INTRODUCTION:

Probiotics are living bacteria that provide health benefits to the host when consumed in sufficient quantity according to WHO^[1,2]. Most microorganisms recognized to date as probiotics are Gram-positive such as Lactobacillus and Bifidobacterium, in addition to Gram-negative, Escherichia coli Nissle 1917 as well as yeast species including most prominently Saccharomyces boulardii among others^[1].

Probiotics are used for the treatment of a wide variety of medical conditions including gastrointestinal disorders ^[3]. The advantages of probiotics are preventing the growth of pathogenic bacteria through releasing of antibacterial substances or metabolites such as lactic acid, motivating the host immune response and enhancing epithelial barrier functions^[4-6].

A number of studies also point to an important role for intestinal microbes in maintaining normal gastrointestinal function^[7,8]. Thus, it is expected that handling the gut microbiota could be connected to preventative and therapeutic effects.

Probiotics are known to be able to correct the condition of dysbiosis^[9,10]. The World Gastroenterology Organization has released a detailed practice guideline on probiotics and prebiotics that summarizes the specific indications, products that have been demonstrated in these indications, and recommended dosages^[11]. Furthermore, several recent studies proposed standardized guidelines for the performance of clinical trials^[12,13] and assessment of safety in relation to pre- and probiotics^[14].

In this review, the specific gastrointestinal disorders for which probiotics have been used are discussed.

IBD:

Crohn's disease (CD) and ulcerative colitis (UC) are two basic types of inflammatory bowel disease and may result in severe symptoms leading to death^[15]. Clinical symptoms include rectal bleeding, abdominal pain, weight loss, diarrhea, fatigue and fever^[16]. CD can include any part of the digestive tract, although most cases stem from the terminal ileum. Inflammation can spread to the serum, leading to the formation of a fistula. UC is limited to inflammation mainly in the mucous membrane of the rectum and colon and consists of continuous involvement of variable severity with ulceration of edema and bleeding along the colon^[17].

Although there is an increasing evidence that dysbiosis is considerably implicated in the etiology and pathogenesis of IBD, it is still unclear whether dysbiosis is a direct cause of the inflammation in IBD, or merely the result of disturbed environment in the gastrointestinal tract^[18].

Probiotics are able to modify the intestinal environment and reduce the severity of inflammation caused by IBD^[19]. The mechanism of action includes: 1-competitive exclusion, whereby probiotics compete with microbial pathogens for a limited number of receptors present on the surface epithelium; 2- Preventing the growth of pathogens by releasing antimicrobial agents such as lactic and acetic acid, hydrogen peroxide, and bacteriocins; 3-immunomodulation of an immune response of gut-associated lymphoid and epithelial cells; 4- enhancement of barrier function^[20]. Not all types of probiotics have the same mechanism; however, some beneficial effects are common to most types of probiotics^[21].

IBS:

Irritable bowel syndrome is a functional gastrointestinal disorder that affects women more than men^[22]. Known as frequent abdominal pain, altered bowel habits and bloating. The diagnosis of irritable bowel syndrome is based on the prevalent symptom such as multiple or unspecified constipation or diarrhea^[23,24]. The pathogenesis of the pathogenic mechanism is not known, but studies point to the role of intestinal flora in terms of its type and quantity^[25]. A decrease in the amount of Lactobacillus and Bifidobacterium was found to cause an immune response that triggers inflammation in the gastrointestinal tract^[26].

The exact mechanisms of probiotics are currently only partly known. Probiotics have been suggested to act through inhibition of pathogenic bacteria overgrowth and prevention of pathogenic invasion of the host, improvement of gut barrier function and receptor interactions, as well as secretion of substances such as short chain fatty acids (SCFAs) and neurotransmitter^[27]. Studies have suggested that different strains of probiotics may improve abdominal pain and reduce visceral hypersensitivity by modulation of expression of neurotransmitters and receptors involved in the modulation of pain, such as the opioid receptor or the cannabinoid receptor^[28,29]. In addition, probiotics have been shown to reduce intestinal cytokine secretion and improve epithelial barrier function^[30].

The theory that probiotic supplements improve IBS symptoms through modulation of the gut microbiota or its metabolic pathways needs further mechanistic evidences. Probiotic supplements with beneficial effects on IBS symptoms may lead to more effective therapy strategies^[31].

Colorectal cancer (CRC):

Colorectal cancer (CRC) is one of the most common cancers in the world. It is the third most common and the fourth most common cause of cancer-related death^[32]. Mutations in specific genes can lead to the onset of colorectal cancer, as happens in other types of cancer^[33].

Personal habits may be risk factors because they increase the chances of developing polyps or colorectal cancer. Some of these risk factors are: age: colon and rectal cancer under the age of fifty is rare^[34], genetic: it includes a personal history of colorectal cancer or IBD, ulcerative colitis^[35] or Crohn's disease^[36], leading to dysplasia which is an abnormal growth cells that are not malignant but can develop into a tumor^[37]. Lifestyle: lack of physical activity and unhealthy nutritional habits can increase the risk of colorectal cancer^[38], obesity: food intake and increased levels of visceral adipose tissue (VAT), a hormonal active component of total body fat that can promote the development of colon and rectal cancer by secreting inflammatory cytokines which can all lead to inflammatory status in the colon and rectum, insulin resistance and metabolism enzyme modification^[39].

Probiotic and CRC:

Probiotics and gut microbes with a specific mechanism have anti-cancer properties but are still not known accurately. The low pH that may be caused by an excessive presence of bile acids in the stool may have a toxic effect on the cells that affects the colon epithelium and causes colon cancer^[40,41]. It has been demonstrated that the Escherichia coli and Clostridium perfringens naturally present in the small intestine produce carcinogens by enzymes such as β-glucuronidase, azoreductase, and nitroreductase^[42]. Several studies have confirmed the positive role of probiotic strains on the activity of bacterial enzymes causing tumor formation^{[43, 44]}.

Many of the compounds that are produced and metabolized by the intestine from the intestinal microflora have a role in preventing carcinogenicity. These substances are SCFAs such as acetate, propionate, and butyrate resulting from prebiotic fermentation. SCFAs are a source of energy, and have also been shown to be molecules that affect the immune system, cell death and proliferation^[45].

Colorectal cancer is strongly linked to lower levels of SCFA and SCFA-producing bacteria dysbiosis^[46]. New studies suggest modifying the bacteria producing short-chain fatty acids through dietary intervention with fermented fibers as a treatment for colorectal cancer^[47].

Some strains of probiotics have the ability to modify the production of anti-inflammatory cytokines and the secretion of prostaglandins, which have a role in preventing cancer. Other studies suggest a mechanism to give strains of probiotics capable of activating phagocytes that eliminate cancer cells in their early stages^[46,48].

The results of the studies showed that probiotics are an essential component that contributes to the success of immunotherapy for cancer^[49-51].

Diarrhea:

Diarrhea is a common symptom of many diseases of the digestive system. Stool harmony occurs when there is an imbalance between the absorption of water, ions and intestinal secretion. Diarrhea is one of the most common health problems in developing countries and the first reason why children are hospitalized^[52]. Treatment of diarrhea mainly depends on replacing lost fluids through oral rehydration solutions^[53], and this reduces the mortality and morbidity without affecting its intensity and duration^[54,55].

Probiotics are one of the strategies currently under study that may reduce the duration of diarrhea^[54,56]. The use of yogurt, considered as a natural probiotic, in treating diarrhea has been known for a long time, as it enhances the health of the host by preventing or treating infection caused by pathogens^[57]. Lactobacillus GG, Lactobacillus reuteri and Saccharomyces boulardii are considered as factors that help improve the course of treating diarrhea in children^[57,58].

Probiotics for diarrhea of viral origin:

Viral factors are responsible for the attacks of diarrhea in children all over the world where rotavirus is the most important factor. A Cochrane database of systematic review compiled pooled estimates of benefit for Lactobacillus in acute rotavirus diarrhea and found a reduction in the duration of diarrhea of 29 hours a reduction in stool frequency on day 2 following the intervention of 1.25 stools per day^[59]. S. boulardii alone or in combination with three types of probiotics including two types of lactobacilli have a role in reducing the duration of diarrhea in the rotavirus^[60].

Although treatment studies have reported the discovery of viral factors other than rotavirus, the studies have not revealed any primary or secondary results of probiotics used to treat diarrhea caused by viral agents other than rotavirus^[61,62].

Children infected with HIV (Human immunodeficiency virus) in a specific population area are at risk of diarrheal disease due to a group of infections^[63,64]. In a large study of children with severe acute malnutrition, more than 40% were HIV-positive and were selected to receive a multi-component probiotic treatment including lactobacillus or placebo. However, the study did not find any improvement in the rate of diarrhea in these patients^[65].

Probiotics for bacterial diarrhea:

Two studies of Lactobacillus rhamnosus GG found no evidence of protection for the 15-20% of children with ‘invasive’ pathogens, principally Salmonella or Shigella ^[66]. In the only study specifically addressing bacterial disease, there was an earlier resolution of diarrhea for LGG (co-treated with trimethoprim-sulfamethoxazole) during an outbreak of Shigella dysentery in Estonia^[67].

Another study in India reported that there is protection against dysentery although there is no effect on the general incidence of diarrhea^[68].

Probiotics for parasitic diarrhea:

In a Cuban study of children with persistent diarrhea caused by giardia cysts in their stool, it was proved that symptoms were improved after taking S. boulardii^[69].

Amoebic dysentery cases, the duration of bloody diarrhea and cyst secretion decreased on the fifth day after taking Saccharomyces in 25 Turkish children^[69].

A randomized trial of 48 children with Blastocystis hominis showed a high rate of cure and the disappearance of cysts from feces after taking probiotics^[70].

Probiotics for Clostridium difficile associated diarrhea (CDAD):

Although a meta-analysis performed by McFarland for the treatment of CDAD found evidence in favor of treatment with S. boulardii^[71]. The Cochrane Group and other reviewers concluded that despite holding promise, current data are insufficient to provide recommendations for use of Saccharomyces or another probiotic to treat primary CDAD or relapse^[72-74].

Probiotics for antibiotic associated diarrhea (AAD):

There have been no published RCT investigating the effect of probiotics for the treatment of non-Clostridium difficile AAD in children; thus, their use cannot be recommended at this time.

A Cochrane meta-analysis of probiotic use of children to prevent or ameliorate AAD documents that probiotics produced a statistically significant reduction in the incidence of AAD with the number needed to prevent one case of AAD being 7^[75].

Probiotics for traveler’s diarrhea:

Several studies have shown the advantages of using lactobacill to protect travelers from diarrhea, but one study has used a combination of strains (containing Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterum bifidum and Streptococcus thermophilus) and the overall decrease in cases of diarrhea was statistically significant^[76].

Travelers to various regions such as North Africa, South America, India and Turkey derive sufficient protection from S. boulardii^[76].

CONCLUSION:

Probiotics are a therapeutic class being increasingly used for a variety of GI disorders including IBD, IBS, colorectal cancer and diarrhea. Many species of probiotics could be used as a single strain or in a combination of different probiotics and it is generally accepted that all probiotics are not created equal. They have been shown to be safe in immune-competent hosts in an outpatient setting. They are considered ‘generally recognized as safe’ (GRAS) and well tolerated in humans. However, some studies reports indicated bacteremia and the presence of blood fungi due to taking probiotics. These side effects were specifically reported when probiotics were administered in GI disorders with compromised gut permeability and gut immunity which could increase the translocation of probiotic’s bacteria into the bloodstream. In a study of Platincx et al., a one-year-old child who suffers from an immunodeficiency has blood fungi after taking S. boulardii to treat gastroenteritis ^[78]. Furthermore, two infants with short bowel syndrome were found to develop bacteremia resulting from treatment by Lactobacillus GG strain of probiotics ^[79]. Thus, future studies should address many of the remaining questions related to the basic knowledge of probiotics.

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Received on 05.02.2020 Modified on 13.03.2020

Research J. Pharm. and Tech. 2020; 13(11):5557-5561.

DOI: 10.5958/0974-360X.2020.00970.1