Gut Associated Lymphoid Tissue (GALT) represents the immune system component in the gut and it is structured with specific subsets of immune cell populations, such as T and B lymphocytes, which protect the body from intracellular parasites and from perpetuating autoimmune responses (T helper 1 cells, Th1) or provide humoral response to fight extracellular organisms (T helper 2 cells, Th2). A balanced immune response involves the activity of other immune cell subsets such as T regulatory cells (Treg), which limit immune response preventing autoimmune responses, and T helper 17 (Th17), which inhibit Treg proliferation enhancing inflammatory response (Vangoitsenhoven and Cresci, 2020). Autoimmune Diseases (ADs) are disorders characterized by an immune response directed against self-antigenic proteins, which causes damage and loss of function of involved tissues. They are mainly classified as polygenic disorders (rheumatoid arthritis, systemic lupus erythematosus, type I diabetes) when several genes are involved in their pathogenesis, or monogenic disorders, when a single gene is associated with their onset (Liu et al., 2021). Although the presence of a genetic background predisposing to monogenic or polygenic ADs has been discovered, it is widely accepted that gut microbes and their metabolites may play a pivotal role in their onset and maintenance since they may affect intestinal permeability, with bacterial proteins translocating in the bloodstream, which in some cases mimic autoantigens and could interfere in the Th17/Treg cell balance (Atarashi et al., 2011). For example, segmented filamentous bacteria (Sczesnak et al., 2011; Goto et al., 2014) and bifidobacteria (Tanabe, 2013; Tan et al., 2016) can induce Th17 cell differentiation, while Bacteroides fragilis (Round et al., 2010), Lactobacillus reuteri and Clostridium cluster IV, XIVa and XVIII (Atarashi et al., 2011) have been demonstrated to promote the induction of colonic Tregs, the latter with a mechanism involving the production of SCFAs (Pryde et al., 2002). Type 1 Diabetes (T1D) has been associated with severe dysbiosis and increased intestinal permeability. In particular, an increase in Bacteroides and Clostridium and a decrease in bifidobacteria and lactobacilli have been found in these patients (Murri et al., 2013; Mejía-León et al., 2014; Pinto et al., 2017). Interestingly, Bacteroides overgrowth has been linked to Treg depletion and epithelial barrier impairment (Gianchecchi and Fierabracci, 2019). Moreover, in T1D patients, the increase in Bacteroides has been correlated to anti-islet cell autoantibodies (Henschel, et al., 2018). Hashimoto’s thyroiditis (HT) and Grave’s disease (GD) are the two main autoimmune disorders affecting the thyroid and are characterized by the presence of antibodies against thyreoperoxidase, thyroglobulin (in TH) and against thyroid-stimulating hormone (TSH) receptor in GD. In both HT and GD diseases, anti-gliadin, anti-transglutaminase and anti-Saccharomyces cerevisiae antibodies have been detected, and both thyroid autoimmune disorders are characterized by intestinal dysbiosis (Köhling et al., 2017). In HT patients, an increase in Prevotellaceae and Pasteurellaceae has been recorded and in particular, at the genus level, an increase in Blautia, Roseburia, Ruminococcus, Romboutsia, Dorea, Fusicatenibacter and Eubacterium. On the contrary, a decrease in Enterobacteriaceae, Veillonellaceae and the genera Rikenella, Faecalibacterium, Bacteroides, Prevotella and Lachnoclostridium has been highlighted (Ishaq et al., 2018; Zhao et al., 2018). It is more than plausible that a microbial pattern like this may affect Treg modulation and functions (Köhling et al., 2017). GM can modulate the synthesis of neurotransmitters, such as dopamine, which can inhibit TSH and modulate the hypothalamus-pituitary axis. So, an imbalance in GM could contribute to thyroid disorder development and maintenance with mechanisms involving microbial metabolic pathways (Zhao et al., 2018; Fröhlich and Wahl, 2019). Coeliac disease (CD) is an autoimmune disorder triggered by the interaction between GALT and undigested gluten peptides that translocate across the epithelial barrier into the lamina propria. An increased relative abundance of Bacteroides, Prevotella and Escherichia, and the concomitant reduction of bifidobacteria and lactobacilli have been supposed to contribute to the disease development by influencing the gluten peptide digestion, by stimulating dendritic cells and Tregs, and also by increasing intestinal permeability (Akobeng et al., 2020). Rheumatoid arthritis (RA) onset has been mainly associated with oral dysbiosis and periodontitis (Gianchecchi and Fierabracci, 2019). In the gut of RA patients, an overall decreased microbial diversity has been clearly evidenced (Chen et al., 2016; Picchianti-Diamanti et al., 2018), with a relatively greater abundance of Prevotella copri and a decrease in Bacteroides (Harmsen and and De Goffau, 2016; Schmidt et al., 2019). Interestingly, a study conducted by Pianta et al. (2017) evidenced epitopes in P. copri, which mimic N-acetyl glucosamine-6-sulfatase and filamin, 2 autoantigens highly expressed in RA patient synovia.

Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract with unknow etiology. Beyond a widely studied genetic background, lifestyle and diet appear to have a crucial impact on these pathologies. In fact, despite being a typical disease of Western countries, epidemiological studies reveal how their incidence is increasing in all populations that have adopted a Western lifestyle, characterized by the consumption of a diet enriched in saturated fats, sugars and processed foods. There is growing evidence that chronic inflammation in IBD is sustained by an inadequate response of the immune system to GM leading to unbalanced production of pro-inflammatory cytokines (Rizzello et al., 2019). GM in IBD patients has been extensively analyzed, with results often differing between studies, especially at lower taxonomic levels (Radhakrishnan et al., 2022). Nevertheless, there are some characteristics that have been confirmed by several studies that could explain the aberrant immune response driving chronic inflammation. A decrease in butyrate-producing species Faecalibacterium prausnitzii in IBD subjects, compared to healthy controls, has been evidenced and linked to Treg depletion (Sarrabayrouse et al., 2014; Khan et al., 2019; Akobeng et al., 2020). Moreover, an overall decrease in microbial diversity with a reduction of Firmicutes and an increase in Proteobacteria is often found in IBD patients and has been linked, at least in Crohn’s disease, to disease severity (Frank et al., 2007; Gevers et al., 2014; Maharshak et al., 2017). It is still debated if the dysbiosis can be linked to IBD onset or if it is a consequence of the disease. However, some clues are provided by studies in IBD patients with anal-ileus pouch. The pouch is a transitional tissue which, after surgery, is colonized de novo by GM (Falk et al., 2007; Kohyama et al., 2009). In a prospective study, a decrease in microbial diversity was observed in fecal samples analyzed before surgery in patients developing pouch inflammation, compared to those who maintained a normal (non-inflamed) pouch (Maharshak et al., 2017). Moreover, an increase in Ruminococcus and Clostridium perfringens was found in a similar study, associated with a reduction in Blautia and Roseburia (Machiels et al., 2017). The efficacy of antibiotics and some probiotics for the management of inflammatory flares seems to confirm the strong impact that, beyond a well-established genetic background, GM composition and functions may have on these diseases (Dalal et al., 2018). Irritable Bowel Syndrome (IBS) is a functional disorder characterized by abdominal pain, bloating and an altered intestinal habit that defines four main IBS subtypes: diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), mixed diarrhea and constipation (IBS-M) and non-classifiable IBS symptoms (IBS-U) (Hellström and Benno, 2019). GM analysis in these patients revealed a dysbiosis characterized by loss of diversity compared to the healthy population. Again, the results from various studies are often conflicting. For example, the ratio Firmicutes/Bacteroidetes was found to be both higher and lower in different studies (Jalanka-Tuovinen et al., 2014; Pozuelo et al., 2015). Conflicting results were also obtained on the abundance of SCFA producers (Rodiño Janeiro et al., 2018). These differences may be due to the different analytic techniques, but also to the different clinical features that characterize the IBS subtypes and that should be considered in data analysis (Rodiño Janeiro et al., 2018). Overall, the most consistent data in IBS describe increased proportions of Proteobacteria and Firmicutes members, such as Veillonella and Ruminococcus (Malinen et al., 2005; Tana et al., 2010; Saulnier et al., 2011), and a decrease in Lactobacillus, Bifidobacterium, Faecalibacterium and methanogens (Malinen et al., 2005; Rajilic´-Stojanovic´ et al., 2011; Zhuang et al., 2017; Zhuang et al., 2017).

GM regulates the host energy balance by various mechanisms, e.g., by inducing monosaccharide uptake from the gut and hepatic production of triglycerides, by regulating nutrient absorption and the expression of adipokines, such as the fasting-induced adipose factor, which are involved in peripheral fat storage, as clearly shown by studies on germ-free mice (Bäckhed et al., 2004; Tilg et al., 2020). GM is responsible for the production of SCFAs and monosaccharides from indigestible carbohydrates in the diet, such as fiber (Flint et al., 2015). In metabolic disorders such as obesity and type 2 diabetes, which are strictly correlated to cardiovascular outcomes, intestinal dysbiosis triggers or contributes to the exacerbation and chronicization of these conditions by impairing metabolic pathways and inducing chronic low-grade inflammation that is a typical feature of these diseases (Angelakis et al., 2012; Cotillard et al., 2013). Less microbial diversity has been found in obese subjects, with an overrepresentation of proinflammatory taxa, such as Ruminococcus and Bacteroides, and a decrease in anti-inflammatory species such as F. prausnitzii (Cotillard et al., 2013). Moreover, in subjects with metabolic syndrome there is a greater abundance of SCFA producers, with an increased ability to extract calories from low-energy foods (Marzullo et al., 2020). In type 2 diabetes subjects, GM analysis showed a decrease in Roseburia intestinalis and F. prausnitzii, associated with high intestinal transport (absorption) of sugars (Qin et al., 2012). A common feature in patients with metabolic disorders is the higher proportion of gram-negative bacteria associated with higher levels of lipopolysaccharide (LPS), a bacterial toxin responsible for increased intestinal permeability and endotoxemia, which leads to systemic inflammation mediated by proinflammatory cytokines (Cani et al., 2007; Qin et al., 2012). This feature may be considered the link between metabolic disorders and cardiovascular diseases such as atherosclerosis, which damages blood vessels predisposing to arterial plaque formations (Novakovic et al., 2020). On the other hand, into the atherosclerotic plaques, Crysenomonas, Helicobacter, Anaeroglobus, Clostridium, Eubacterium, and Roseburia have been detected (Koren et al., 2011), while in the gut the overrepresentation of Lactobacillus, Bacteroides, Collinsella, and Streptococcus has been suggested as a diagnostic marker in patients suffering from cardiovascular disease (Emoto et al., 2017). Together with low gut diversity, some bacterial genera such as Lactobacillus, Oscillibacter, Faecalibacterium and Ruminococcus showed some correlations with a higher level of C-reactive protein, which is considered a marker of inflammation and cardiovascular disease (Kazemian et al., 2020). From the metabolic point of view, some species belonging to Proteobacteria and Firmicutes have been associated with the synthesis of trimethylamine (TMA) and its derivative trimethylamine N-oxide (TMAO), which is considered a risk factor for myocardial infarction and stroke (Tang et al., 2013; Liu et al., 2015; Hu et al., 2017).

GM involvement in carcinogenesis is mainly linked to the release of some chemical mediators called microorganism-associated molecular patterns (MAMPS), which can enhance tumor progression or cause an impairment of the immune system (Schwabe and Jobin, 2013). In animal models of hepatocellular carcinoma as well as in pancreatic cancer, LPS released from GM is able to activate Toll-like receptor 4 (TLR4) and negatively modulate immune responses (Dapito et al., 2012; Ochi et al., 2012). Furthermore, several studies showed a typical GM signature in cancers, such as colorectal cancer (CRC) in which a particular strain of Fusobacterium nucleatum appears to be involved in tumor initiation and progression by inducing the local release of pro-inflammatory cytokines, such as IL-6, IL-8 and TNF-α, thus developing an immunosuppressive tumor-favoring microenvironment (Shang and Liu, 2018). In non-small cell lung cancer, localized depletion of butyrate producers such as F. prausnitzii, Clostridium leptum, Clostridium cluster I, Ruminococcus spp., Clostridium cluster XIVa, and Roseburia spp., is supposed to deregulate Treg differentiation and immune responses against the cancer cells (Cheng et al., 2019; Gui et al., 2020). Acute lymphoblastic leukemia is characterized by increased abundance of Enterococcaceae, Porphyromonadaceae and other Bacteroidetes members, and by depletion in Blautia, Erysipelotrichales, Lachnospiraceae and Clostridiales members in the GM, while in acute myeloid leukemia, an abundance of Staphylococcaceae and Streptococcaceae has been found (Dutta and Lim, 2020).

There are different ways by which GM contributes to the physiological modulation of the central nervous system (CNS). For example, commensal bacteria such as Escherichia (Lee et al., 2020), Streptococcus (Macrì et al., 2018) and Enterococcus may contribute to the regulation of dopamine levels, while Bifidobacterium and Lactobacillus can produce gamma-aminobutyric acid, which is also involved in dendritic and T cell differentiation (Powell et al., 2017). The inflammatory component associated with neurodegeneration and the contribution of GM in the regulation of neurotransmission make it plausible to associate psychiatric or neurodegenerative disorders such as Alzheimer Disease (AD), Parkinson Diseases (PD), Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and Huntington’s disease with GM alterations (Uniyal et al., 2021). Interestingly, epidemiological data suggest that diet could play a preventive or delaying role in prion and prion-like neurodegenerative diseases, and diet is a major driver of GM variation (Toni et al., 2017). Nevertheless, to date, the most reliable data on the connection between neurodegeneration and GM come from studies on AD and PD. In AD, an altered GM appears to be linked to LPS production, alterations of the blood-brain barrier and deregulation of Treg/Th2 responses, which promote AD development and fibrillogenesis of β-Amiloid (Li et al., 2017; Tsunoda 2017). Instead, amyloid proteins may be released by GM components, and it has been observed that Escherichia coli, Salmonella Typhimurium, Bacillus subtilis, Mycobacterium tuberculosis, Salmonella enterica, and Staphylococcus aureus are all bacteria capable of generating functional amyloid, contributing to accumulation of proteinaceous misfolded particles, oligomers and fibrils (Jiang et al., 2017; Fang et al., 2020).

In PD patients, impairment of the motor system has been associated with the presence of non-motor symptoms, linked to autonomic dysfunctions, now recognized as a part of this disease. Among these autonomic dysfunctions, intestinal constipation can arise even 20 years before the onset of motor symptoms and could be linked to GM alterations (Mertsalmi et al., 2017). An increase in the relative abundance of Bifidobacteriaceae, Lactobacillaceae and Verrucomicrobiaceae has been observed (Fang et al., 2020) and the increase in Enterobacteriaceae has been clearly associated with postural instability (Sampson et al., 2016). Furthermore, the decrease in Prevotella has been associated with reduced mucin synthesis and increased gut permeability in PD patients (Sampson et al., 2016). These modifications also correlate with alterations in the microbial metabolism of tryptophan and beta-glucuronides (Bedarf et al., 2017), involved in neurotransmitter biosynthesis. In addition to this, GM dysbiosis could be involved in PD development by enhancing alpha-synuclein aggregation in the intestinal submucosa neurons, which may propagate to the CNS via the vagal nerve route (Fang et al., 2020; Uniyal et al., 2021).

The major GM alterations observed in non-communicable diseases are summarized in Table 1.

Hericium erinaceus is the most used mushroom for all gastrointestinal disorders. It is an edible mushroom, which has a long history of use in traditional Chinese medicine for the protection of mucous membranes, gastric ulcers, acute and chronic gastritis and nervous degeneration (Khan et al., 2013; Friedman, 2015; Thongbai et al., 2015). The parts of the fungus used are the fruiting body and/or the mycelium in aqueous, hydroalcoholic or alcoholic extracts titrated and standardized in one or more of the following components: polysaccharides, beta-glucans (with antibacterial and anti-inflammatory action), alpha -glucans, diterpenes and triterpenes or polyphenols (He et al., 2017). Although the most studied activities of this fungus concern its immunomodulatory effects on the gut, its prebiotic activities have aroused much interest (Sheng et al., 2017). A single protein, called HEP3, isolated from H. erinaceus and administered to rats, treated with trinitrobenzenesulfonic acid (TNBS) to induce experimental colitis, was able to restore microbiota diversity in a relatively short time. Treatment with this single H. erinaceus protein increased the amounts of Actinobacteria and Tenericutes, reduced those of Bacteroidetes and Firmicutes, and was able to restore a biodiverse and healthy ecological structure (Diling et al., 2017). The efficacy of HEP3 in positively modulating the GM has also been confirmed in other animal models of colitis (Shao et al., 2019). Crude extracts of H. erinaceus were also tested on animal models of colitis. The results indicate that the formulations used (polysaccharide extract, alcoholic extract or whole extract) were able to positively modulate the GM, but while the polysaccharide extract appeared to play an important prebiotic role, the alcoholic extract and the whole extract showed important bactericidal effects (Diling et al., 2017). Similar results were obtained in a mouse model of sodium sulfate dextran-induced colitis (DSS). Treatment with DSS resulted in an increase in the relative abundance of Verrucomicrobia and Actinobacteria and a decrease in the amount of Bacteroidetes in fecal samples, compared to the control group. Treatment of colitic mice with dry extract of the fermented mycelium of H. erinaceus reversed most of the changes, including the increased levels of A. muciniphila. Taken together, these results showed that H. erinaceus effectively modulates the GM of colitic animals, restoring a microbial composition similar to that of healthy rodents (Ren et al., 2018).

Inonotus obliquus commonly known as Chaga is a parasitic fungus mainly of Birch trees (Betulaceae family) with numerous biological properties, and has been commonly used as a folk remedy in Northern European countries for various disorders affecting the digestive system (Shashkina et al., 2006; Balandaykin and Zmitrovich, 2015). The most used formulations are powder, aqueous extract and hydroalcoholic extract, which can be titrated in polysaccharides, beta-glucans, alpha-glucans and polyphenols. I. obliquus has also been successfully used to ameliorate the negative effects of DSS in mice, and the polysaccharides of this fungus have shown a positive regulatory effect on the microbiota (Chen et al., 2019). In a model of mice with chronic pancreatitis, the GM profile, compromised by the disease, was partially restored by the administration of I. obliquus polysaccharides, which led to increased diversity and richness of GM and also improved the clinical condition of the mouse (Hu et al., 2017). Ganoderma lucidum (Reishi in Japanese) is a mushroom with a woody consistency and a bitter taste, which grows preferably on oaks and chestnuts. The main traditional use in China and Japan is aimed at counteracting the allergic and inflammatory state (Bhardwaj et al., 2014). Recent studies have identified more than 400 bioactive molecules present in this mushroom. Some of these were firstly identified in this species and consequently their name referred to the species, such as ganoderiol, ganolucidinic acids and ganoderman-triol (Ahmad, 2018). There is strong evidence of prebiotic activity of G. lucidum, although this may be secondary to a direct effect on components of the immune system. In DSS-induced colitis in rats, G. lucidum glucans increased SCFA-producing bacteria such as Ruminococcus, and reduced pathogens such as Escherichia and Shigella in both small intestine and cecum (Xie et al., 2019). In high fat diet (HFD)-fed mice, which exhibit body weight gain and diet-associated dysbiosis, treatment with G. lucidum mycelium reverted HFD-induced intestinal dysbiosis, decreasing the Firmicutes-Bacteroidetes ratio and the Proteobacteria relative abundance. Furthermore, Reishi treatment reduced metabolic endotoxemia by restoring the integrity of the intestinal barrier. This demonstrated that one of the main mechanisms of action of G. lucidum in the intestine is related to the modulation of GM. Polysaccharides with a high molecular weight (>300 kDa) have been identified as the most responsible for this modulation of GM, since these polysaccharides are present in G. lucidum in considerable amounts (Chang et al., 2015). Similar results were obtained in a rat model of type 2 diabetes, in which treatment with G. lucidum reduced the relative abundance of harmful bacteria, such as Aerococcus, Ruminococcus, Corynebacterium, and Proteus, while increased that of Blautia, Dehalobacterium, and Parabacteroides. GM analysis indicated that Reishi treatment could also restore the microbial metabolism of amino acids, carbohydrates, inflammatory substances and nucleic acids, altered by obesity and diabetes (Chen et al., 2020). In a mouse model of pancreatitis induced by diethyldithiocarbamate (DDC), polysaccharides of G. lucidum were able to positively modulate the GM, decreasing the relative abundance of Bacteroidetes and increasing that of Firmicutes. Reishi polysaccharide supplementation increased the relative abundance of beneficial bacterial families, such as Lactobacillaceae and Lachnospiraceae, especially Roseburia. These results confirmed that the therapeutic mechanism on chronic pancreatitis could also depend on the restoration of a healthy eubiotic GM (Li et al., 2016).

It should be noted that all plants, if rich in fiber content, can have prebiotic activities. Despite this, some plants in particular have shown the ability to modulate the GM in a much more decisive way than would be expected from their unique prebiotic effect due to their fiber content. Cichorium intybus is a perennial herbaceous plant whose rhizome and roots are traditionally used in Europe for the treatment of gastrointestinal disorders (Thumann et al., 2019). Used to supplement the diet of farmed broilers and to improve their production performance, C. intybus has been shown to induce significant changes in the ileal microbiota, consisting of lowering E. coli counts and increasing Lactobacillus ones. These effects have been clearly associated with improved growth performance. Dietary C. intybus powder has an undoubted prebiotic effect linked to the high content of soluble fiber, and in particular inulin (Khoobani et al., 2019). However, different modulations of the Firmicutes/Bacteroidetes ratio and of some bacterial genera, such as Alloprevotella, Blautia, Alistipes and Oscillibacter, were observed in mice fed with different chicory cultivars, with a variable effect depending on the genotype of the chicory and not on the fiber content (Khoobani et al., 2019). Boswellia serrata is an arboreal plant that forms an aromatic resin also known as “frankincense”. B. serrata resin was used as a supplement in rabbit diets at different dosages to obtain changes in the caecal microbiota. Results indicated that substantial changes were found in the microbial populations in the cecum of rabbits treated with B. serrata, with a significant decrease in total bacterial count and in particular a decrease in Salmonella enteritidis and E. coli compared to the untreated control group. These results could be attributed to the high polyphenol content of B. serrata and to the presence of boswellic acids, which have a powerful antimicrobial effect (Ismail et al., 2019). Pistacia lentiscus is a shrub or small evergreen tree that produces a resin called Chios mastic gum, used as a natural food supplement. The effect of P. lentiscus was studied in mice with obesity, non-alcoholic steatohepatitis (NASH) and HFD-induced liver fibrosis. Treatment with P. lentiscus promoted a partial but significant recovery of GM diversity associated with a decrease in the relative abundance of Bacteroidetes (Kannt et al., 2019). Olea europaea is an evergreen fruit tree that is traditionally found in the Mediterranean area. The extra virgin oil (EVO) obtained from the fruits of this plant is able to induce a greater GM biodiversity and promote the growth of beneficial commensal bacteria, both in humans and in laboratory animals (Marcelino et al., 2019). The leaf extract of O. europaea administered to obese mice was able to improve their GM by partially restoring the quantities of Actinobacteria, Bacteroidetes and Verrumicrobia. Furthermore, the relative abundance of Akkermansia spp. was restored, suggesting a possible positive effect on intestinal barrier functions in treated mice (Vezza et al., 2019). As for Angelica arcangelica, Achillea millefolia and Cetraria islandica, officinal plants traditionally used to treat intestinal dysbiosis and inflammation, there are no scientific studies published so far to support their positive modulation action on GM. This does not mean that these medicinal plants are not effective in modulating GM ecology, but only that documented scientific evidence of their alleged therapeutic activities is still too scarce.