Probiotic Effects on Disease Prevention and Treatment

Abstract

Research on the probiotic effect in preventing or treating diseases has attracted scientists’ attention for many decades. Findings of probiotics effects on human health indicate that they are not only no detrimental but also may have a beneficial effect on the host. Indeed, the effectiveness of probiotics depends on the type of utilized strain, duration, dose administration, and single or combined strains used that can be different in a specific disease. Therefore, probiotics can play a significant role in the treatment and prevention of different diseases through several mechanisms; for instance, stimulating respiratory immunity in the airway and enhancing resistance to respiratory tract infections, can prevent or reduce the duration of respiratory system diseases. By ameliorating glucose metabolism, reducing inflammation and oxidative stress in pancreatic cells, and preventing the destruction of β-pancreatic cells, may prevent the onset of diabetes and the pathogenesis of diabetic retinopathy as well. Moreover, using their metabolites, especially short-chain fatty acids production, probiotics may have an important effect on weight modifications. Finally, from the regulation of important neurotransmitters and regulation of inflammatory markers, it may be effective in mental disorders improvement.

1. Introduction

Research on the probiotic effect in preventing or treating diseases has attracted researchers’ attention for many decades. The importance of probiotics in such areas can be indicated by close to 300 meta-analyses published from 2000 to 2020 investigating the efficacy of probiotics in preventing and treating diseases. Probiotics are defined as live non-pathogenic microorganisms that confer beneficial health to the host when administered in a sufficient number [1] (1 × 10⁹ colony forming units (CFU) per serving [2]). However, a concern has increased that probiotics may not survive in sufficient numbers when they are added to dairy products or pass through the gastrointestinal tract and may not be helpful as would be expected [3, 4]. Therefore, improving the shelf-life of probiotic strains is important. According to research, microencapsulation of probiotic strain by spray drying through adding additives like tragacanth to skim milk could remarkably enhance the survival of the cells during drying [5]. Amara and Shibl showed that probiotics are not only helpful in supporting health or managing pathogenic infections, but also effective for the treatment and controlling of diseases [6]. In addition, the utilization of fermented foods which are the usual source of lactic acid bacteria can confer remarkable health benefits, such as decreasing the incidence rate of type 2 diabetes and cardiovascular illnesses [7], and also helpful metabolic effects [8].

Categorizing 294 meta-analysis articles have been done from the year of 2000 until 2020, on the effects of probiotics in the prevention and treatment of diseases, demonstrated that only 21% of these studies reported the ineffectiveness of probiotics in the prevention or treatment of various diseases but 79% showed a positive effect. It is worth saying that no analysis was found to report a negative effect of probiotics. This shows the importance of probiotics on human health that they are not only not detrimental but also may have a beneficial effect on the host. Besides, the statistics of the efficacy percentage of probiotics on diseases indicate that probiotic supplements may be more effective in preventing or treating some diseases (80.95–100%), including; diabetes, infections, irritable bowel syndrome, enterocolitis, and diarrhea. It is worth mentioning that these results have been conducted with more than 14 meta-analysis articles from 2000 to 2020 on each of these diseases (Figure 1).

Figure 1.

The effectiveness percent of probiotics on diseases with the highest number of studies (from 2000 to 2020).

Probiotics have been used to modulate the microbial community in a beneficial way and as a result, immunity improves against many infections that threaten human and animal lives [9]. Probiotics exert their beneficial effects on the host through different mechanisms different mechanisms including straightly eliminating or inhibiting the growth of pathogens by producing antimicrobial substances, destroying toxins, regulating the immune system, reintroducing the microbiota balance, competing with pathogenic microbes for adhesion sites and nutrients, enhancing intestinal barrier function, and immunomodulation [10, 11, 12, 13].

Using antibiotics in a large amount unselectively annihilates normal intestine and genital tract flora, and damages the host’s mechanisms of immunity [14]. Nowadays, spreading antibiotic resistance among human pathogens is a major public health concern in the world. It can affect people at any stage of life, as well as the healthcare, veterinary, and agriculture industries. As it is clear antimicrobial resistance is increasing nowadays due to the overuse or misuse of antibiotics against infections; however, probiotics can be used as a great alternative to them [15, 16]. As probiotics help to balance the intestinal microbiota composition, they can protect the host against diseases [17]. However, it should be noted that to produce probiotic supplements for humans or animals, strains containing antibiotic resistance genes must be distinguished from other strains, as there is a possible risk of spreading resistance genes to other pathogenic or non-pathogenic strains [18].

It is the purpose of this chapter to provide a comprehensive review of the research that has been conducted on the importance of probiotics in the prevention/treatment of several common human diseases.

2. Distribution of probiotic articles by type disease

Figure 2 shows the distribution of meta-analysis probiotic articles published from 2000 to 2020 by anatomical of physiological target. The greatest number of studies were associated with digestive system diseases (139 out of 283 or 49.11% of the total) and the least of them were related to disorders of the nervous system, eye, and adnexa. Figure 2 illustrates the proportion of probiotics in the treatment of different diseases as well.

Figure 2.

Distribution of probiotics-disease-related meta-analysis articles based on the category of diseases (2000–2020). The effectiveness of probiotics was defined as the percentage of completed curing or just improvement of some parameters in patients based on the result of each meta-analysis study.

3. Efficacy of probiotics on gastrointestinal diseases

Probiotics have a positive effect on intestinal function. They enhance the structure of mucus barrier and make intestinal connections closer by boosting the amount of mucus produced. They decrease inflammation and restore normal bowel movements as well [19, 20]. So, these mechanisms of action lead to probiotics having a major role in the management of gastrointestinal disorders.

3.1 Diarrhea

Among the probiotic studies conducted on digestive system diseases, diarrhea is approximately the most studied case. Evidence demonstrates that epidemiological relevance of acute diarrhea, whether caused by virus or associated by using antibiotic, is very high in the world, particularly, in developing countries [21]. Evidence show Limosilactobacillus reuteri ATCC 55730 [22, 23] and Saccharomyces boulardii [24, 25] play an important role in treating acute diarrhea in children. Research shows that two probiotic strains including Lactobacillus GG and Saccharomyces boulardii play important role in preventing antibiotic-associated diarrhea in both adult patients and children as well [21, 26]. Research reported that treatment by probiotics could reduce acute diarrheal illness by approximately 1 day [27, 28, 29, 30, 31, 32].

Probiotics’ preventive or therapeutic effect in almost all types of diarrheas is related to some parameters including strain type, the antimicrobial and anti-inflammatory properties of the probiotic strain, and utilized dosage [11, 12, 13]. The effectiveness of probiotics on diarrhea has been imputed to their immunostimulatory effect and also restoring gut microflora to the balance situation [33, 34].

3.2 Irritable bowel syndrome (IBS)

In rodents with intestinal inflammation, it has been proven that probiotics can reduce intestinal cytokine secretion and improve epithelial barrier function [35]. And a reduction of IBS symptoms happened in IBS patients due to enhanced cytokine profile [36] after probiotic supplementation was used [19, 37, 38, 39]. A meta-analysis of 15 human studies including 1793 IBS patients also indicated that probiotic therapy reduced pain and symptom severity scores in these people [40]. Furthermore, studies both in humans and animals show that different probiotic strains can be effective in alleviating abdominal pain and decreasing visceral hypersensitivity by changing the expression of neurotransmitters and receptors which are associated with the pain pathways such as the opioid or the cannabinoid receptors [41, 42]. However, taking into account the effectiveness of probiotics based on the type of strain used, duration, dose of administration, and single or combined strains used, can be different in a specific disease. Although many research showed the efficacy of probiotics on IBS patients, however, Connell et al. reported that VSL#3 probiotic supplement which is the combination of eight bacterial strains, not had any positive effect on abdominal pain, stool consistency, abdominal bloating, or quality of life in patients with IBS [43].

3.3 Inflammatory bowel disease (IBD)

IBD is a collective term used to describe Crohn’s disease (CD), ulcerative colitis (UC), and nonspecific colitis [44]. The inflammation of the gastrointestinal tract is in common characteristic of these diseases although each of them has distinct features, the inflammation may lead to pain, diarrhea, and bleeding [44]. The precise cause of IBS is unknown; however, it is thought that a multifactor is involved, the complex interplay of genetics and epigenome, environmental factors, and microbiome [45].

It is shown that probiotic administration alleviated the severity of the colitis by decreasing the NF-κB DNA binding activity, and also reducing the accumulation of leukocytes, and downregulating IL-6 and TNF-α production. Probiotics also might be useful in preserving remission and preventing relapse of UC [46, 47]. Other researchers demonstrated the efficacy of probiotics on this disease as well [48, 49]. It should be noted that based on investigating all meta-analysis studies of probiotics on UC published from 2000 to 2020, probiotics supplementations was 100% effective for remission induction and preventing relapse of UC. Therefore, probiotic therapy seems to be a safe and effective method for patient with UC, however, evidence has not proven efficacy of this supplement on CD patients so far [49, 50, 51, 52]. A clinical trial confirmed this statement. In a randomized, double-blind, placebo-controlled trial of adult patients with UC and CD, treatment with a multi-strain probiotic supplement or placebo for 4 weeks. The result showed that utilizing probiotics could reduce intestinal inflammation in patients with UC, but not in CD [53].

4. Efficacy of probiotics on respiratory diseases

Studies report that probiotics can play a significant role in treatment and preventing or reducing the duration of respiratory system diseases [54, 55, 56] and it might be a practical alternative to promote recovery from these diseases [57, 58]. Besides, some evidence showed that probiotics may stimulate respiratory immunity by improving T regulatory response in the airway and enhance resistance to respiratory tract infections caused by bacteria and viruses [59, 60, 61]. Probiotics impact lung microbiota [62] and then exert anti-inflammatory activity in the lungs [63]. For instance, orally administered of Lactobacillus helveticus can modulated the immune response in a positive way [64, 65, 66, 67]. And this probiotic strain by increasing the number of cells secreting IgA in the intestine and bronchial-associated lymphoid tissue has an immunoprotective impact on mucosal immunity [68]. Evidence indicates that lactic acid bacteria and their metabolites move from gut to lung and exert various immunomodulatory actions [69]. Different probiotic strains including Bifidobacterium and Lactobacillus were reported to be a great option in treating rotavirus infection in both animals and humans [70, 71, 72]. Besides, among chronic respiratory diseases, some probiotic strains have improved at least one symptom of allergic rhinitis (AR). In particular, Lactobacillus paracasei LP-33 can enhance the quality of life of patients with AR, according to a meta-analysis study carried out recently [73].

4.1 Influenza

An animal study was done by Lu et al. [69] evaluated the effect of Lactobacillus mucosae 1025, Bifidobacterium breve CCFM1026, and their mixture on mice infected with the influenza virus for 19 days. The result shows that the clinical symptoms were improved by probiotic treatments. L. mucosae 1025 could directly decrease viral loading in the lung, and B. breve CCFM1026 might alter the immune responses. However, the mixture reduced viral loading and increased the antiviral protein MxA expression, which none of the single strains alone were not able to increase MxA expression. It is reported this is because of increasing the amount of butyrate production resulting from changing the gut microbiota composition [69]. In addition, other probiotic strains which are tested in mice with influenza infection and their effectiveness were determined are Bacillus subtilis 3 [74], Lactobacillus rhamnosus M21 [75], Bacillus subtilis PY79 [76]. Studies indicate Bacillus subtilis 3 is not only effective for the prevention and treatment of influenza but also helpful in the prevention and treatment of bacterial infections in both animal models [77, 78] and humans [78, 79]. The antibacterial property of this strain is due to its ability to produce an antibiotic named aminocoumarin which can suppress a wide range of pathogens and also strengthen host resistance [80]. Furthermore, a double-blinded, placebo-controlled trial of the combination of different probiotic strains containing Lacticaseibacillus paracasei subsp. paracasei, Lactobacillus casei 431 and Lactobacillus fermentum PCC on patients with a common cold and influenza-like infections was conducted by Zhang et al. [81]. In this trial, probiotic mixture 50–60% compared to the placebo group decreased the outbreak of common cold and influenza-like symptoms [81].

4.2 Covid-19

The evidence indicates that gut microbiota dysbiosis happened in COVID-19 patients even 6 months after recovery [82]. Restoring gut microbiota balance has been demonstrated to promote host resistance to viruses or invading pathogens at the respiratory mucosa level [83, 84]. Therefore, administration of prebiotics and probiotics are suggested to COVID-19 patients, to modulate the balance of gut microbiota and decrease the risk of secondary infection due to bacterial translocation [85].

In Covid-19 infected patients, reducing probiotic strains, especially Lactobacillus and Bifidobacterium may postpone recovery. Consequently, it is suggested that host-microbiota balance should be preserved in the gut and lung which can be beneficial in fighting against COVID-19 [86]. Besides, Mahooti et al. [87] recommend that because probiotics have antiviral properties against other viruses, so they can be a complementary treatment against SARS CoV-2.

In numerous human studies, it has been shown that probiotics, especially, Lactobacillus rhamnosus GG, has the ability to improve the barrier of intestinal and lung and homeostasis, by increasing regulatory T cells, enhancing anti-viral defense, and reduce pro-inflammatory cytokines in systemic and respiratory infections. These immunomodulatory agents may be helpful in individuals who have been infected or are at risk of developing, COVID-19 [88].

4.3 Pneumonia

It seems probiotic therapy is a fascinating option as a nonantibiotic method for protection of the host microbiota balance and VAP prevention. Probiotics may probably decrease the incidence of VAP through diverse local and systemic effects that limit the colonization of pathogen species or improve host immune defenses [89]. Numerous studies confirmed the promising efficacy of probiotics on the prevention of VAP [90, 91, 92, 93, 94, 95].

A RCT shows that the combination of four probiotic strains including Lactobacillus acidophilus LA-5, Lactobacillus plantarum, Bifidobacterium lactis BB-12, and Saccharomyces boulardii could reduce the incidence of VAP by 11.9%, the time of stay in the intensive care unit (ICU) and the length of hospital stay [96]. In addition, a clinical trial shows that using a mixture of probiotic supplements containing Lactobacillus, Bifidobacterium, and Streptococcus spp. for 14 days, can significantly reduce the length of ICU and hospital stays in VAP patients [97].

Despite a meta-analysis of including 15 randomized controlled trials involving 2039 patients which reported that probiotic therapy could prevent ventilator-associated pneumonia (VAP), and decrease the duration of antibiotic treatment of VAP, however, they had not shown any significant impact on the duration of mechanical ventilation, ICU length of stay and mortality [98]. Another meta-analysis also confirmed that there was no remarkable difference in ICU length of stay between probiotics and placebo groups [92].

Among the investigation we have done on reviewing probiotic meta-analysis studies until 2020, out of 6 studies on pneumonia, 5 of them related to VAP, and one study was on nosocomial pneumonia. The statistics show that probiotic supplementation could be 66.66% effective to prevent ventilator-associated pneumonia.

5. Efficacy of probiotics on metabolic diseases

Many hypotheses surround the feasible involvement of the intestinal microbiota in metabolic disorders such as diabetes and obesity.

5.1 Diabetes

Some evidence suggests that in diabetic patients, disruption in antioxidant defenses happens and free radicals are produced in large amounts [99, 100]. Oxidative stress is considered as one of the major factors in insulin resistance [101], the onset of diabetes and the pathogenesis of diabetic retinopathy as well [102, 103]. Evidence recommends that some probiotic strains are effective in reducing inflammation and oxidative stress in pancreatic cells [104, 105], and they play an important role in preventing the destruction of β-pancreatic cells [106, 107]. A preclinical study of the effect of probiotics on diabetic rats showed that the combination of two probiotic strains including Lactobacillus acidophilus and Lactobacillus casei could significantly suppress oxidative damage by repressing the lipid peroxidation and protecting the antioxidant content of glutathione, superoxide dismutase, catalase and glutathione peroxidase in their pancreases [108]. It has also been demonstrated that Bifidobacterium adolescentis enhances insulin sensitivity [109] by increasing the amount of production of glucagon-like peptide 1 (GLP-1) [110]. GLP-1, a growth factor for pancreatic cells, through complicated mechanisms like modulation of insulin secretion, pancreatic cell mass and food consumption improve glucose tolerance [111]. Furthermore, probiotics have also been found to be effective in reducing blood glucose levels [112, 113, 114]. This may be because of properties of probiotics that can ameliorate glucose metabolism via increasing the bioavailability of gliclazide, suppressing or postponing the intestinal absorption of glucose and changing the autonomic nervous activity [115, 116, 117]. The result of a clinical trial on 79 diabetic people who had used metformin as a daily treatment, and received multi-probiotic strains or placebo two times a day for 12 weeks, indicates glycated hemoglobin (HbA1c), and weight significantly decreased in the probiotic-utilizing group compared to placebo [118].

5.2 Obesity

Many recent meta-analysis studies proved that probiotics significantly had a promising effect on weight loss and body mass index (BMI) improvement [119, 120, 121, 122]. Besides, in one study, it was shown that when the combination of different probiotic strains was used for more than 8 weeks, reducing the body weight and BMI happened [123]. However, some other meta-analysis studies did not approve this statement [124, 125]. Furthermore, in another research was done by million and colleagues reported different species of Lactobacillus have different effects on weight in both humans and animals [126]. According to this research probiotic strains associated with weight gain in animals were Lactobacillus fermentum and Lactobacillus ingluviei. And a probiotic strain with anti-obesity effect was Lactobacillus plantarum, in addition, Lactobacillus gasseri was an effective strain for weight loss in both humans and animals [126]. Contradictory results on the effect of probiotics in weight modifications may be due to differences in the probiotic strains and host.

The gut microbiota effects on energy regulation can be a prime factor in the development of obesity [127, 128]. Human intestinal microbiota is a complicated ecosystem that includes numerous kinds of microorganisms like bacteria, viruses, archaea, fungi, protists, nematodes, and phages, involved in various functions of host metabolism [129]. A higher proportion in the strains of Bacteroides fragilis, Clostridium leptum, and Bifidobacterium catenulatum and a lower percentage of Clostridium coccoides, Lactobacillus sensu lato, and Bifidobacterium display considerable weight loss [130, 131], therefore, probiotics may be a powerful tool in modulating obesity by changing the gut microbiota composition [132, 133].

The gut microbiota remarkedly can ferment the indigestible carbohydrates into short-chain fatty acids (SCFAs). SCFAs are the main metabolites of intestinal microbiota which have an important role in energy, glucose, lipid homeostasis and intestinal health [134, 135]. The most plentiful SCFAs are acetate, butyrate, and propionate (encompass 95% of all SCFAs), which are the main substrates for glucose metabolism [129]. Multiple animal studies have shown that the gut microbiota and their metabolites, especially SCFAs, have a significant role in obesity [136, 137, 138] and also in the prevention and treatment of obesity-associated insulin resistance [139, 140, 141, 142]. Therefore, it is recommended that SCFAs have the ability to control host energy metabolism in the advancement of diet-induced weight and also can be applied for de-novo synthesis of lipid and glucose [143]. However, in human studies, there is contradiction in the association between SCFAs and obesity. For instance, some studies have demonstrated a positive interaction between fecal SCFAs levels [144, 145, 146] and obesity while others reported an unfavorable result [147]. Evidence shows that acetate plays an important role in the hypothalamic control of appetite [139] and also increase anorexigenic neuropeptide expression [139] so it is suggested that acetate may be a functional treatment for obesity. Among acetate-producing probiotic strains we can suggest Methanobrevibacter smithii and Blautia hydrogenotrophica [148]. Chambers et al. have demonstrated that colonic propionate can acutely lessen energy intake and prevent long-term weight gain in people [149]. Considering probiotics, the species of genera Lactobacillus and Bifidobacterium basically create butyrate and propionate [150]. Butyrate has the ability to alleviate obesity and other metabolic complications which are very usual in western nations [151]. For presentation, a decrease in the number of microbes that produce butyrate in humans is connected with an elevated threat of metabolic disease [152]. Clostridium butyricum, Faecalibacterium prausnitzii, Eubacterium rectale, Roseburia are some of probiotic strains found in the intestines of healthy animals and humans which produce butyrate [153, 154].

5.3 Other metabolic disorders

Meta-analysis studies reporting the effectiveness of probiotic supplementation on lipid and glucose metabolism on pregnant women [155] and patients with diabetes [156]. And also, the result of another meta-analysis study suggests that probiotics should be used as a new way to control and management of lipid profile and blood pressure in type 2 diabetic patients [157]. Probiotics play their role in reducing serum cholesterol (hypocholesterolemia) through some mechanisms including binding cholesterol and fatty acids to the probiotic bacteria’s cellular membrane [147], deconjugation of bile acids by the presence of bile salts hydrolase enzymes in lactic acid bacteria [139, 148, 149, 150], the transformation of cholesterol to coprostanol and excreted into feces [147]. A clinical trial of 84 pregnant women with gestational diabetes mellitus (GDM) receiving 300 mg/day of yogurt contained two probiotic strains including Lactobacillus acidophilus and Bifidobacterium lactis or placebo (ordinary yogurt) for 2 months reported that consumption of yogurt probiotics can manage blood glucose better and also the rate of macrosomia might be reduced in pregnant women by GDM through this regimen [158].

6. Effect of probiotics on mental illnesses

6.1 Depression and anxiety

Depression and anxiety are common psychological disorders that they are highly comorbid with each other, and are important public health problems. The efficacy of probiotics on depression and anxiety through meta-analysis studies over the course of 20 years (from 2000 to 2020) was reviewed comprehensively. Half of these studies showed that probiotics could improve the symptoms of these patients [159, 160, 161, 162] while the other half reported, probiotic therapy for these mental disorders is not proven [163, 164, 165, 166]. In a randomized, double-blind, placebo-controlled trial treatment of 65 multiple sclerosis patients with multi-strain probiotics, promoted mental health parameters [167]. Recent research found that two hypotheses may explain the potential positive effect of probiotics on mood and cognition; one theory is controlling important neurotransmitters and the other is regulating inflammatory markers by these probiotics [168]. Studies exhibit that cytokines increase by inflammatory factors, and subsequently, cytokines effect on synthesis, release, and absorption of neurotransmitters [169, 170, 171]. Ultimately, the increased levels of proinflammatory cytokines are associated with neurological disorders such as depression and anxiety. Probiotics improve mood and insomnia in depressed patients [172, 173, 174] by reducing inflammatory cytokines Interleukin-1 beta (IL-1β), [175, 176], Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) [172, 173, 174, 176].

7. Conclusion

The effects of probiotics have been widely investigated in a broad spectrum of diseases and are currently suggested as a possible treatment or prevention for several diseases. Different mechanisms are known for the beneficial effects of probiotics, including directly eliminating or preventing pathogens growth by producing antimicrobial substances, eliminating toxins, competing for binding to receptors of epithelial cells, regulating the immune response, reintroducing the microbiota balance, enhancing tight intestinal connections, and also increasing mucus production. Probiotic therapy seems to be a safe and effective method especially, for patients with UC for remission induction and preventing relapse of UC, but, evidence has not proven the efficacy of this supplement on CD patients so far. However, it is needed to taking into account that the biological effects of probiotics on a special disease can be distinctly strain-specific. Therefore, more randomized clinical trials of various probiotic strains in both form of single and mixture on those patients are needed to definitively prove the effectiveness of probiotic microorganisms on these diseases.

Conflict of interest

The authors declare no conflict of interest.