2.1. Literature Search

An extensive literature search was performed using peer-reviewed articles from authentic databases, which were retrieved from PubMed and Gov Google Scholar, as well as several other databases. The search intended to find studies that focused on the field of ME and its relation to health. The following keywords were utilized: some of the key terms that were used while filtering the articles include microbial endocrinology; gut microbiota; hormones; SCFA; gut-brain axis; modulation; neurotransmitters; immune function; metabolism; reproduction; and dysbiosis. The Boolean operators were then applied to narrow the articles as much as possible.

2.2. Inclusion and Exclusion Criteria

The types of studies included, non-systematic search criteria covering quantitative and qualitative studies, involved the following inclusion criteria to select the articles: The studies had to be published in any peer-reviewed English language journals between 2010 to the present timeframe. The included papers had to find the relation between gut microbiota and endocrine systems with more attention to hormonal synthesis, elimination, or alteration by the gut microbiota. Specific exclusion criteria allowed the researcher to remove articles that are not refereed and peer-reviewed, research papers that do not focus on the field of microbial endocrinology, and research not containing new data and information.

2.3. Data Extraction and Analyses

A systematic approach was employed in reviewing the selected studies to maintain the quality of data extraction and analyses. Especially, information on ME like hormonal, immunity, and metabolism themes to which future research should pay attention have been analyzed and distilled.

3.1. Early Discoveries and Evolution of Microbial Endocrinology

Primary arguments were based on many early findings pointing to the fact that microbiota could dictate the physiological state of the host, especially the hormones [17]. The provision by microbes of hormones used to manipulate the behavior of the host entails microbial endocrinology, a field established by Michael Lyte in the early 1990s [18]. Later investigations revealed that bacteria release such neurotransmitters as serotonin and GABA and pointed out that gut microorganisms direct the endocrine activity of the host [19]. The recent finding of the gut-brain axis added more strength to the link between microbiota and behavior/mood and pinpointed the role of the microbiome in endocrine regulation [20,21,22,23].

3.2. Effects of Modern Technology

At the turn of the century, the emergence of enabling technologies like polymerase chain reaction (PCR), Denaturing Gradient Gel Electrophoresis, Real-Time PCR, and internal transcribed spacer provided a clearer perspective on exploring the gut microbiome. It was during the last decade of the 2000s that molecular techniques advanced in tandem with high-throughput sequencing technologies [24]. At present, ME is acknowledged as the essential field of research that is involved in understanding the diverse states of health and diseases such as obesity, diabetes, and mental health disorders [25]. The field remains active to date and it can be predictable as experts continue to study the mechanisms of microbial endocrinology, the prospects of novel therapeutic targets of the microbiome are likely to improve the health of the patient [7,26,27].

5.1. Microbial Production of Hormones

Most strikingly, the gut microbiota possesses the versatility to synthesize and release virtually any hormone that can impact the host’s physiology. In microbial endocrinology, it has been found that definite bacterial species are capable of producing neurotransmitters and hormones as synthesized by the host itself [3,7,26]. For example, some gut bacteria synthesize catecholamines, serotonin, and GABA which are significant for mood, appetite, and stress regulation respectively [22,23]. The processes that microbes use to generate these hormones are through the regulation of certain enzymes and the route of metabolism [7,26]. There are genetic components in bacterial genes and gene clusters that participate in the synthesis of some neurochemicals. For instance, the tyrosine decarboxylase (tdc) gene cluster of the Lactobacillus species codes for enzymes that are involved in the conversion of amino acids such as tyrosine and tryptophan into neurotransmitters dopamine and serotonin respectively [28,29]. The westernization of diet and widespread use of antibiotics disrupt the balance of gut bacteria, leading to increased permeability of the gastrointestinal tract and elevated levels of bacterial endotoxins. These changes, in turn, trigger the heightened synthesis of α-synuclein and the formation of toxic Lewy bodies (LBs), which are associated with Parkinson’s disease (PD). These LBs impair the substantia nigra and influence neuronal apoptosis using mitochondrial dysfunction and lowered dopamine (Figure 1). In PD, there is a deficiency in the formation of beneficial bacteria which secrete neurotransmitters, and on the other hand; there is a high formation of harmful bacteria that quickens the disease progress [30]. Compared to healthy controls, Specifically, gut microbiomes of PD patients have higher relative abundances of putative pro-inflammatory genera, Akkermansia, and lower relative abundances of putative SCFA-producing genera Butyricicoccus and Coprococcus [31].

Gut dysbiosis increases intestinal epithelial permeability and systemic body exposure to microbial endotoxins, which causes over-expression of α-synuclein. This excess expression promotes the misfolding of α-synuclein into Lewy bodies (LBs). Intestinal LBs from the enteric nervous system reach the CNS via the vagal nerve, ultimately damaging the substantia nigra and contributing to the clinical symptoms of PD [32]. In healthy individuals, α-syn regulates dopamine release; however, in PD patients, its overexpression and the formation of LBs result in decreased dopamine levels, as LBs are highly toxic.

Mitochondrial dysfunction occurs under pathological conditions, leading to the release of cytochrome C (Cyto C) and activation of apoptotic pathways, causing neuronal cell death. In PD, there is an increase in harmful bacteria (e.g., Enterobacteriaceae, Ralstonia, Proteobacteria) and a decrease in beneficial bacteria (e.g., Bacillus spp., Lactobacillus spp., Streptococcus spp.) that produce neurotransmitters like GABA, serotonin, and dopamine [30].

Microbial hormone production is influenced by various factors, including diet, host genetics, and the presence of other microbes. The availability of precursor molecules, such as amino acids, can drive the synthesis of specific hormones. Furthermore, quorum sensing, a biological process by which several bacterial species interconnect and harmonize their behavior according to the cell density, has been revealed to control the genetic expression of those involved in hormone synthesis [33,34].

5.2. Hormone Degradation by Microbes

Besides synthesizing hormones, the gut microbiota can also catabolize and transform host-derived hormones, which influence the hormones’ availability and efficacy. Some bacterial species, depending on the presence of specific enzymes like β-glucuronidases and sulfatases, are capable of hydrolyzing conjugated hormones later, freeing their active forms [35]. For example, the composition of the gut microbiota may affect the ability of estrogen metabolites to promote their reabsorption as they deconjugate, and therefore increase their systemic concentrations. This process referred to as enterohepatic recirculation can lead to hormone-dependent diseases such as estrogen-dependent cancers including breast cancer [36,37,38], and GIT tumors [39,40,41]. These hormones in the environment can also be metabolized by microbial species, resulting in the formation of new metabolites that may have distinct biological activities [42]. Depending on how these metabolites affect the hormone receptors some have an antagonizing effect, while others exhibit agonizing effects adding a twist to the relationship between the microbiota and host steroid hormones. There is variation in hormones breakdown by bacteria depending on the availability of enzymes and cofactor substances and each bacterial species possesses its own ways of breaking down these hormones [15]. Therefore, it is possible that diet, antibiotic use, and host genotype and phenotype may alter the composition and metabolic functions of the gut microbiota, thereby affecting the bacteria’s ability to degrade hormones [7,26,43].

6.1. Microbial Production of Hormones and Neurotransmitters

Some bacteria residing in the human intestine can produce and release hormones and neurotransmitters of the host [23,44]. For example, Lactobacillus species can transform amino acids such as tyrosine into dopamine and tryptophan into serotonin according to the enzymes that are synthesized and metabolic pathways that are active within a given strain [28,29].

6.2. Bacterial Sensing of Host Hormones

6.3. Super-Microorganisms

Oleskin AV, described in 2013 what is called “Supermicroorganisms” is thought to have become multicellular organisms throughout the evolution [45]. Human-microbiome association can be considered a step of integration in evolution, constituting a superorganism. Many emergent diseases are related to the loss of part of this microbiome and different strategies can achieve its restoration [46]. Gut microbiome imbalance is particularly associated with numerous inflammatory, immune, and nervous system-related diseases by a communication pathway called the microbiome-brain axis [10,20,46]. Modulation of the microbiome by administering prebiotics, like arabinoxylans, and symbiotics is a plausible treatment for dysbiosis, the regulation of neurotransmitters, and the alleviation of neurological manifestations [46].

6.4. Modulation of Host Hormone Levels

Some current investigations indicate that gut-associated bacteria can alter the sex steroids, which are crucial components defining the host’s condition in a major way; this includes the reactivation of estrogen and deactivation of androgen hormones [47,48]. The gut microbiota has been compared to an endocrine organ because it can impact distant organs and systems such as the central nervous system and modulate, behavior and mood [22,23].

Notably, some revisions showed a reciprocal association between the gut microbiota and the endocrine system. For example, postmenopausal estrogen deficiency could lead to dysbiosis of the gut microbiota, which might in turn influence various immune responses and bone remodeling [49].

Another intermediary is the enterochromaffin cells of the enteric nervous system (ENS) which also mediate with the gut bacteria [50]. Serotonin is synthesized by enterochromaffin cells located in the gut and requires the support of the gut microbiota for its biosynthesis; it has a functional role in mucosa and platelets [51]. The predictors of ENS developed by the gut microbiota encompass neurotransmitters including serotonin, γ-aminobutyric acid (GABA), histamine, catecholamines, and acetylcholine [52]. Also, enteric neurons possess TLRs, that recognize extracellular microbial products such as LPS and PG or intracellular viral RNAs [53].

Additionally, short-chain fatty acids produced by gut bacteria are considered the primary effects of the microbiota on the host. These acids function similarly to characteristic hormones, regulating various host physiological processes [16,54]. The SCFAs can affect the concentrations of the host hormones by way of directly regulating the production of the hormones or by changing the activity of the genes of the host through the action of the SCFAs. Some bacterial metabolites are SCFAs which are reported to communicate with the host and control the host gene expression [11,12].

6.5. Microbial Degradation of Hormones

Specific enzymes like β-glucuronidases and sulfatases which are produced by gut bacteria can break down and metabolize the hormones produced by the host. Depending on the specific change to the proteins, this process can affect the bioavailability and functionality of such hormones, which might relate to hormone-related disorders [36,37,38].

7.1. Immune System Modulation

The development of proper gastrointestinal and systemic immune reactions is profoundly impacted by the interplay between the gut microbiota and components of the individual’s immune system [55,56]. Gut microbiota has an essential function, particularly in regulating the immune response of the host [55,57]. Dysbiosis of gut microbiota is related to various amendments of the immune system [14]. The microbial metabolites including SCFAs derived from the fermentation of DF could improve the intestinal barrier function and the generation of regulatory T cells that are important for controlling immune responses to avoid inflammatory reactions [57,58]. For instance, a microbial tryptophan metabolite, indole-3-aldehyde causes AhR activation which in turn elicits epidermal barrier protection and immune modulation [2,59]. These processes can be disturbed due to the dysbiosis or the imbalance in the hosts’ microbiota that results in an increased vulnerability to infections and autoimmune diseases, (Figure 2).

7.2. Metabolic Regulation

The gut microbiota significantly influences metabolic processes, including energy homeostasis and nutrient absorption [57]. SCFAs, such as butyrate, propionate, and acetate, are produced by gut bacteria and serve as important energy sources for colonocytes, while also regulating lipid metabolism and glucose homeostasis through signaling pathways involving G-protein-coupled receptors [2,59]. Also, microbiota influences the release of hormones like insulin and glucagon-like peptide 1 (GLP 1) which plays a role in appetite and glucose homeostasis [60]. It is hence possible for alterations in microbial communities as well as indices to cause metabolic diseases such as obesity and type 2 diabetes (Figure 2 and Figure 3) [16].

7.3. Neurological Effects

The gut microbiota also affects neurological functions through the gut-brain barrier through which hormonal signals alter brain health and behavior. For instance, neurotransmitters generated from gut bacteria with influence on mood and cognition include serotonin and GABA [22,47]. Some types of bacterial strains have been known to change the levels of these neurotransmitters and could partially alleviate anxiety and depression (Figure 3) [26,61]. In addition, CNS cross-talk with the bacterial flora seems to be mediated by immune responses and hormonal activities, indicating that microbial condition strongly encompasses psychological status [44].

7.4. Neurotransmitters in Microbes

In addition to the effect of the neurotransmitters on the host, the microbial cells are also affected. For example, serotonin stimulated the cellular aggregation and the cellular growth of the bacterial cells of Streptococcus faecalis, Candida guilliermondii [62], Saccharomyces cerevisiae [63], E. coli K-12 and Rhodospirillium ruhrum [64]. The cell aggregation and microbial growth stimulation of serotonin in micromolar and millimolar quantities have been proven. This was applied to both Gram-positive and Gram-negative bacteria. Interestingly, Oleskin, [10] described what is called “Supermicroorganisms” which are thought to have become multicellular organisms throughout evaluation. These neurotransmitters may serve as inhibitors for microbial aggregation and can be used as protectors against microbial growth. Serotonin can modulate the growth and composition of the gut microbiome. High levels of serotonin have been shown to inhibit the growth of certain bacterial species, such as Lactobacillus and Bifidobacterium. Serotonin can also influence the production of bacterial metabolites and the expression of virulence factors in some pathogens [1].

8.1. Infectious Diseases

Furthermore, it has been established that catecholamines can enhance and amplify certain aspects of bacterial growth and pathogenicity. This, in turn, increases the host’s susceptibility to bacterial infections and influences how bacterial pathogens contribute to the disease process [8]. Hence, it can be concluded from this interaction that the neuroendocrine environment of the host can determine the response and pathogenicity of microbes and later, change the outcome of the disease. For instance, in reaction to stress, some hormones are released that can shut down the immune mechanisms of the host and increase its vulnerability to diseases [67]. Moreover, certain bacteria release neuroactive substances that regulate the host’s immune system, creating a vicious cycle that enhances the pathogen’s virulence [1,68,69].

8.2. Metabolic Disorders

Microbial endocrinology also focuses on the roles played by gut microbiota on metabolic activity which is of paramount importance [33]. It is documented that dysbiosis, the shift in the establishment of microbiota, is associated with metabolically related diseases [70] like obesity and T2DM [71]. The microbiota can modulate hormones that are associated with metabolisms, such as insulin and GLP-1 and GLP-2 through metabolites, for instance, SCFAs [16]. The significance of GLP-1 and GLP-2 in orchestrating the interaction between the intestine, microbiota, and immune system to preserve intestinal wall integrity, inflammation, and metabolic balance has been highlighted in many recent studies [13,72]. Writing these metabolites can increase insulin sensitivity and control hunger, meaning that microbiota influences the metabolic state [3,73].

8.3. Neurological Conditions

The gut-brain axis is one of the aspects of ME showing how gut microbes are connected to neurological well-being [9,74]. For instance, it has been discovered that gut bacteria synthesize neurotransmitters such as serotonin and GABA that are connected to mood alterations and other cognitive procedures [23,75,76]. The imbalance has been reportedly linked with assorted neurological conditions such as anxiety, depression, and autism spectrum disorders [25]. These observations indicate that the microbiota is capable of affecting the neurochemical signaling patterns implying that manipulating the microbiome could provide novel approaches to managing these disorders [3,20].

8.4. Reproductive Health

Recent studies suggest that gut microbiota could be linked with reproductive health depending on hormonal changes and reproductive functions. It is noteworthy that fertility and pregnancy are the crucial factors that respond to the changes in the microbiota [77], and correcting abnormal gut microbiomes may lead to enhanced reproductive outcomes [78]. Generally, infertility is the inability to conceive a child after at least one year of unprotected intercourse with your partner; this status impacts the male and female reproductive system [79]. It can stem from such causes as hormonal imbalances, which may interfere with the functioning of hormones, essential for human reproduction [80,81,82,83,84]. ME reveals the systematic relationship between the gut microbiota and hormones which might be related to fertility. Some of the latest evidence suggests that gut microbiota is also involved in meeting hormones and reproductive functions [85,86]. The disruption of the microbiome has been associated with specific hormone imbalances including polycystic ovary syndrome which impacts fertility and women’s reproductive health [3]. The potential for the microbiota to modulate sex hormones and the hormones’ metabolites capable of interfering with the signaling pathways regulating reproduction reaffirms the significance of the microbiota in reproductive health [85,86]. Moreover, the imbalance in the host’s microbiome has been linked to polycystic ovary syndrome, which is characterized by hormonal disorders and violations of the functioning of the reproductive system [26,61]. Researching this association could open new possibilities for using microbiome interventions and modifying the microbiome to treat reproductive diseases.

9.1. Probiotics and Prebiotics

Probiotics are the live beneficial microorganisms; prebiotics are the food for these microorganisms; and postbiotics are the valuable by-products generated by the probiotics. All are involved in this mutual interaction with the human host and they all contribute to the maintaining or regulating of body balance [87]. Prebiotics promote the growth of specific beneficial intestinal bacteria, while probiotics contribute to the healthy composition of gut microorganisms and reduce harmful processes and substances. This can help address or treat certain diseases [88]. For instance, research has shown that supplementing the patient with probiotics can help overcome the poor efficiency of cancer treatments and the immune system [89].

9.2. Fecal Microbiota Transplantation (FMT)

FMT has a historical background and originated in the fourth century, and it gained much importance after the US Food and Drug Administration (FDA) approved FMT in 2013 for managing recurrent and resistant C. difficile infection [90]. FMT has therefore gained popularity as a treatment for gastrointestinal disorders alongside extra-gastrointestinal diseases and is rapidly expanding [91]. FMT entails the administration to a recipient with dysbiosis or abnormal composition of gut bacteria of fecal matter harvested from a healthy individual [92,93]. This method has been beneficial in the treatment of recurrent C. difficile infection and is being investigated for other diseases like irritable bowel syndrome and metabolic syndrome [90]. Studies indicate that fecal microbiota transplantation (FMT) can restore microbial balance and functionality, thereby improving patients’ health [94].

9.3. Dietary Interventions

The most researched and potentially most effective way to change gut flora is through diet. Indeed, the composition of the microbiota can be altered, boosting richness and diversity, by some dietary treatments (such as increasing fiber consumption) that cause quick changes in the levels of particular nutrients [95,96]. Particular foods, which are described as high-fiber diet, polyphenols, and fermented foods have the potential to foster the regulation of the gut microbiome [97]. For example, the Mediterranean diet is believed to enhance microbial richness and the subsequent metabolically beneficial profile [98]. The roles of polyphenols and other possible one of the largest classes of plant secondary metabolites, including anti-inflammatory, antibiotic, anti-adipogenic, antioxidant, and neuroprotective effects of polyphenols have recently come into focus [99,100]. Due to polyphenols’ complex nature and high molecular weight, major portions of dietary polyphenols are not absorbed across the gastrointestinal tract. However, the gut microbiota residing in it, bio-transforms them into biologically active low molecular weight phenolic acid metabolites in the large intestine [97,101].

9.4. Personalized Microbiome Therapy

This approach works with the differences in the composition of the microbiome, genetic profile, and lifestyle of the patient, to achieve the best results in the organization of interfering treatments. There are reasons to believe that individual approaches can yield higher effectiveness of treatments since they aim at the response to patients’ microbial signatures – the existing problem of variability of reactions to microbiota manipulations. [102].

9.5. Therapeutic Potential of Microbial Endocrinology in Cancer Treatment

Microbial Endocrinology offers promising therapeutic potential in cancer treatment through several mechanisms:

1. Modulation of Immune Responses: It has been observed that the immune system is mainly developed by the gut microbiota, and this immune system is responsible for cancer detection and prevention. Some of the gut bacteria can boost immune response and ‘sensitize’ the organism against tumors, as they affect increased recruitment of T-cells and natural killer cells [4,55,58]. For instance, certain types of probiotics have been found to increase the effectiveness of immunotherapy through the regulation of gut microbiota as well as the enhancement of systemic immunity against cancer cells [59].

2. Influence on Hormonal Regulation: ME provides an impression about how gut microbiota can influence the metabolic process of hormones involved in tumorigenesis. For instance, gut bacteria can metabolize estrogens, influencing their levels in circulation. Dysbiosis has been linked to altered estrogen metabolism, which can contribute to hormone-dependent cancers, such as breast and prostate cancer. By restoring a healthy microbiome, it may be possible to achieve better hormonal balance and reduce the risk of hormone-related cancers [3,73].

3. Production of Bioactive Metabolites: Gut bacteria produce various bioactive metabolites, including SCFAs, which have been shown to exert anti-cancer effects. Through their control over apoptosis, autophagy, metabolism, the EMT process, the cell cycle, signaling pathways, and onco-/tumor suppressor genes in a variety of cancer types, SCFA-producing intestinal microbes, and SCFAs, primarily butyrate, that originate from the gut microbiota, were closely linked to the inhibition of cancer cell growth [103], (Figure 4).

4. Enhancement of Chemotherapy Efficacy: Recent studies suggest that the gut microbiome can influence the effectiveness and toxicity of chemotherapy. Certain microbial communities may enhance the metabolism of chemotherapeutic agents, leading to improved efficacy or reduced side effects [4]. By manipulating the microbiome through probiotics or dietary interventions, researchers aim to optimize chemotherapy outcomes and minimize adverse effects.

5. Gut-Brain Axis and Cancer-Related Symptoms: The gut-brain axis, a key aspect of microbial endocrinology, may also play a role in managing cancer-related symptoms, such as pain, anxiety, and depression [10]. By targeting gut microbiota and their neuroactive metabolites, it may be possible to alleviate these symptoms and improve the quality of life for cancer patients.

10.1. Recent Advances

Over the past years, many studies have improved the comprehension of how the host microbiome communicates with the endocrine system. Key developments include:

10.2. Technological Developments

Several investigations in ME in the past several years have enhanced the understanding of mechanisms of the microbiota-host interaction with the endocrine system. Key developments include: