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Effetti positivi dei probiotici (ma ne parla un articolo sui prebiotici)
I prebiotici, oltre a nutrire la flora batterica intestinale e a farle produrre catene corte di acidi grassi come primo effetto immediato, ha una serie di effetti positivi non immediati:
6.1.1. Irritable Bowel Syndrome and Crohn’s Disease
There are a few studies about the effects of prebiotics on irritable bowel syndrome (IBS) and Crohn’s disease. IBS is a gastrointestinal syndrome characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. Crohn’s disease is a type of chronic, relapsing inflammatory bowel disease (IBD), which can involve any part of the gastrointestinal tract from the mouth to the anus. It has been reported that in both IBS and Crohn’s disease, the Bifidobacteria and Faecalibacterium prausnitzii population along with Bacteroides to Firmicutes ratio were decreased [29,98].
A double-blind cross-over study demonstrated that the administration of oligofructose at the dose of 6 g/day for 4 weeks had no therapeutic effects on patients suffering from IBS [99]. Similarly, another randomized, double-blind, placebo-controlled trial published in 2000 implicated that 20 g/day FOS supplementation failed to improve IBS [100]. In contrast, two more recent randomized, double-blind, clinical trials have shown IBS symptoms improvement after consuming 5 g/day FOS for 6 weeks [101] or 3.5 g/day GOS for 12 weeks [102].
A group study in 2006 reported that supplementation with 15 g/day FOS for 3 weeks elevated Bifidobacteria population in the feces and improved Crohn’s disease [103]. However, the other randomized, double-blind, and placebo-controlled trials demonstrated no clinical benefits after administrating 15 g/day FOS in patients with active Crohn’s disease [104] and 20 g/day oligofructose-enriched inulin in patients with inactive or mild-to-moderately active Crohn’s disease [105] for a duration of 4 weeks.
6.1.2. Colorectal Cancer
Colorectal cancer, ranked as the third most common malignancy worldwide, is a multi-step disease from genetic mutation to adenomatous polyps, which then leads to invasive and metastatic cancer [106]. It has been demonstrated that prebiotics fermentation products, such as butyrate, could have protective effects against the risk of colorectal cancer, as well as its progression, via inducing apoptosis [106,107,108]. In addition, a clinical trial demonstrated that symbiotic therapy (Lactobacillus rhamnosus and Bifidobacterium Lactis plus inulin) could reduce the risk of colorectal cancer by reducing the proliferation rate in colorectal, inducing colonic cells necrosis, which leads to improving the integrity and function of epithelial barrier [106,109,110].
6.1.3. Necrotizing Enterocolitis
Necrotizing enterocolitis (NEC) is a gastrointestinal emergency condition primarily in premature neonates, in which portions of the bowel undergo necrosis. It can lead to high morbidity and mortality rates [111]. Since prebiotics, such as FOS and GOS, can stimulate the growth of gut microbiota (e.g., Bifidobacteria) and reduce the pathogenic bacteria in preterm infants [112,113,114], it is claimed that they can prevent NEC [111]. Moreover, SCFAs can improve feeding tolerance by enhancing both gastric emptying and bowel motility [115,116,117]. A meta-analysis of four randomized controlled trials showed that FOS, GOS or their mixture could elevate the concentration of fecal Bifidobacteria, but had no significant effect on risk reduction and progression of NEC [118] (Table 1). Therefore, more clinical trials need to be done to elucidate the definite effects of prebiotics on NEC.
6.2. Prebiotics and the Immune System
Consuming prebiotics can improve immunity functions by increasing the population of protective microorganisms. Animal and human studies have shown that prebiotics can decrease the population of harmful bacteria by Lactobacilli and Bifidobacteria [12,121,122,123,124]. For example, mannose can reduce colonization of pathogens by promoting mannose adhesion to Salmonella. Mannose binds to Salmonella via type 1 fimbriae (finger-like projections) [125]. In addition, pathogens are not able to bind to the epithelium in the presence of OSCs. Prebiotics can also induce the expression of immunity molecules, especially cytokines (Table 2).
Interestingly, maternal prebiotics metabolites are able to cross the placenta and can affect the development of the fetal immune system [12,126]. In 2010, Fugiwara et al. [127] reported that FOS administration in a pregnant mouse model modified offspring microbiota, and consequently, their skin inflammation was attenuated. In contrast, Shadid et al. [128] in a placebo-controlled, randomized, and double-blinded study demonstrated that bifidogenic effects of prebiotics supplementation in humans could not be transferred to the next generation. The details of well-known prebiotic effects on the immune systems are discussed below:
- I- Oligofructose and inulin mixture: The mixture of oligofructans and inulin can improve antibody responses toward viral vaccines, such as influenza and measles [129].
- II- FOS: Studies have shown the improvement of antibody response to influenza vaccine following FOS consumption. Moreover, the side effects of the influenza vaccine are reduced [130,131]. Diarrhea-associated fever in infants is also reduced by this category of prebiotics. Apart from these, it can decrease the use of antibiotics, duration of disease, and the incidence of febrile seizures in infants [132,133]. β(2→1) fructans can up-regulate the level of interleukin 4 (IL-4) in serum, CD282+/TLR2+ myeloid dendritic cells, and a toll-like receptor 2-mediated immune response in healthy volunteers [134]. In contrast, another study demonstrated that the salivary immunoglobulin A (IgA), immune cells in serum, and activation and proliferation of T cells and natural killer (NK) cells were not changed after consuming β(2→1) fructans [135]. It has been noted that FOS reduces the risk of some immune diseases in infants, such as atopic dermatitis [136,137]. This type of prebiotic decreases the expression of IL-6 and phagocytosis in monocytes and granulocytes [138].
- III- GOS: Studies showed that GOS increased the blood level of interleukin 8 (IL-8), interleukin 10 (IL-10), and C-reactive protein in adults, but decreased IL-1β. It has been found that the function of NK cells improves by consuming GOS [139,140]. In infants, GOS reduces the risk of atopic dermatitis and eczema [136,137,141].
- IV- AOS (acidic oligosaccharides): The possibility of atopic dermatitis is reduced by AOS in low-risk infants [136].
6.3. Prebiotics and the Nervous System
modificaThe gastrointestinal tract is connected to the central nervous system through the “gut-brain axis” [142]. For instance, administration of prebiotics in piglets decreases the gray matter in order to improve neural pruning [143]. But the regulatory effects of prebiotics on the human brain have not been completely defined. Gut microbiota affects the brain through three routes, including neural, endocrine, and immune pathways [142,144,145].
- I- Neural Pathway: The products of prebiotics fermentation can affect the brain by the vagus nerve [146]. Some prebiotics, such as FOS and GOS, have regulatory effects on brain-derived neurotrophic factors, neurotransmitters (e.g., d-serine), and synaptic proteins (e.g., synaptophysin and N-methyl-D-aspartate or NMDA receptor subunits) [147,148].
- II- Endocrine Pathway: Hypothalamic-pituitary-adrenal axis is a neuroendocrine pathway. The microbiome growth in mice can induce corticosterone and adrenocorticotropic hormone in an appropriate way [149]. In addition, prebiotics act as a regulator of other hormones, such as plasma peptide YY [147].
- III- Immune Pathway: As discussed before, prebiotics can affect different aspects of the immune system. Beside neurological functions, prebiotics are also capable of influencing mood, memory, learning, and some psychiatry disorders by changing the activity and/or composition of gut microbiota [145] (Table 3).
- IV- Mood: Stress hormones are able to affect anxiety-related behaviors [150,151]. It was demonstrated that the level of stress hormones (adrenocorticotropic hormone (ACTH) and corticosterone) increased in germ-free mice following exposure to controlled stress. After administrating Bifidobacterium infantis, corticosterone and ACTH reached normal levels [149].
- V- Memory, concentration, and learning: Recently, a number of studies have shown the relation between memory and administration of fermentable compounds in both animals and humans [152]. Investigations on a different kind of prebiotics have implicated memory improvement in middle-aged adults [153,154]. Some prebiotics, such as arabinoxylan and arabinose, can enhance general cognition and attenuate the accumulation process of dementia-related glial fibrillary acidic protein in mice [155]. Prebiotics may be more efficient in preserving recall and learning rather than the development process. In 2015, a randomized, double-blind, and placebo-controlled study was performed to examine the effects of FOS and GOS daily consumption for three weeks on the level of salivary cortisol and emotional alteration regarding this hormone. FOS had no significant effect, but 5.5 g GOS intake increased the level of cortisol in saliva and enhanced the concentration in adults [156]. A randomized, double-blind, placebo-controlled trial demonstrated that administration of non-starch polysaccharides (3.6 g per day) for twelve weeks enhanced recall and memory processes in the middle-aged adult [153,154]. In contrast, the mixture of FOS, GOS, and AOS could not enhance the development of the nervous system in preterm infants after 24 months [157]. In two other clinical investigations, Smith et al. observed that administration of inulin-enriched oligofructose might enhance mood, recognition, immediate memory, and recall (after 4 hours). However, this prebiotic failed to recover long-term memory (after 43 days) [158,159]. In another study, administration of polydextrose and GOS mixture decreased anxiety-like behavior in male piglets and promoted positive social interactions in rats [143,160]. Furthermore, the consumption of this mixture boosted their cognition memory [160,161].
- VI- Autism: 70% of people with autism are suffering from concomitant gastrointestinal disorders compared to 9% of healthy individuals. Chronic constipation (and other diseases as a result of constipation), abdominal pain with or without diarrhea, gastroesophageal reflux disease, abdominal bloating, disaccharide deficiencies, gastrointestinal tract inflammation, and enteric nervous system abnormalities are examples of gastrointestinal symptoms and signs that are reported for patients with autism spectrum disorders [162]. The severity of autism is shown to be correlated to higher gastrointestinal disorders [163]. Interestingly, a review article published in 2016 confirmed these statements [164]. The composition of gut microbiota is changed in patients with autism disorders. Some studies have shown high levels of Clostridium and depleted Bifidobacterium in feces. In children with autism, gut metabolites are different from healthy individuals. For example, the amount of SCFAs in children with autism is lower than healthy ones [163,165]. Various prebiotics, such as wheat fiber, may have therapeutic effects on patients with autism by decreasing the population of Clostridium perfringens and increasing the rate of Bifidobacteria [166]. Catecholamines, which are a category of neurotransmitters, are increased in individuals with autism. These neurotransmitters are produced by tyrosine hydroxylase. An in vitro study in a rat adrenal medulla cell line demonstrated that SCFAs, the products of prebiotic fermentation, could induce the expression of tyrosine hydroxylase [167]. However, further investigations are required to understand which prebiotics have therapeutic effects on human autism.
- VII- Hepatic encephalopathy: Hepatic encephalopathy happens when the liver does not function properly. The main reason for hepatic encephalopathy is the increases in the level of blood ammonia. This condition causes numerous psychiatric and neurologic complications, including personality, speech, and movement disorders, as well as cognition impairment, and may eventually result in coma and death. In 1966, it was demonstrated that lactulose could effectively treat hepatic encephalopathy by decreasing the level of ammonia in the gut. Lactulose can improve the life quality of people suffering from hepatic encephalopathy. This prebiotic also has preventive effects on hepatic encephalopathy [143,168,169,170]. Lactulose exerts its beneficial effects on hepatic encephalopathy through different pathways. First, the product of lactulose fermentation is lactic acid, which is able to reduce the colonic lumen pH by releasing H+. The ammonia in the gut reacts with proton and produces ammonium. This conversion develops a concentration gradient that increases the amount of ammonia reuptake from the blood into the gastrointestinal tract [171]. Second, in the presence of lactulose in the gastrointestinal tract, the bacteria utilize the energy of lactulose fermentation instead of the conversion of amino acids to ammonia energy. Third, lactulose can inhibit glutaminase and prevent the production of ammonia from glutamine [143]. Finally, lactulose shortens the colonic transit time. Thus, it can reduce the level of ammonia in the gastrointestinal tract. Other compounds, such as lactitol, may also be as effective as lactulose in the treatment of hepatic encephalopathy. Interestingly, the side effects of lactitol are much fewer than lactulose (e.g., flatulence and nausea) [172,173,174].
6.4. Prebiotics and Skin
As mentioned in the previous sections, the consumption of prebiotics was shown to decrease the risk of development, as well as the severity of allergic skin diseases, such as atopic dermatitis [136,137]. In hairless mice exposed to the UV, the consumption of GOS for 12 weeks enhanced water retention and also prevented the development of erythema [175]. On the other hand, GOS can improve skin barrier by increasing dermal expression of cell adhesion and matrix formation markers (e.g., CD44 and collagen type 1). Upon metabolizing aromatic amino acids by gut microbes, some compounds, such as phenols, may be produced. These compounds are transferred into the skin. Phenols, such as p-cresol, may be toxic for patients with underlying kidney diseases [176]. In women, consumption of GOS with or without probiotics, such as Bifidobacterium breve, can abolish the reduction of water and keratin caused by phenols [177,178,179,180] (Table 4).
6.5. Prebiotics and Cardiovascular System
According to the statistics, 30% of the deaths in the United States in 2013 were caused by cardiovascular diseases (CVD). The main reason for this growing trend is the alteration of people’s lifestyles and eating habits [181]. Therefore, many researchers have studied the influence of fibers and prebiotics consumption on CVD. However, the direct beneficial functions of prebiotics in this regard have not been demonstrated yet. In this section, we summarized some of the indirect effects of prebiotics on CVD.
Prebiotics are able to lower the risk of CVD by reducing the inflammatory elements. Several investigations demonstrated an improvement in the lipid profile by consuming prebiotics. In a randomized, double-blind, and placebo-controlled crossover clinical trial, Letexier et al. [182] treated healthy individuals with 10 g/day inulin for three weeks. They observed that this regimen decreased blood triacylglycerol (TAG) and liver lipogenesis, but it had no statistically significant effect on the cholesterol level.
In line with these findings, in a randomized and double-blinded cross-over trial, Russo et al. [183] demonstrated that the consumption of inulin-enriched pasta with a formulation of 86% semolina, 11% inulin, and 3% durum wheat vital gluten decreased both TAG and lipogenesis in healthy individuals, rather than cholesterol level. In contrast, Frochen and Beylot [184] reported that the consumption of 10 g/day inulin-type fructans for six months had no significant effects on lipogenesis in the liver of healthy subjects.
To assess the effects of oral L-rhamnose and lactulose on lipid profile in a partially randomized crossover study, Vogt et al. [185] administered 25 g/day of these two prebiotics for four weeks in healthy individuals. They observed a significant reduction in the synthesis and level of TAG but not cholesterol. Opposed to that, the results of another investigation in 1991 suggested that lactulose increased blood cholesterol (up to 10%) and B-apolipoprotein (up to 19%) [186].
In a double-blind, randomized, placebo-controlled, crossover study on overweight subjects with ≥3 risk factors of metabolic syndrome, Bimuno® Galacto-oligosaccharides (B-GOS) administration for 12 weeks decreased circulating cholesterol, TAG, and total:HDL (high-density lipoprotein) cholesterol ratio [187]. However, in the elderly, this prebiotic had no significant effect on the total:HDL cholesterol ratio [139]. The effect of β-glucan intake on lipid profile was measured in a meta-analysis study (from 1990 through Dec. 2009). It was implicated that β-glucan consumption could reduce the level of total cholesterol and LDL [188]. Finally, a meta-analysis of relevant randomized controlled clinical trials published between 1995 and 2005 implicated that FOS could reduce TAG level with an average rate of 7.5% [189].
Paradoxically, prebiotics may have a detrimental effect on lipid profile through producing some SCFAs, such as acetate. Acetate can be converted to acetyl-CoA, which is a substrate to synthesize fatty acids in hepatocytes [190]. This can justify the increase in the blood concentration of cholesterol and triglycerides after rectal infusion of acetate [191]. However, some other SCFAs, such as propionate and butyrate, may improve lipid profile. Propionate can inhibit lipid synthesis from acetate [192]. Therefore, prebiotics, such as FOS and L-rhamnose, may have lipogenic effects by producing acetate, butyrate, and propionate [14,193]. Hence, it is crucial to determine the end products of prebiotics to select the appropriate one for this purpose. Although prebiotics are claimed to be beneficial for obesity-related diseases, such as fatty liver disease, particularly, non-alcoholic fatty liver issue in one study [194], there is at least another clinical trial that refuted this opinion [195] (Table 5).
6.6. Prebiotics and Calcium Absorption
Statistics have shown that more than 28 million people in the United States have osteoporosis or low bone mass, and in European Union, one out of eight citizens over 50 years old have spinal fracture each year [196]. There are clinical trials on the impact of prebiotics dietary fibers on the absorption of minerals, such as calcium, but the results are conflicting. Some studies have shown that consumption of lactulose, TOS or inulin + oligofructose in doses ranged between 5 to 20 g/day significantly absorb calcium absorption. In contrast, such a phenomenon is not observed for GOS or FOS (Table 6) [197].
Note
modifica- ^ (EN) Dorna Davani-Davari, Manica Negahdaripour e Iman Karimzadeh, Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications, in Foods, vol. 8, n. 3, 9 marzo 2019, pp. 92, DOI:10.3390/foods8030092. URL consultato il 2 giugno 2025.
