Personalized and Targeted Gut Microbiome Modulation in the Prevention and Treatment of Chronic Diseases

Abstract

The gut microbiota is being recognized as a factor with a significant influence on host physiology, health maintenance, and disease prevention. Distinct alterations of the gut microbiota are correlated with several chronic diseases. Currently, gut microbiota can be modulated by diet, probiotics, prebiotics, postbiotics, pharmabiotics, and fecal microbiota transplantation. An effective strategy in gut microbiota modulation is needed for the prevention and supportive treatment of chronic diseases. New and more effective approaches toward gut microbiota modulation are emerging, namely personalization and targeted modulation. The composition of novel products and treatments based on the individual gut microbiome, metabolome, strain specificity, and clinical data analysis can reveal and address specific changes to the diversity, composition, and function of gut microbiota. These analyses enable the development of personalized and targeted gut microbiota modulation, by the application of beneficial microorganisms, their consortia, their metabolites, and their effective combination.

1. Introduction

The gastrointestinal tract is a major immunological organ that evolved to tolerate commensal and dietary antigens, yet retains the ability to mount a protective immune response to pathogens. The complex co-evolved community of the gut microbiota impacts the development of immunity and health of an individual. Although much of the gut microbiota is deemed non-culturable.,the advent of high-throughput sequencing techniques has greatly improved the ability to clarify gut microbiota composition and function. New technologies enable to include estimation of the gut microbiome diversity as well as species and novel gene identification. Average human gut microbiota is now better defined and has been estimated to exceed 1000 bacterial species [1, 2]. Bacteroidetes and Firmicutes represent predominantly in the gut microbiota. Other phyla such as Proteobacteria, Actinobacteria, Cyanobacteria, and Verrucomicrobia, as well as methanogenic Archaea, mainly Methanobrevibacter smithii, are present in the gut microbiota only in a minority [3, 4]. The distribution of these phyla in the gut depends on a wide range of host factors including genetics, epigenetics, local immune response, oxygen gradient, dietary intake, and interactions among microbes.

Gastrointestinal microorganisms can influence host processes to impact host physiology, immunology, and metabolism. The composition, diversity, and functionality of the gut microbiota can alter signaling events between the microbiome and the host to influence gut homeostasis and host health [5]. Analysis of the microbiota can be performed in different states of diseases, and its results together with the application to animal experimental models can provide a simpler system in which the disease pathogenesis can be examined [5].

Reduction of the bacterial diversity and overall disbalance of the gut microbiota also known as dysbiosis is associated with many chronic diseases [6]. In some instances, gut microbiota alterations can affect intestinal permeability, allowing the transfer of lipopolysaccharide originating from the walls of gram-negative bacteria into the circulation, leading to endotoxemia and low-grade inflammation in different parenchymatous organs, resulting in metabolic disorders and chronic diseases [7].

The etiology of chronic diseases is often multifactorial, and gut microbiota is also one of the key factors. Current therapy for chronic diseases mostly does not reflect this fact, which limits its overall effectiveness. A better understanding of gut microbiota cross-talk mechanisms and their subsequent effects could provide new insights into the role of gut microbiota and dysbiosis in disease pathogenesis. This knowledge and technology can allow the development of potentially effective alternative approaches for preventive and therapeutic measures based on gut microbiota modulation [5, 8, 9]. More effective methods and biotherapeutics are needed for personalized and targeted gut microbiota modulation as supportive therapy for chronic diseases.

Targeted modulation of the gut microbiota represents an approach when specific bacterial strains have clinically proven effects of changes in the microbiota and human health. These bacteria are used in products to deliver specific predetermined effects for the host based on his disease and microbiota composition.

2. The gut microbiota in chronic diseases

The gut microbiota alterations are observed in almost all chronic diseases, including inflammatory bowel diseases (IBD), irritable bowel syndrome, metabolic syndrome, obesity, diabetes, cardiovascular diseases, cancer, neurodegenerative diseases, and mental disorders. Microbiota alterations appear characteristic for each disease state. To date, it is unclear if dysbiosis is a cause or a consequence of the disease [6].

Inflammatory bowel disease is an umbrella term for ulcerative colitis (UC) and Crohn’s disease (CD). Changes in the composition of the gut microbiota are reported in patients with IBD, namely a decrease in populations of Firmicutes and Bacteroidetes and an increased Enterobacteriaceae. Other significant differences in gut microbial composition for CD include increased representation by Ruminococcus gnavus and decreased beneficial bacteria Faecalibacterium prausnitzii, Bifidobacterium adolescentis, Dialister invisus, as well as an uncharacterized cluster of Clostridium XIVa. IBD patients have a reduced number of butyrate-producing bacteria and an increased number of sulfate-reducing bacteria, which promote further inflammatory processes [10]. The loss of obligate anaerobes with an increase of facultative anaerobes was also observed in patients with IBD [11]. It has been found that patients with IBD have altered metabolism including defective microbial and intestinal bile acid metabolism [6, 12, 13]. A higher level of fecal trypsin was detected in patients with CD suggesting altered protein degradation [14].

Decreased gut microbial diversity is associated with metabolic syndrome and obesity. The gut microbiota changes in these diseases are characterized by an increased ratio of Firmicutes to Bacteroidetes [15]. It seems that gut microbiota is in close correlation with obesity and can affect the transfer of the number of calories from the diet to the host and the host metabolism of absorbed calories [16].

Type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D) differ in the mechanisms of pathogenesis. Both types of diabetes are associated with dysbiosis, but with different characteristic patterns. T1D is associated with a decrease in mucin degrading bacteria, Bifidobacteria, Lactobacillus, and Prevotella and an increase in Bacteroidetes and Clostridium. T2D is characterized by a decrease in Clostridium and an increase in Lactobacillus and Bacteroidetes. In both types of diabetes mellitus, changes of the microbiota were observed such as a decrease in the gut microbiota diversity, a decrease in butyrate-producing bacteria and Firmicutes, disrupted epithelial barrier integrity, and increased gut permeability [12].

Autism spectrum disorders (ASD) are characterized by social and communication deficits and repetitive behaviors. A significant increase in the Firmicutes/Bacteroidetes ratio was found in autistic individuals due to a decrease in the relative abundance of Bacteroidetes. At the genus level, a decrease in the relative abundance of Alistipes, Bilophila, and Parabacteroides was detected, while Corynebacterium and Lactobacillus were significantly increased. The increase in Clostridiales bacteria in constipated autistic individuals can be important in the pathogenesis of autism by the production of propionic acid, which can permeate into the brain and cause cognitive impairments [17]. It was also observed that the relative proportion of the fungal genus Candida was more than double in autistic than neurotypical subjects, but this difference was only partially significant due to a larger dispersion of values [18].

Dysbiosis in patients with colorectal cancer (CRC) is characterized by a decrease of butyrate-producing bacteria and an increase in the proportion of several potentially pathogenic bacteria. It has been suspected that bacterial species, such as Bacteroides fragilis, Clostridium septicum, Fusobacterium spp., and Escherichia coli, are involved in colorectal carcinogenesis. A decrease in Firmicutes and an increase in Proteobacteria, Bacteroidetes, and Fusobacteria were observed in CRC. In colorectal cancer tissue, an increase in the population of Akkermansia muciniphila and Fusobacterium nucleatum has been detected. It was found that the composition and numbers of dominant microbial species in CRC-associated dysbiosis in the gut lumen differ depending on disease severity and tumor stage [19, 20].

3. Current possibilities of the gut microbiota modulation in chronic diseases and future development

Current knowledge suggests that gut microbiota and gut dysbiosis could play an important role in the etiology and pathogenesis of chronic diseases and gut microbiota modulation could be an effective tool for their supportive treatment.

Nutrition significantly affects the diversity, composition, and function of the gut microbiota and human health at an early age, in adulthood, and also in old age. Diet high in fiber, fermented foods, and a diet containing omega- 3 fatty acids have a very positive effect on the composition and metabolic activity of beneficial microorganisms of the gastrointestinal tract. Diet represents a safe, readily modifiable, and cheap method of early intervention in chronic diseases, which may have significant health benefits by regulating the gut microbiota and mucous barrier [21].

New knowledge about the mutual communication between gut microorganisms and the whole organism makes it possible to develop new and effective methods of modulating the gut microbiota using beneficial microorganisms or their metabolites [22].

Probiotics are proposed as alternatives to antimicrobial drugs, and they can be an adjuvant therapy in the treatment of diseases associated with gut dysbiosis. Prebiotics modulate gut microbiota by stimulating the growth and metabolic activity of gut-beneficial microorganisms [23]. It has been shown that the positive effect of probiotic bacteria, prebiotics, or natural bioactive substances in functional foods can effectively reduce the incidence of chronic diseases [24]. The beneficial effects of probiotics on the host can be significantly improved by potentiated probiotics [25], which contain a suitable combination of probiotic bacteria with natural bioactive substances such as oligosaccharides, polyunsaturated fatty acids, and plant extracts [26, 27, 28, 29]. Experiments in gnotobiotic piglets have shown that polyunsaturated fatty acids increased the adherence ability of lactobacilli and their inhibitory effect on the adhesion of Escherichia coli O8: K88ab: H9 in the gut [26, 27]. Effects of probiotic (PRO) Lactobacillus plantarum and combination of PRO and prebiotic (PRE) inulin enriched with oligofructose (2%) and PRO with Linioleum virginale (O) on gut bacteria in 1,2-dimethylhydrazine exposed rats were studied. It was shown that combinations of PRO-O and PRO-PRE had a synergistic effect which was higher than the effect of administering only PRO [28]. Preventive application of L. plantarum LS/07 alone or in combination with inulin to rats with chronic inflammation reduced the inflammatory process in the gut mucosa by down-regulating of pro-inflammatory cytokine synthesis and suppression of NF-κB activity in mucosal cells [29].

The next-generation probiotics hold promise to treat diverse medical conditions, and they can be more effective than single or multi-strains commercial probiotics. Moreover, several different strains with proven health benefits such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Bacteroides fragilis, Bacteroides uniformis, Eubacterium hallii, and members of the Clostridia clusters IV, XIVa, and XVIII. can be considered candidates for the next generation of probiotics and other microbiota-based drugs. The development of the next generation probiotics holds promise for innovation in both the food/feed sector and the pharmaceutical industry [30].

New knowledge of the role of microbiota in health and diseases allows to expand the possibilities of administration of probiotics, in relation to their application form, depending on the intended use. Increasing interest in the application of probiotics in clinical practice will likely require specific regulatory approaches, if they are administered in a diseased population. More recently, the European Food Safety Authority has defined a new “live biotherapeutic products” (LBP) category, clarifying pharmaceutical expectations. Similar to all products intended to prevent or treat diseases, LBPs will have to be registered as medicinal products to reach the market in the USA and Europe [31].

Fecal microbiota transplantation (FMT) is the administration of fecal microbiota from a healthy person (donor) to a patient with a disease associated with dysbiosis. FMT is an effective therapeutic alternative for Clostridium difficile infection (CDI) but could be a promising therapeutic approach in patients with other diseases such as inflammatory bowel diseases (IBD), irritable bowel syndrome, metabolic syndrome, and obesity [32, 33]. It is hypothesized that FMT improves colonization resistance of recipient gut microbiota, but the mechanisms are not well understood. Fecal microbiota can be transplanted also in lyophilized encapsulated form. Another possibility of FMT is to use human gut microbiota cultured anaerobically in vitro. In choosing the route of FMT administration, the indication should be taken into account [12, 34, 35, 36].

Next-generation-based therapies, including synthetic stool products or bacterial consortia, currently have been coming to the fore, as an alternative to FMT, as they have much fewer side effects. It was shown that gut microbiota could be effectively modulated by the administration of defined microbiota. Application of 33 bacterial strains, isolated from human stool or a stool substitute mixture comprising a multi-species community of bacteria, may be protective against C. difficile or S. typhimurium enteral infection. The defined consortium of 8 bacterial strains (altered Schaedler flora) could be effective to diminish fecal urease activity and ammonia production [12, 37, 38].

Autoprobiotic technology can be applied to modulate gut microbiota using selected indigenous probiotic bacteria isolated from a healthy donor. The isolated bacteria are stored in cryobanks and returned to the host if dysbiotic conditions occur [39].

One of the new therapeutic approaches targeting the gut microbiota is based on metabolites of microorganisms—“postbiotics”. They are produced, modulated, or degraded by the microbiota and act directly on the host with their metabolic and signaling function. These metabolites, such as short-chain fatty acids, flavonoids, or organic acid taurine, serve as a means of communication in interactions between hosts and microorganisms. Postbiotics target microbial signaling pathways by mitigating the negative effects of deficiency or excess of metabolites involved in signaling pathways. Postbiotics do not affect the gut dysbiosis, but have the potential to correct its negative effects. In contrast to the application of living microorganisms, their dosage and methods of application follow the principles of pharmacokinetics [40]. The term “pharmabiotics” refers not only to living microorganisms but also to dead or altered microorganisms, such as bacteria, but also their metabolites [41].

4. Personalized and targeted microbiota modulation and its potential for more efficient prevention and treatment of chronic diseases

Current knowledge suggests that the gut microbiome plays an extraordinary role in the development of chronic diseases. A better understanding of the mechanisms of its involvement in the pathogenesis of diseases is crucial for successful and effective microbiota modulation. The composition and functional characteristics of a healthy microbiome remain to be defined. Certain parameters such as the diversity of the microbiota, an abundance of certain genera (i.e., Bifidobacteria, Lactobacillus, etc.), or specific ratios between main bacterial phyla are considered markers of a healthy microbiota. The characterization of a healthy microbiota would make it possible to optimize nutrition and modify the microbiota to prevent diseases and to improve the effectiveness of therapy in people with gut dysbiosis and associated diseases [42].

Although some diseases have been correlated with dysbiosis, it is not clear if dysbiosis is a cause or consequence. Several trials have shown that therapies correcting dysbiosis, including fecal microbiota transplantation and probiotics, are promising in inflammatory bowel disease [10]. However, current knowledge shows that fecal microbiota transplantation does not have the same high effectiveness in inflammatory bowel disease as it does in Clostridium difficile infection. Dysbiosis occurs in both diseases, but the etiology and pathogenesis of inflammatory bowel disease are more complex in comparison with Clostridium difficile infection [43] and the same problem of complexity applies to many other diseases. Various strategies have emerged in the modulation of the gut microbiota in the prevention or treatment of diseases. Progress in this area is hampered due to ambiguities in the exact role of the microbiota in a given disorder, variations in the phenotype of the human disease, and variability in the formulation and delivery of the intended therapies. The use of gut microbiota modulation in medical practice requires a significant shift on all these fronts [41]. It is known that pathogenic microorganisms can cause various diseases, including cancer, and gut dysbiosis plays a very negative role in the pathogenesis of diseases. It is, therefore, reasonable to assume that modulation of gut microbiota may be a very effective means of prevention, but also supportive therapy for many chronic diseases shortly.

We have effective means to fight against chronic diseases through gut microbiota modulation. The suitable diet, probiotics, prebiotics, postbiotics, and gut microbiota transplantation represent them. However, what we need the most is a strategy for their effective use to the patient in individual’s illness. Personalized and targeted modulation of gut microbiota has all the prerequisites to become a key strategy for the prevention and supportive therapy of chronic diseases [44, 45]. Personalized and precision medicine creates prerequisites for the application of new methods of treatment for many chronic diseases aimed at modifying the gut microbiome, including cancer therapy. Taking into account the role of gut microorganisms in disease pathogenesis could significantly contribute to increasing the effectiveness of their treatment [46].

Patient-tailored manipulation of the human microbiome may enable the development of precision microbiome-targeting treatment for a variety of multi-factorial disorders. More effective methods of adjusting the gut microbiome can be personalized probiotics and prebiotics, personalized nutrition taking into account the composition and functionality of the gut microbiota, postbiotics containing metabolites of microorganisms affecting the communication of microorganisms with the host, and phage therapy. However, their use in clinical practice requires the establishment of standard sampling procedures, their analysis, and interpretation of the obtained results. The use of personalized and precision medicine procedures will thus make it possible to streamline the diagnosis and therapy of diseases in which the gut microbiome plays an important role [47].

The development of precision probiotics, next-generation prebiotics resulting from a better understanding of metabolic interactions among members of the microbial ecosystem, and personalized dietary therapies tailored to an individual’s microbiota will form the new frontier in the field of personalized medicine [48].

It can be assumed that new knowledge will make it possible to increasingly use the modulation of the gut microbiota to improve the effectiveness of disease prevention and their supportive therapy. It is highly likely that a suitable solution will be the application of a personalized approach using various possibilities of gut microbiota modulation through beneficial microorganisms or diet. However, it will be necessary to gain new knowledge about the composition and functionality of the optimal gut microbiota and the role of gut dysbiosis in the pathogenesis of diseases [49].

Effective modulation of the gut microbiome will require research and development of more effective methods and products for personalized and targeted modulation of the gut microbiome [24, 45]. Personalized medicine uses and combines genomic and clinical data to more accurately predict an individual’s susceptibility towards development of the disease and his response to treatment. Personalized approach thus allows optimization of patient care. Personalized medicine approach and targeted approach in gut microbiota modulation should be based on analyses of the patient’s clinical data and an analysis of the patient’s gut microbiome and metabolome that reveals the specific changes in his gut microbiota diversity, composition, and function. These analyses allow using personalized and targeted gut microbiota modulation, by the application of beneficial microorganisms, their consortia, and their metabolites. It can be assumed that this method of modulation will in many cases require a combination of personalized probiotics, probiotic strains with specific effects, and metabolites of microorganisms—postbiotics.

The study of the application of personalized probiotics was conducted on 48 patients. The aim of this study was to determine changes in selected markers within the microbiota after 3 months of treatment by the personalized probiotic supplement. The probiotic composition (species, number of species, and number of CFU) of the probiotic mixture was designed based on gut microbiome analysis and prepared for each patient separately. After 3 months of probiotic supplementation, control samples were analyzed. Data confirmed a statistically significant increase of specific beneficial bacterial groups (lactobacilli, bifidobacteria, and actinobacteria) as well as the total number of species, thus increasing the overall diversity of the microbiota, which is considered a marker of a healthy gut microbiome. Results showed that the probiotic supplementation improved stool frequency in both cases—constipation and also diarrhea. The study confirmed the significance of a personalized approach in probiotic supplementation [50]. Of course, further data and studies are needed to demonstrate the effectiveness of a personalized approach in the clinical field.

It can be expected that also a new method of personalized and targeted modulation of gut microbiome combined with the auto-transplantation of ex vivo modulated patient’s gut microbiota will be developed in near future for clinical practice [45, 51]. Innovative animal experimental models and clinical studies will greatly aid the shift in gut microbiome research and modulation that will enable the production of high-quality products for the patients [52].

5. Conclusions

Gut microbiota has an important role in the health and etiology and pathogenesis of chronic diseases. Future research on gut microbiome in chronic disease should be aimed to clarify the association between gut microbiota dysbiosis and disease pathogenesis. Diet, probiotics, prebiotics, postbiotics, and fecal microbiota transplantation can be used for gut microbiota modulation. Research on gut microbiota and its role in health and disease constantly brings new knowledge, which in the foreseeable future will significantly streamline not only prevention but also supportive therapy of many chronic diseases. New strategies such as personalized and targeted modulation of gut microbiota are emerging based on analysis of the patient’s microbiome, metabolome, and clinical data. They will result in the application of beneficial microorganisms, their consortia, and metabolites to address the specific problem for specific people. The analysis of the patient’s gut microbiota could also serve for early diagnosis in people at risk of chronic disease, and intervention can be made that will prevent chronic disease from occurring.

Conflict of interest

The authors declare no conflict of interest.