Trp is an essential amino acid for humans: its availability as a substrate for biosynthesis relies on dietary intake (13). Moreover, its bioavailability is influenced by several factors such as the presence of other essential amino acids (15). Trp is involved in crucial metabolic pathways that results in various end-products, among them proteins, the neurotransmitter 5-HT and kynurenines such as quinolinic acid, 3-hydroxykynurenine and kynurenic acid. Two are the non-protein viae of Trp metabolism: kinurenine (KYN) (16, 17) and methoxyindole. The most of Trp (at least 95%) is metabolized via the KYN pathway. The reaction is catalyzed by the rate-limiting enzymes Trp 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase 1 (IDO1) and generates immunomodulatory and neuroactive metabolites. The methoxyindole pathway is the one where 5-HT synthesis occurs (13).

“Once absorbed by the body, Trp travels around the periphery circulation, either bound to albumin or in free form. The two states are in equilibrium, with the former accounting for up to 90%” (16). However, “Trp can only be transported across the blood–brain barrier in its free form by the competitive and non-specific l-type amino acid transporter” (16). “Trp reaches the brain when ingested food is rich in this amino acid and not excessively rich in other large neutral amino acid (LNAAs), that could compete with it” (15).

5% of the available Trp is used as substrate to synthesize the biogenic monoamine 5-HT in a two-step reaction via the methoxyindole pathway (17). The first step is catalyzed by the rate-limiting enzyme tryptophan hydroxylase (TPH), existing in human body in two isoform (TPH1 and TPH2) (18) and leads to the intermediate products 5-hydroxy-tryptophan (5-HTP) (13). The second step is controlled by 5-hydroxytryptophan decarboxilase and leads to 5-HT. The final step of the methoxyindole pathways is controlled by the enzymes monoamine oxidase (MAO) and aldehyde dehydrogenase that lead to 5-hydroxyindole acetic acid (5-HIAA) finally excreted in the urine (13).

Despite its well-known role in the CNS, only approximately 5% of body 5-HT is found in the brain, thus it is important to remember its production and actions in the periphery (19). “Enterochromaffin (EC) cells produce and secrete far more 5-HT than either central or peripheral serotonergic neurons to reach the GI lumen and blood” (20). Indeed, 95% of body 5-HT is found in the gastrointestinal (GI) tract: 90% in EC and 10% in serotonergic neurons of myenteric plexus (20). GI tract is the sole source of blood 5-HT, taken up by 5-HT transporter (SERT) (19).

The serotonergic system is involved in the regulation of many neurophysiological processes and behavioral functions, among them nociception, sensory function, appetite, gastrointestinal function, motor function, mood, cognition, sleep, sexuality, neuroendocrine function (19). 5-HT also plays diverse roles in cardiovascular system (21) and its contribution is emerging in communication between CNS and immune system (19).

d-Fructose (fructose) is a hexose sugar naturally present in fruit and honey. In the last decades its consumption is making an increasing contribution to the Western diet since it is used in industrial products as sweetener in the form of high fructose corn syrup (22). The transport of fructose into and out cells in human body is mainly mediated by three proteins: GLUT5, GLUT2, and GLUT7 transporters, characterized by different substrate specificity and tissue expression. Minor contribution to fructose transport is reported also for the other transport proteins in Class II, that exhibit sequence similarity to GLUT5 and 7: GLUT9 and GLUT11 (23). GLUT5 is a low-capacity transporter, glucose independent and specific for fructose. It is mainly expressed in the jejunal region of the small intestine, but also in kidney and brain. GLUT2 is glucose-dependent low-affinity fructose co-transporter. GLUT7 transports glucose and fructose with high affinity for both (23). GLUT7 has the closest sequence similarity to GLUT5 and is primarily expressed in the distal region of the small intestine, ileum, and colon (24).

Different factors may influence the absorption of free fructose: alterations in the functional capability of GLUT5 may influence the absorption efficiency and a role might also be played by dietary intake of fructose and sucrose too, that influence the transporter expression (25). Moreover the expression of the GLUT5 gene seems to have a diurnal variation (26). Furthermore, the co-ingestion of glucose or galactose considerably enhances fructose absorption activating apical GLUT2 mechanism (25).

Fructose is present in human diet in three forms: as pure monosaccharide, as disaccharide sucrose, in complex with glucose, and in the polymerized forms as oligosaccharides and polysaccharides (25). Chains of fructose units with a terminal glucose molecule are called fructans (27), but some authors reserve the term only for longer fructose chains classified into the class of polysaccharides (28). Thus, fructose chains with a 2- to 9-unit length are variably referred to as oligofructose (27) or fructo-oligosaccharides (FOS) (28) and those with ≥10 units as inulins or fructans (27, 28). Human ability to break down oligo- or polysaccharides in the small bowel is limited and only 5–15% of fructan can be absorbed (27). It is due to the lack of enzymes to fully hydrolyze glycosidic linkages in the complex polysaccharides, determining the presence of non-absorbed fructans in the colon (27).

Interesting results confirm the crucial role of food intake on 5-HT availability and the biochemical and physiological mechanisms that directly or indirectly determine FMS symptomatology.

The core of the hypothesis is that a gastrointestinal malabsorption has a central role as a primarily cause of FMS and that it is mainly due to fructose. This way, the core of the treatment is the contrast of Trp malabsorption, favoring its normal absorption.

At the very beginning, the hypothesis springs from the observation of marked worsening of pain and stiffness in a FMS patient after a breakfast of fruit, marmalade, and rye bread leading to the hypothesis of the involvement of fructose as symptom trigger. The data of decreased serum Trp concentrations in fructose malabsorbers supports the view that fructose malabsorption interferes with Trp metabolism (29). Moreover, the concept that an impairment of Trp absorption can be related to sugar malabsorption is supported by evidences that link lactose and fructose malabsorption to depression, reported in few but significant observations in the literature (29, 39–41).

The implication of the presence of fructose may be not limited to Trp malabsorption but could affect the absorption of other essential amino acids, since Maillard reactions occur not only in the presence of Trp: some experimental data converge in this direction. Maes et al. reported a significantly lowered plasma concentrations of valine, leucine, isoleucine, and phenylalanine in FMS patients than in controls (43) and similar results on an altered amino acid homeostasis were reported by Bazzichi et al. (44). Furthermore, the negative implications of Maillard reactions may have a crucial role on the absorption of some minerals, such as zinc (14). The involvement of zinc in many biochemical pathways (45) reveals its importance for human health and the hidden consequences that fructose malabsorption could directly and indirectly have. In fact, “a prolonged low zinc intake deprives the organism of the local potential beneficial effects of zinc, including interactions with oxidative free radicals and nitric oxide metabolism” (37).

So, the presence of non-absorbed molecules in the gut could also directly or indirectly produce a microbiota deterioration activating a positive feedback loop: the increasing microbiota deterioration reduces the functionality of absorption both of fructose and Trp in the gut, entering a vicious circle. Apart from the order of the events the result is the same: the reduction of Trp absorption and 5-HT synthesis as consequence.

My main hypothesis to explain the fructose malabsorption condition is a reduced transport capacity of GLUT5 due to a mutation able to impair the functionality of binding. Indeed, a single point mutation in the substrate-binding site would be enough to switch the substrate-binding preference of GLUT5 from fructose to glucose (46).

Although fructose malabsorption plays a primarily role, it appears reasonable that it is not the sole cause of FMS, mostly because the incidence of fructose malabsorption (28) is well greater than the FMS ones (4). Maybe, it can just be considered the main risk factor for FMS.

The therapeutic idea for the symptomatic remission of FMS is to sustain serotonin synthesis allowing proper Trp absorption, or reversely: to allow Trp absorption to guarantee its bioavailability for 5-HT synthesis. The core of the cure treatment is the exclusion from the diet of some carbohydrates and the marked reduction of some others. Given that fructose is a high reactive sugar, it is the major target of the treatment. The essential is the limitation of total dietary fructose as marked as possible, not neglecting the role of other molecules, such as sorbitol and also fructose chains, as fructans and inulins. The essence of the treatment is removal of what is bad but ensure what is good. Theoretically, the most efficacious management would be a fructose free, fructan restricted, lactose free, sorbitol free, aspartame free, low sucrose diet, together with proper Trp intake.

Given its foundations, the cure is expected to obtain a remission, not a final recovery. The straying from the treatment is expected to cause the reappearance of the symptoms.

Periodic blood exams should be considered to assess vitamin and mineral salt levels before, during, and after the clinical implementation of this protocol. Proper vitamin supplements and mineral salt supplements should be taken into consideration if deficiency are revealed.

As already mentioned, the target is minimizing the presence of not-absorbed molecules in the gut, removing them from the diet, up to the complete withdrawal in severe FMS conditions.

Due to the fact that fructose is a high reactive reducing sugar (14), it is the major responsible for the impairment of Trp absorption in the gut. Anyway, the role of other sugars has to be considered and will be briefly addressed.

The presence of not-absorbed fructose may have different causes: the easiest one to face and solve is the fructose overload. Reducing its intake is the fastest and easiest way to reduce the symptoms; the second cause is fructose malabsorption, maybe due to a condition of failure in the transporter protein conformation or acquired weakness that impairs the substrate-binding, leading to a low capacity of the transporter. Avoid free fructose intake, reduce fructans intake, and balance the amount of fructose, eventually ingested, with the co-ingestion of glucose to activate the GLUT2 co-transport via, is the way to face up this condition. Excessive amount of fructose is very easy to be reached, as modern Western diets are rich in fructose due to industrial food containing high fructose corn syrup (HFCS), fresh fruit that naturally contains fructose, honey, soft drink, and beverages containing HFCS and saccharose (27, 28, 34, 47). In addition, wheat and the most of cereals, the most of legumes and many vegetables contain fructans (28), contributing to increase the total amount of ingested fructose.

Lactose might have the same consequences of fructose in the gut, especially if the enzyme lactase is deficient.

Disaccharide sucrose would be a separate matter, because in this case fructose is naturally present in equimolar concentration to glucose. This way the pathway of the high-capacity glucose-dependent fructose co-transporter GLUT2 is activated, considerably enhancing fructose absorption (25). The contribution of sucrose malabsorption per se to Trp malabsorption and/or microbiota deterioration can be supposed less relevant, in fact the deficiency of the enzyme sucrase is a very rare congenital condition except in Greenland (25).

The other hexose sugars, xylose and arabinose, are passively absorbed (28), this way they might be potentially involved in Maillard reactions, and their withdrawal is suggested.

Despite structural similarities with fructose, sorbitol lacks a specific transport system and it has only passive absorption (28). Its withdrawal from the diet is suggested too, since even glucose co-ingestion does not facilitate sorbitol absorption. Sorbitol exacerbates symptoms in fructose malabsorbers (42), as it directly inhibits GLUT5 (30). Artificial sweeteners and confectionery food often contain sorbitol and the other polyols (27).

Trp supplements (like Trp tablets) are not suggested in any way, as their intake has potential for important side effects by themselves or due to the interaction with serotonergic drugs, up to life-threatening effects related to serotonin syndrome (48).

Suggested food containing Trp are: meat, eggs, fish, rice, potatoes, dark chocolate, and walnuts.

A further note concerns monosodium glutamate (MSG) and aspartame: their withdrawal from the diet is suggested too. MSG naturally exerts excitatory action in both the central (49) and peripheral nervous system (50). Nevertheless, when artificially introduced in food, it can have excitotoxic effects (51). Aspartame might significantly impair the release of 5-HT in the brain (52). “It can increase the supply of phenylalanine, which subsequently can promote a decrease in Trp uptake by brain tissue or a depression in Trp conversion to 5-HT” (52).

The evaluation of this restrictive diet as possibly inappropriate from a nutritional perspective must be properly considered. The withdrawal of fructose-containing food could lead to a concomitant reduction of vitamin and mineral salt intake. Periodic blood exams must be considered to evaluate their levels: vitamin and mineral salt supplements must be considered to address deficiencies already present and to prevent possible ones during and after the protocol implementation.

The Marked difference among sexes in the rate of 5-HT synthesis (38) may be the most relevant factor to explain the lower incidence of FMS in males, once more supporting the crucial role of 5-HT synthesis in FMS pathophysiology. In fact, males and females seem to have similar stores of brain 5-HT, but the mean rate of 5-HT synthesis is significantly lower in women.

Nevertheless, some other considerations can be made. The association between decreased serum Trp concentrations and sugar (fructose and lactose) malabsorption was observed in experimental studies significant only in women. This could be a consequence of the greater activity of the hepatic enzyme TDO, which is estrogen dependent (39, 40). In fact, estrogens have a stimulatory effect on the liver enzyme TDO, thus shifting the Trp metabolism away from the 5-HT pathway and toward the KYN ones (40).

Stress may also provoke similar effect activating the same biochemical pathway, contributing in the exacerbation of patient conditions: besides estrogens, indeed, TDO is inducible by Trp itself and glucocorticoids (53). The glucocorticoid cortisol is rapidly release in response to emotional stress, stimulating the Trp-KYN pathway activity (52), once more reducing the availability of Trp for 5-HT synthesis.

Last but not least, since the expression of GLUT5 occurs primarily in the small intestine, but lower levels are also expressed in the cells of testes, skeletal muscle (24), and adipose tissue (23), an impairment or reduced capacity of this transporter will have a major impact on women, since skeletal muscle amount is on average less than in men and testes obviously lack.