Introduction

Research involving the gastrointestinal tract, and its systemic influences, have been developed for a long time. Still, in the 17th century, Antoni van Leeuwenhoek wrote about “animalcules” – bacteria – that he identified in his oral cavity with the help of his homemade microscopes, identifying differences between them and some bacteria that he observed in the faeces (Leeuwenhoek, Reference Leeuwenhoek1683). The 19th century was marked by publications that boosted the foundations of perceptions of the interaction between microorganisms and the host, mainly addressing the role of the germ in disease, and the importance of microorganisms in physiology. The publication “A flora and fauna within living animals,” detailing anatomy, reproductive cycle, and specific aspects of “entozoa,” “ectozoa,” and “entophyte” of humans, was essential to induce research aimed at what would come to be defined as the microbiota (Leidy, Reference Kim, Kim, Choi, Kim, Park, Lee, Kim, Kim, Choi, Hyun, Lee, Choi, Lee, Bae and Mook-Jung2012). Pasteur and collaborators, in 1879, described vibrios and their negative repercussions when present in wounds, supporting the “germ theory,” but also suggested that some microorganisms could be significant in human physiological processes, not only in pathologies (Pariente, Reference Pariente2019).

However, with the publication of the Henle–Koch postulates and the successful use of them to identify the relationship between a bacillus and tuberculosis (Koch, Reference Koch1882), researchers at the time began to focus on the search for causative agents of pathology, which led to the “first golden age of microbiology.” Studying the beneficial relationship between microorganisms and humans remained in the background during this period, progressing more slowly until 1916. In that year, there was a correlation between the presence of specific bacterial strains and the inhibition of Salmonella replication, already known to be related to dysentery (Nissle, Reference Nissle1916). When he successfully isolated Escherichia coli from a soldier who had not succumbed to dysentery, Nissle began to cultivate it on agar and filled gelatine capsules with the cultures patenting the creation for the pharmaceutical industry at the time (Sonneborn, Reference Sonnenborn2016). However, the first recognised use of the intestinal microbiota as a treatment method occurred in proving faecal transplantation effectiveness in treating patients with recurrent Clostridium difficile infection in 1958 (Eiseman et al., Reference Eiseman, Silen, Bascom and Kauvar1958).

Research in this line of treatment has become increasingly frequent, especially with the increased antibiotic resistance in recent decades (Sonnenborn, Reference Sonnenborn2016). The intensification of these researches, combined with new technologies, allowed the analysis of the influence of the intestinal microbiota beyond the barriers of the gastrointestinal tract, as well as the demonstration of the systemic influence on these microorganisms. Still in the 1970s, the ability of stress to alter the intestinal microbiota was demonstrated, considering it the causal factor of the observed differences (Tannock and Smith, Reference Tannock and Smith1972). In the clinical setting, the effect of stress on these microorganisms has already been demonstrated through the analysis of faecal content before and after the participation of volunteers in adverse situations with potential stressors (flight training and astronaut diet), evidencing the variation in the composition of the microbiota (Holdeman et al., Reference Holdeman, Good and Moore1976).

Although the first study to demonstrate that hormones produced in the central nervous system (CNS) are also found in the gastrointestinal tract was carried out in the 1930s (Euler and Gaddum, Reference Euler and Gaddum1931), the term brain–gut axis took several decades to emerge. One of the first studies to use the term identified negative feedback on the major release of cholecystokinin (CCK) from the increase in the plasma concentration of this hormone, with the gastrointestinal tract as a possible modulator since the substance does not cross the blood–brain barrier (Banks, Reference Banks1980). Moreover, in this way, the existence of the afferent pathway of the brain–gut axis was evidenced.

The proof of the existence of the efferent pathway occurred years later. In the year 2000, there was a flood that contaminated drinking water in a city in Canada, infecting part of the population with microorganisms, such as Campylobacter jejuni. This population was evaluated, and 8 years later, 2,451 individuals completed the reassessment, out of a total of 4,561 who became infected, and approximately half of the re-evaluated participants (1,166 individuals) were diagnosed with irritable bowel syndrome, having as independent risk factors anxiety and depression (Marshall et al., Reference Marshall, Thabane, Garg, Clark, Moayyedi and Collins2010). Another research, looking for treatment alternatives for hepatic encephalopathy, demonstrated that the oral administration of a low-spectrum antibiotic with the main action on enterobacteria could reverse hepatic encephalopathy more efficiently than the intravenous route. It was seen remission of behavioural symptoms, as well as normalisation of laboratory tests, improvement of mental status, and intellectual abnormalities in patients with decompensated liver disease (Schiano, Reference Schiano2010).

Seeking greater insight into the subject, an experimental study conducted by Neufeld et al. Reference Neufeld, Kang, Bienenstock and Foster(2011) compared brain development and behavioural expression between germ-free (GF) mice (i.e., animals that do not have contact or colonisation by normal microbiota) and rats raised in an environment free of specific pathogens (SPF; i.e., animals colonised by the normal microbiota and isolated from contact with disease-causing microorganisms). The results showed divergences, demonstrating that the SPF population showed behaviour similar to anxiety, which did not occur in GF animals. In addition, there were differences in the central expression of genes, culminating in modifications in the amygdala, hippocampus, and dentate gyrus, areas involved with behaviour and composers of the intrinsic signalling pathway of the CNS responsible for triggering feelings such as fear, anxiety, and the fight or flight response. When subjected to the SPF-rearing environment, the GF population did not present anxiety-like behaviour, only their offspring, which were reared in the same environment as the SPF. These analyses were able to demonstrate that the differences in the CNS level in the SPF rats were related to the composition of their intestinal microbiota (Neufeld et al., Reference Neufeld, Kang, Bienenstock and Foster2011). Heijtz et al. (Reference Heijtz, Wang, Anuar, Qian, Bjorkholm, Samuelsson, Hibberd, Forssberg and Pettersson2011) obtained similar results, showing that the GF animals explored the environment they were exposed to more inadvertently and extensively when compared to the SPF group, which showed greater caution in the unknown environment. A new population of GF rats was obtained and inoculated with the same microbiota as the SPF group shortly after birth, forming the group of conventionalised adults (CON). Their behaviour was similar to the SPF population after undergoing the same tests. Research indicates that GF mice showed lower activation of genes related to fear and anxiety in cortical regions such as the hippocampus, cingulate cortex, and amygdala (Heijtz et al., Reference Heijtz, Wang, Anuar, Qian, Bjorkholm, Samuelsson, Hibberd, Forssberg and Pettersson2011).

In the clinical field, a double-blind trial with 55 properly randomised participants used probiotics (BP) and placebo (PL) for 30 days, seeking to compare levels of anxiety and depression between the groups through questionnaires. After the treatment period (30 days), only the PB group showed an improvement in the psychological distress score, as well as in the self-blame score and higher score in problem-solving in addition to a decrease in the mean urinary cortisol level. The comparison was performed with results obtained in tests before the period of administration of PB or PL. The probiotics used included the genera Lactobacillus and Bifidobacterium (Messaoudi et al., Reference Messaoudi, Lalonde, Violle, Javelot, Desor, Nejdi, Bisson, Rougeot, Pichelin, Cazaubiel and Cazaubiel2011).

The identification and subsequent understanding of the neural axis responsible for this neurotransmission took place through the observation that vagotomised rats do not present behavioural or neurochemical differences after the use of probiotics, pointing out the vagus nerve as an important communication route between the intestinal microbiota and the CNS (Bravo et al., Reference Bravo, Forsythe, Chew, Escaravage, Savignac, Dinan, Bienenstock and Cryan2011). Although the vagus nerve is the main extrinsic neural pathway from the CNS to the intestine, other communication pathways have already been demonstrated. It is a bidirectional connection in which the CNS can interact with the intestine, and the intestine with the CNS (Wang and Wang, Reference Wang and Wang2016), through the vagus nerve itself, spinal nerves, other divisions of the autonomic nervous system, endocrine and immune pathways (cytokines), in addition to other pathways that are still under investigation (Margolis et al., Reference Margolis, Cryan and Mayer2021). Brain imaging has already demonstrated this reciprocal activation, in which intestinal stimuli simultaneously activate crucial brain regions involved in emotion regulation (Mayer, Reference Mayer2011).

In addition, under clinical aspects, symptoms of gastrointestinal disorders have been associated with psychological disorders and psychiatric diagnoses. More than that, significant diseases such as Parkinson’s can cause dysfunction in the gastrointestinal tract even before neurological symptoms are evident (Bove and Travagli, Reference Bove and Travagli2019). In this context, the intestinal microbiota also began to be investigated, especially after the publication of the aforementioned study on the use of oral antibiotics for the treatment of hepatic encephalopathy. Among the pathways of influence of the microbiota on the CNS, it has been shown that 90% of the body’s serotonin is produced by intestinal cells through signalling by compounds metabolised by bacteria, culminating in the activation of central nervous areas through the conduction of the stimulus by the vagus nerve afferent (Reigstad et al., Reference Reigstad, Salmonson, Rainey, Szurszewski, Linden, Sonnenburg, Farrugia and Kashyap2015; Yano et al., Reference Yano, Yu, Donaldson, Shastri, Ann, Ma, Nagler, Ismagilov, Mazmanian and Hsiao2015). The intestinal microbiota is also responsible for helping to maintain the intestinal mucus layer, so changes in the microbiota induced by inadequate diet cause compromise of the mucus layer, allowing access to pathogens to dendritic cells. Due to this exposure, immune mediators are released into the systemic circulation, which can cause immune activation in different locations, including the CNS (André et al., Reference André, Laugerette and Féart2019). This activation correlates with neurodegenerative disease pathophysiology (Margolis et al., Reference Margolis, Cryan and Mayer2021).

With this in mind, researchers have developed experimental designs involving transgenic animals with Alzheimer’s disease (AD), seeking to improve symptoms from changes in the intestinal microbiota through probiotics and faecal microbiota transplantation (FMT). The results indicate that probiotic supplementation in mice decreased β-amyloid plaques in the hippocampus, when combined to exercises (Abraham et al., Reference Abraham, Feher, Scuderi, Szabo, Dobolyi, Cservenak, Juhasz, Ligeti, Pongor, Gomez-Cabrera, Vina, Higuchi, Suzuki, Boldogh and Radak2019). In addition, probiotic treated mice show reduced inflammation and permeability of the intestinal wall, as well as a tendency to normalise inflammatory modulators in the systemic circulation, although central-level effects on the reduction of β-amyloid plaques, cytokine levels and gliosis were absent (Kaur et al., Reference Kaur, Nagamoto-Combs, Golovko, Golovko, Klug and Combs2020). FMT also affects these animals since the transplantation of microbiota from healthy animals to models with Alzheimer’s caused a decrease in the number of central B-amyloid plaques, improvement in cognition, and reversal of abnormalities in the expression of genes that modulate the activity of macrophages (Kim et al., Reference Kim, Kim, Choi, Kim, Park, Lee, Kim, Kim, Choi, Hyun, Lee, Choi, Lee, Bae and Mook-Jung2020; Dodiya, Reference Dodiya, Lutz, Weigle, Patel, Michalkiewicz, Roman-Santiago, Zhang, Liang, Srinath, Zhang, Xia, Olszewski, Zhang, Schipma, Chang, Tanzi, Gilbert and Sisodia2021). Furthermore, the Federal Drug Administration (FDA) recently approved the rectal administration of a probiotic suspension to prevent recurrent C. difficile infection. The technique is also more cost-effective when compared to traditional treatment (i.e., prolonged use of antibiotics, without subsequent administration of the probiotic suspension; Lodise et al., Reference Lodise, Guo, Yang, Cook, Song, Yang, Wang, Zhao and Bochan2023; Walter and Shanahan, Reference Walter and Shanahan2023).

Due to the beneficial effects of healthy microbiota on the brain–gut axis and its repercussion on AD symptoms, already demonstrated in extensive literature with animal models, intestinal microbiota emerges as a potential ally in treating AD patients.