Microbiota is a key factor in our survival and its existence is fundamental to human health. A lot of agents define the diversity in microbiome content among individuals, such as environment, nutrition, age, genes, infections, and antibiotic use. The largest numbers of the human microbiota live in the gut. The number of intestinal microorganisms is higher than the number of body cells. We have approximately 10¹³–10¹⁴ microbes in our gut. They affect a lot of systems and organs in the human body. One such organ is the brain. Recently, the intestinal microbiota has been regarded as an important regulator of the intestinal brain axis, the term which refers to a bidirectional link between the intestine and the brain ^[1][2][3][1,2,3].

The intestinal microflora, or microbiome, is a complex system that affects many of the body’s functions. In addition to digestion, the microbiota plays a role in immunomodulation, modulating the inflammatory processes, and the endocrine system, and plays a role in neurological and behavioral processes through the gut–brain axis. Its role has been verified in some oropharyngeal, or gastrointestinal tumors, as well as their antitumor effects. 

Through the gut–brain axis, the central nervous system can also affect the intestinal microenvironments by regulating intestinal movement, excretion, and mucosal immunity. Vagal nerve, tryptophan metabolites, and microbial products such short-chain fatty acids (SCFAs) or peptidoglycan are the main channels of communication between the intestinal microbiota and the brain ^[4][8]. External factors such as diet, lifestyle, infections, antibiotic therapy, and hormones also regulate the composition of the intestinal microflora. At the same time, bacteria also act on the nervous system’s neurotransmitters and neuromodulators as a response to the effects mentioned above. Such modulators are of bacterial origin, such as choline, tryptophan, short-chain fatty acids, or hormones such as ghrelin or leptin. Changes in the intestinal flora can sometimes become self-sustaining and lead to the development of chronic non-infectious diseases. When detected in time, changing the external factors can reverse the process.

2. Causes of Dysbiosis

Dysbiosis is a condition where the intestinal flora is altered due to earlier antibiotic therapy or other factors. It can cause various diseases such as metabolic disorders, obesity, hematological malignancies, and neurological or behavioral disorders. Some studies have suggested that dysbiosis can affect the gut–brain axis and contribute to some neurological diseases, such as anxiety, depression, autism, Alzheimer’s disease, stroke, Parkinson’s disease, and migraine ^{[5][6][7][8][9][10][11]}[10,11,12,13,14,15,16]. Diet is the most common cause of dysbiosis worldwide. The influence of a long-term diet on the intestinal microbiome is far-reaching. The Western diet has sped up changes in the human microbiome. Highly processed foods, animal products, and sugars alter the microbiome to cause intestinal inflammation ^[12][7]. It has been demonstrated that many environmental factors influence the microbiome. Lifestyle, socioeconomic factors such as alcohol dependence, smoking, and sedentary lifestyle may be related to microbial dysbiosis. Medicines can affect the balance of the microbiome and modify the microbiome unfavorably. Antibiotics and proton pump inhibitors usually reduce bacterial diversity and increase the number of potential pathogens such as Clostridiodides difficile. Selective serotonin reuptake inhibitors affect intestinal motility and, like antibiotics, may reduce microbial diversity ^[12][7].

3. Dysbiosis and Migraine

Migraine is a neurological disorder that causes severe pain on one or both sides of the head. There is increasing evidence that the alteration of the intestinal microbiota balance plays a role not only in gastrointestinal functions and immune system maturation processes, but it can also affect migraine ^{[11][12][13][14]}[7,16,18,19]. The composition of the microbiota appears to be associated with certain pains, such as spinal cord, visceral pain, or pain in irritable bowel syndrome (IBS), as well as migraines and sometimes headaches. After antibiotic treatment, the intestinal flora is damaged, leading to dysbiosis and resulting in changes in colon sensor and motor functions. Amaral et al. showed that inflammatory hypernociception was induced by lipopolysaccharide (LPS), TNF-α, and IL-1β, and the chemokine CXCL1 was reduced in germ-free mice; such result was induced by prostaglandins and dopamine ^[1][15][16][1,25,26]. A meta-analysis has shown that Helicobacter pylori infection is associated with migraine ^[17][27], with 45% of migraine sufferers having H. pylori infection, compared to 33% of healthy control people. H. pylori infection is thought to be related to a persistent chronic inflammatory state, producing inflammatory and vasoactive agents ^{[17][18][19][20]}[27,28,29,30].

Direct and Indirect Evindences of the Role of Gut Microbiota in Migraine

Several studies have shown that the gut microbiota is crucial to the emergence and maintenance of migraine. The relationship between altered gut microbiota and the development of migraines has both direct and indirect evidence ^[21][32]. Direct evidence of the role of the gut microbiota in migraine: Nitroglycerin (NTG) is commonly used to model migraine in rats. Wen and colleagues discovered that the pro-duction of metabolites by the microbiota was significantly altered by the prolonged usage of NTG ^[22][33]. In a different investigation, Lanza et al. discovered that the short-chain fatty acid can lessen the hyperalgesia caused by NTG ^[21][23][32,34]. More than 100 older women’s feces were studied, and it was discovered that reduced bacterial diversity and less butyrate production directly correlate with migraine ^[21][24][32,35]. Indirect evidence: The gut microbiota is affected by various external factors, such as diet, probiotics, vitamins, and lifestyle. There is indirect evidence for the gut microbiota’s participation in migraine. The results of double-blinded or placebo-controlled randomized trials demonstrated that external factors could affect migraine frequency and intensity ^[21][32]. Metabolites and their role in migraine: Metabolites generated by the intestinal microbiome also have been shown to influence the intestinal brain axis. Short-chain fatty acids (SCFAs) consist of more than 95% acetate, butyrate, and propionate (usually with a 60:20:20 ratio) and smaller amounts of valerate, fomate, and caproate and the branched-chain fatty acids isobutyrate, 2-methyl butyrate, and iso-valerate. Relationships are dependent on the mixing of bacteria in the colon. These molecules have important physiological effects ^[12][7]. Butyrate and propionate have been studied in more detail, and from this, butyrate is regarded as the most important SCFA. Propionate protects the blood–brain barrier (BBB) from oxidative stress ^[25][44]. Propionate production is related to the presence of other species, such as Bacteroides vulgatus, B. uniformis, Alistipes putredinis, Prevotella copri, Roseburia inulinivorans, Veilonella spp., and Akkermansia mucinophila, which have a high capability to produce propionate ^[25][26][27][42,43,44]. In addition, short-chain fatty acids can affect neural inflammation by modulating the pro-duction of immune cells and cytokines ^[28][45]. Certain metabolites produced by bacteria can act as essential neuroactive molecules in the central nervous system. A few species of Lactobacillii and Bifidobacterii can produce acetylcholine and gamma-amino butyrate (GABA) neurotransmitters ^[29][30][46,47].  Besides serotonin, the role of other neuropeptides in migraine headaches is unquestionable. Glutamate plays a key role as a neurotransmitter in the pathophysiology of migraine through central sensitization by stimulating the trigeminovascular system. The activation of trigeminovascular pain routes is designed to mediate some of the qualities of migraine pain by releasing neuropeptides, such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) ^[31][50].

4. How to Modify the Gut Microbiota

4.1. Dietary Influence of the Intestinal Brain Axis

Different dietary approaches have been suggested to influence the intestinal brain axis. Healthy diets such as the Mediterranean diet, a traditional Japanese diet, Dietary Approaches to Stop Hypertension (DASH), the Mediterranean–DASH intervention for neurodegenerative delay (MIND) diet, vegetarian diets, ketogenic diets, and so on are known to produce a more balanced, anti-inflammatory microbiome over time. Patients on a ketogenic diet report less frequent and milder migraine episodes. While dietary change may help in inflammatory bowel disease, celiac disease, and other gastrointestinal diseases, the ability of a dietary change to alter neurological conditions is less clear and has so far yielded various results ^[12][7]. In humans, the effects of prebiotics are less easily established and have often been inconclusive, perhaps because of the heterogeneity of the gut microbiome and differences in study design. Although prebiotics may encourage some bacterial groups to increase in numbers, they do not increase the diversity of microbiomes. In conclusion, dietary approaches are extremely difficult to determine due to difficulties in maintaining dietary strategy, establishing dietary compliance, and designing blind studies ^[12][7].

4.2. Probiotics

The use of probiotics as a dietary supplement may reduce the number and severity of migraine episodes ^[32][56]. Its hypothetical effect is on SCFA production, improving the integrity of the epithelium, and improving proinflammatory cytokine levels by the suppression of kappa factor B ^{[32][33][34][35][36][37][38]}[56,57,58,59,60,61,62]. The results of human trials are mainly related to neurodegenerative diseases such as Alzheimer’s disease and autism spectrum disorder ^[12][7].

4.3. Carbohydrates

Dietary switching to carbohydrates with a low-glycemic index has been shown to increase SCFA levels ^[18][28]. In one randomized study, the effect of the drug used for migraine prevention was compared with carbohydrate intake and an almost equal decrease in the severity of seizures was observed after 90 days on the diet ^[18][39][28,63].

4.4. Vitamins

The B2 vitamin, or riboflavin, is crucial for oxidative metabolism and may lessen migraine risk. According to randomized controlled trials, taking vitamin B2 can significantly reduce the number of migraine days by 1–3 per month. By boosting the amount of short-chain fatty acid makers, microbial variety, and richness, the riboflavin and other vitamin Bs influence the gut microbiome in a favorable way ^[40][64].

4.5. Other

Magnesium insufficiency may affect the NMDA receptor blockade, calcium channel, glutamate, and NO activity, as well as the affinity of the serotonin receptor. Only a few studies have demonstrated a reduction in the length and severity of migraine headaches. In dysbiosis, magnesium serves as an adjuvant therapy ^[41][42][66,67]. Connected to the etiology of migraines are the n-3 and n-6 fatty acids. They act as a source of numerous oxylipins, which are bioactive lipid mediators and are regulators of pain. Strong antinociceptives include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

4.6. Fecal Microbiota Transplantation

Significant efficacy of FMT in recurrent Clostridioides difficile infection has been demonstrated by a large number of randomized controlled studies, systematic reviews, and meta-analyses, even though the mechanisms underlying its effectiveness are not fully understood. There are several concerns about its use, such as the unpleasantness of the procedure, the invasiveness of the intervention, the small but important risk of transmission of infections, and the difficulty of choosing the right donor ^[43][70]. The Food and Drug Administration (FDA) draws attention to potential serious risks, such as the possible transmission of multi-resistant pathogens ^[44][71].

5. Fecal Microbiota Transplantation and Their Effects

5.1. Donor Screening Criteria

When choosing a donor, it is especially important to exclude transmissible infectious diseases and multidrug-resistant (MDR) colonization during screening. The donor should have a normal stool habit and should not suffer from cancer or chronic metabolic disease. After a health check (including the previous six months of medication, travel, lifestyle, chronic disease, and stool habits), donor screening should include general blood collection and the exclusion of infectious agents that can be transmitted through feces. This should include screening for HAV, HBV, HCV, HEV, EBV, CMV, HIV, lues, toxoplasma, fecal parasites, bacteria, and the C. difficile toxin and antigen. Anal sampling should also be performed to exclude MDR-colonizing bacteria ^[45][46][72,73].

5.2. Transplantation Methods

Several methods have been tried in recent years to deliver donor stool to the recipient. Several studies and meta-analyses have compared the effectiveness of fresh and frozen feces and found no significant differences ^[47][48][76,77]. Vigvári and colleagues found that the preparation of lyophilized stool was as effective as fresh stool ^[49][50][51][78,79,80] and that the mode of administration through the nasogastric or nasojejunal tube was also similar ^[47][48][76,77]. Therefore, we can use fresh stool, as well as prepared stool, which can be frozen (at −80 °C) or freeze-dried. The fresh stool should be used within 6 h; frozen stool can be stored for about 6 months, and freeze-dried stool can be stored under appropriate conditions, theoretically indefinitely ^[4][8].

5.3. Microbiological and Metabolic Changes after FMT

Bacteriophages are viruses that specifically target specific bacteria. Numerous studies have shown that the number of bacteriophages (Caudovirales) changes significantly, and that the success of transplantation is best when the amount of Caudovirales in the donor stool is higher ^[52][83]. Mycobiota changes: after successful transplantation, colonization occurs with different donor fungi belonging to the Saccharomyces and Aspergillus genera, while in unsuccessful transplantation, Candida species are dominant ^[4][52][8,83]. Metabonomics investigates metabolic responses due to various medications or other interventions. In the case of FMT, the significant role is played by short-chain fatty acids. In mice, it was found that the presence of high SCFA producers acted as a protective factor in inhibiting C. difficile growth. Valerate, butyrate, acetate, and propionate may also have an important protective effect in this condition and in the restoration of dysbiotic flora ^[52][53][83,84]. Immunological mechanisms suggest that the intestinal microbiome plays a significant role in the proper functioning of mucosal immunity, and through immunomodulation, it can also regulate the immune system of the whole organism.

6. Conclusions

As an alternative therapy, attempts to change the microbiome can be considered. The human intestinal microbiome contains the greatest number of bacteria in the organism and may influence metabolism ^[12][7]. It is an accepted fact that gut microbiota homeostasis is important for both the maintenance of the intestinal flora and brain physiology and normal function. The intestinal microbiome can become imbalanced through dietary changes, medication use, lifestyle choices, environmental factors, and aging ^[12][7]. Current evidence shows that the gut–brain axis influences migraines, even though the mechanism of this interaction is not fully clear. This interaction appears to be influenced by several factors, such as intestinal microbiota, neuropeptides, inflammatory mediators (IL-1β, IL-6, IL-8, and TNF-α), nutritional substances, stress hormones, and serotonin pathways. The neuropeptides, such as CGRP, SP, VIP, and NPY, are thought to have antimicrobial effects on various gut bacterial strains [1]. The relationship between the gut and the brain is bidirectional. Dietary strategies can affect the course of migraines and are valuable tools for improving migraine management. However, due to limited evidence for the treatment of migraines with diet, a firm conclusion cannot be proved. It can be assumed that prescribing the diet is beneficial to the microbiota and the gut–brain axis. The dietary approaches include consumption of fiber, a low-glycemic index diet, vitamin D, probiotics, and weight-loss diet plans (for obese patients), which can also lead to an improvement in migraine-related characteristics ^[18][28]. A new, yet unproven, approach to treating migraines could be fecal transplantation. Gut microbial restoration is more effective and durable with FMT. The most important evidence for the efficacy and utility of FMT has been provided by randomized clinical trials.