with radiotherapy treatment are much different from the patients with GI microbiome treatment. Actinobacteria was found 30 times higher than healthy people and Fusobacteria was 7.4 times lower [78].

7.10.2. Uterine cancer: Pelvic inflammatory diseases (PID) which is related to endometrial cancer development can be caused by vaginal dysbiosis. Dysbiosis of VBM particularly with bacterial vaginosis (BV) are confirmed to be related to higher risks of PID. Decreased numbers of Lactobacilli and increased numbers of anaerobic bacteria like Gardnerella, Prevotella, Atopobium, Mobiluncus, Ureaplasma, and Mycoplasma lead to BV diseases. Cellular damage caused by radiotherapy in uterine cancer can result into the atrophy in these patients. Lactobacillus is found less in numbers in this condition. Moreover, chronic inflammation which is occurred due to the crossing the pathogenic bacteria through damaged epithelium can cause atrophy state to getting worse[78].

7.10.3. Ovarian cancer: Because of the first symptoms of ovarian cancer like abdominal pain, bloating, indigestion, constipation, and early satiety which are similar to GI symptoms; GI microbiom can be significantly useful in this kind of cancer. Developing ovarian cancer may be affected by chronic inflammation in the upper tract. Fallopian tube may be also influenced. Therefore, one of the main risk factors of this cancer is considered BV associated bacteria [78]. Two major treatments including CpG-oligonucleotide immunotherapy and platinum chemotherapy can be influenced by GI microbiota disruption [80]

7.10.4. Probiotics and gynecologic cancers: Probiotics are showed to be effective in alleviation of diarrhea induced by radiation in gynecologic cancer patients. Furthermore, different mechanisms by Lactobacilli are useful for vaginal health [78], Some mechanisms are including improving immune monitoring and regulatory T cells (TREGS) in order to alleviate the chronic inflammation [77]. There are different strains of Lactobacilli which are effective for vaginal health each of which have their own mechanism. Regulating host defense, pathogen growth interference, anti-adhesion and anti-virulence factors induction and disruption of bioﬁlm formation are some mechanisms caused by Lactobacillus rhamnosus GR-1 and L. reuteri RC-14 strains. Also, reducing the rate of recurrence of unitary tract infection (UTI) and increasing the chance of VBM with domination of Lactobacilli are reported through oral administration of GR-1/RC-14 combination. Another strain is L. crispatus CTV05 which can deliver intravaginally and reduce level of vaginosis caused by bacteria and also recurrence of UTI when it persists more than 28 days[78]. Combination of Lactobacillus and Biﬁdobacterium species with the concentration of 5× 10⁹ colony forming units per day which are taken orally for 5 days are proved to be effective [77]. Probiotics are also reported to have impacts on HPV treatment. One study confirmed that mice with normal gut microbiota showed more efficacies in common treatments like CpG oligonucleotide immunotherapy or platinum chemotherapy regimens than the mice in germ-free environment or mice with wntibiotic treatment [80]. decreasing the gut Th17 inflammation and promotion of anti-inflammatory Treg cells by probiotics alone are some examples of mechanisms preventing sarcomas [81]. A probiotic can also change the tumor microenvironment if it is used for gynecological tumors directly or by injection. Impacts of vaginal microflora on increasing the rate of apoptosis are already proved by in vitro studies [77] It also affects dendritic and Treg cells for anti-inflammatory cytokines production [82].

7.11. Leukemia: Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are two major kinds of leukemia. Damaging the gut microbiota, mucosal protection, and immunological balance resulted in to intestine inflammation are the most common side effects of chemotherapy and antibiotic therapy. Another problem is increasing the rate of mortality by suppression of immune system through using anticancer drugs. A good alternation solving these problems is targeted therapy including using probiotics supplement, microbiome transplantation and special diets for improving specific microorganisms[83] Damaging cells, cell wall and DNA of Lactobacillus strains (Lactobacillus rhamnosus, Lactobacillus paracasei and Lactobacillus coryniformis) through heat showed inhibitory effects on leukemia cells. Also apoptosis activity against cancer cells is reported by bacterial cell, homogenate and cell walls of Lactobacillus strains [84]. Apoptosis signaling pathways activated by tumor necrosis factor (TNF) in myeloid leukemia-derived cells by Lactobacillus. reuteri is reported in another study. It is proved that cytotoxicity resulted from TNF could be enhanced from 3% to 38% by probiotics. The expression of Bcl-2 and Bcl-xL which are anti-apoptotic proteins and cell proliferative factors like Cox-2 and cyclin D1 are induced by TNF and could be suppressed by factors secreted from L. reuteri (Lr-S 6475). Suppression of these proteins leads to apoptosis induced by TNF. Over expression of Cox-2 in neoplastic cells could cause enhanced rates of invasion, angiogenesis and antiapoptosis in cells. Down regulation of Cox-2 cyclin D1 by Lr-S 6475 have some impacts on cell cycle and growth. Lr-S 6475 can also suppress the activation of NF-kB signalling induced by TNF which regulates the Cox-2, cyclin D1, Bcl-2 and Bcl-xL proteins [85].

Probiotics are some bacteria which are mainly present in gastrointestinal tract. Two major strains are Lactobacilli and Bifidobacterium which show significant antimicrobial and anticancer activities. Therefore, the dietary ingredients, presence of probiotics and their metabolic activities are important environmental factors in carcinogenesis. However biological complexity as a barrier for full elucidation of the multiple pathways by which host microbial condition may affect clinical states. Current and future studies will be helpful for conquering these barriers and developing use of probiotics as more natural and less disruptive treatment for different types of cancer.

SCFA: Short chain fatty acids

HDAC: Histone deacetylases

GPCR: G-protein coupled receptors

ENS: Enteric nervous system

BSH: Bile salt hydrolase

HPV: Human papilloma virus

IAV: Influenza A virus

BV: Bacterial vaginosis

PPI: Proton pump inhibitor

IBD: Inﬂammatory bowel disease

RAP: Recurrent abdominal pain

CVD: Cardiovascular diseases

BP: Blood pressure

MAPK: mitogen activated protein kinase

EC: Esophageal cancer

GC: Gastric cancer

HCC: Hepatocellular carcinoma

PAMP: Pathogen-associated molecular pattern

UTI: Urinary tract infection

ALL: Acute lymphoblastic leukemia

AML: Acute myeloid leukemia

TNF: Tumour necrosis factor

CRC: Colorectal cancer

Acknowledgment

We would like to thank all our colleagues for their assistance. The facility for this study was provided by Research Deputy of Kashan University of Medical Sciences to ZSS and HHK.

Funding

No financial support was received.

Availability of data and materials

Not applicable

Author contributions

ZSS, AP and HHK conducted the literature and drafted the manuscript. All authors reviewed the manuscript and made significant revisions and approved the final version of the manuscript draft.

Competing interests

The authors declared that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable

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No competing interests reported.

The microbiota, secondary metabolites and diseases: a putative role of probiotics in prevention and treatment of cancers

Status:

Version 1

Abstract

Figures

1. Introduction

2. Bacterial And Fungal Probiotics

3. Secondary Methabolites

4. Probiotics And Infectios Disease

5. Probiotics And Mechanisms Of Antimicrobial Activity

6. Probiotics And Other Disease And Disorders

7. Probiotics And Cancers

8. Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1