INTRODUCTION:

L-glutamic acid, an amino acid that is naturally found in many food products, is the source of the flavour enhancer monosodium glutamate (MSG), which is used frequently in food preparation¹.MSG has a distinct flavour known as umami, which was first valued as a prominent flavour in Asian civilizations and only much later in Western ones^1,2. Additionally, to salty, sour, sweet, and bitter, Kikunae Ikeda identified this molecule as the fifth basic taste almost a century ago. MSG can be found in foods heavy in protein, like meat and fish, as well as in some types of cheese and vegetables^1,3. Along with its basic distinctiveness, the umami flavour can intensify overall flavour and increase the palatability of food. The concentration of the substance having the greatest impact on this effect is umami as well as food matrix⁴.

MSG is an additive added to several processed foods, having a projected average per day consumption of 0.3 to 1.0g in developed European nations. MSG consumption is safe according to food safety regulatory organizations, however, several preclinical and clinical research have questioned this, particularly after long-term exposure. The debate is probably stoked by the realization that endogenous glutamate participates in both physiological and pathological processes⁵. Glutamate serves several physiological roles, including being an important substrate for enterocytes' energy production, an intermediary substance in protein metabolism, a precursor to important metabolites like glutathione or N-acetyl glutamate, and a centralexcitatory neurotransmitter. On par to status epilepticus, cerebrovascular accident, or traumatic brain injury and chronic neurodegeneration, a rise in central nervous system (CNS) glutamate levels is connected to brain damage^6,7. In this narrative review, as a primary goal, we explored the probabilities of MSG affecting gut health through various mechanisms and searched databases of standard publications like PubMed and Scopus using keywords like MSG, monosodium glutamate, intestinal disorders, and cancers.

MSG-GLUTAMATE EXCITOTOXICITY- INTESTINAL DISORDERS:

Glutamate is subject to oxidation in enteric cells of the small intestine after oral ingestion. The minimal amount that is eventually seen in the portal blood probably occurs through intestinal glutaminase function and not through the assimilation from dietary glutamate, but rather through glutamine catabolism. Almost all enterally administered glutamate is eliminated through the splanchnic bed via first pass in human subjects who are healthy. Glutamate serves as a precursor for the generation of many biologically active chemicals or is further transformed into various amino acids after oxidation.

The gut uses around 30% of all glutamine, making it clear that this nutrient is important for the intestine among the different tissues that use glutamine at significant rates⁸. Studies on healthy adults have shown that most of the glutamine ingested enters splanchnic tissues, with the remaining 25% being metabolised in the colon^9,10. When serum glutamine goes through the small intestine, one-fourth of it is absorbed¹¹. The intestine is thought to compete for glutamine available from body's supply of amino acids and food sources, among tissues¹². It has been extensively investigated how glutamine is metabolised in the gut. Its role includes preserving intestinal barrier and nucleotide metabolism, reducing inflammation, and controlling apoptosis and stress responses^13-15.

Throughout the brain and spinal cord, glutamate is a key excitation neurotransmitter that is essential for the regulation of healthy physiological as well as pathological circumstances^16,17. There is mounting evidence that glutamate may also play a role in the control of certain peripheral nervous system activities, which involves the functioning of the gut¹⁸. The potential function of glutamate to be a neurotransmitter/neuromodulator throughout GI tract has been the subject of numerous investigations over the past 30 years. This effort has produced immunohistochemical, biomolecular, as well as physiological findings that point to the presence of the entire glutamatergic neural transmitter system in the intricate circuits of the enteric nervous system (ENS), that involves in localised integration of GI functioning in addition to brain-gut axis¹⁹.

Histological as well as biochemical evidence that the glutamatergic neurotransmitter system, comprising vesicular transport and neurotransporters, iGlu and mGlu receptors, are present in the ENS was demonstrated in the late 1990s²⁰. Many investigations have also demonstrated that the brain-gut axis related neural connections across the central nervous system and the gastrointestinal tract are regulated in part by glutamate signalling. Along this axis, signals from the central nervous system to the GI tract regulate the GI tract's muscular and secretory processes, whereas electrical and chemical impulses from the GI tract transmit sensory data to brain²¹. IgGlu and mGlu receptor subtypes in all species, including rat, mouse, guinea pig, and human, were distributed in intrinsic and extrinsic neurons that regulate the activity of secretory and motor mechanisms along the GI tract^20,22.

It is known that abnormalities in glutamate discharge, absorption, biotransformation, and signalling contribute to the aetiology of CNS diseases, such as neurodevelopmental, neurodegenerative, as well as psychiatric conditions²³. Evidently,there is mounting scientific data suggesting enteric glutamatergic dysregulation contributing to the emergence of manifestations in a number of diseases, including those affecting the gut system. Although severe gastrointestinal trauma, like that experienced in inflammatory or I/R injury, has been linked to neurotoxicity, brought on by a significant rise in extracellular glutamate levels, alterations in receptor expression as well as function are what primarily cause this disarray. Excessive glutamate-mediated postsynaptic excitement from increased pre-synaptic release combined with insufficient absorption along with cytosolic efflux causes excitotoxicity²⁴.

Intestinal mucosa is constantly inflamed and uncontrolled in Inflammatory bowel disease, which can affect the entire digestive system, as in Crohn's disease, or just restricted to rectum and colon as manifested in Ulcerative colitis^25,26. Following the inflammatory challenge, mucosal injury, aberrant secretion, and visceral feeling may be temporary symptoms. However, these symptoms might be followed by more protracted changes in the enteric neural circuits and intestinal muscles, which would lead to dysmotility. Afferent neuron hyperexcitability, altered inhibitory neuromuscular neurotransmission, synaptic facilitation, and abnormal enteric neural circuitry are all effects of inflammation²⁷.

An intricate combination of inflammatory mediators like cytokines, neuronal transmitters, and hormones may be released by neuronal cells and mucosal immunocytes in the ENS to regulate their interactions with one another. Neutrophils may be drawn to the region and mast cells may degranulate as a result of neuronal stimulation. On lymphocytes, which can be stimulated by SP or VIP, are receptors for neuropeptides generated by enteric neurons that can cause differentiation and changes in immunoglobulin synthesis²⁸. The development of damage at GI regions away from the sites of inflammation may potentially be explained by neuro-immune associations. Reduced NA and ACh release was seen in rats with colitis caused by trinitrobenzensulphonic acid (TNBS), and this effect was seen in both the normal ileum and the inflamed colon²⁹. It's interesting to note that elevated IL-6 and histamine levels throughout inflammatory processes may have a presynaptic suppressive action on discharge of several neurotransmitters even at locations far from the affected site^30-32. The results of these researches support the concept that various subpopulations involving enteric neurons with immunocytes have distinct biological interactions with one another³³.

To avoid the formation of more pronounced inflammatory disorders, it is particularly crucial in this situation to identify potential regulators of pro-inflammatory processes in GI tract. There are numerous publications that show how glutamatergic transmission contributes to the emergence of neuroinflammatory processes. In connection with inflammation, glutamatergic mechanisms trigger an extensive series of molecular processes that could entail the modification of oxidation as well as nitrosative mechanisms³⁴. Through activating the NMDA receptor and raising the intracellular free calcium, glutamate can cause the synthesis of reactive oxygen species, particularly superoxide, with xanthine oxidoreductase as well as NO production through activating NOS³⁵. Peroxynitrite is produced as a result of the interaction of ROS with NO and has been linked to the pathophysiology of a number of chronic as well as acute inflammatory diseases, including GI system³⁶.

Additionally, free radicals produced from arachidonic acid metabolism induced by NMDA may exacerbate oxidative damage³⁷. It's interesting to note that in pro-inflammatory settings, prostaglandin as well as NO may both play significant roles in lowering motility in the gastrointestinal tract, based on clinical evidence³⁸. A different hypothesis suggests the development of neuroimmune reflexes during inflammation may be mediated by enteric glutamatergic mechanisms. Following this scenario, IL-1b- as well as TNFa-dependent mechanisms allow enteric neurons to release a variety of inflammatory mediators, which support the infiltration of immune cells in ENS independently³⁹. These cytokines, which are pro-inflammatory, can trigger neuronal damage in the central nervous system (CNS) by activating microglia, causing the release of NO along with arachidonic acid, and producing prostaglandins as well as inflammatory eicosanoids⁴⁰. In addition, IL-1b along with TNF-alpha influence the expression and location of NMDA as well as AMPA receptors, and they also impact the release and absorption of glutamate at the glial level, resulting in glutamate-induced excitotoxicity⁴¹.Glutamate has been demonstrated to promote IL-1b and TNFa production in neuronal cells independently, via NMDA receptors, as well as influence IL-1b-induced neuronal damage in vitro^41,42. Accordingly, glutamate which is intestinal excitation neurotransmitter, may be crucial for the transmission of local signalling from inflammation that affect gastrointestinal motility.[Figure 1]

Figure 1: Monosodium glutamate mediated intestinal epithelial dysfunction and inflammation. IL- interleukin, TGF- tumor growth factor, rER- rough endoplasmic retinaculum, MSG- monosodium glutamate.

MSG-OBESITY-INTESTINAL DISORDERS:

It has been demonstrated that lymphocytes and thymocytes consist of glutamate receptors. MSG therapy of newborn pups may be employed to create obesity models in mice⁴³. Adiponectin transcription decreased and a mild chronic inflammatory state with increased pro-inflammatory cytokines was seen^44,45. Mice fed with MSG had high insulin levels, increased serum cholesterol and triglycerides, and elevated glucose levels in their serum biochemical profiles⁴⁶. In fact, neonatal MSG treatment to mice results in an obese model with compromised glycemic control and elevated serum levels of leptin and resistin⁴⁷. Interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF), resistin, and leptin mRNA expression increased, and both peroxisome proliferator-activated receptors (PPAR) and (PPAR) were activated, expressing the pro-inflammatory characteristics caused by MSG⁴⁷. [Figure 2]

Obese mice induced by MSG revealed changes in metabolism, that differed in gender susceptibilities throughout life and as they aged⁴⁵. In this situation, inflammation and hepatic steatosis induced by obesity were directly linked to the development of liver cancer^48,49. Human non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and pre-neoplastic lesions are also related to obesity, diabetes, and steatosis induced by MSG⁵⁰. In reality, non-neuronal excitatory receptor activation, sodium voltage-gated channels, and excitatory glutamate as a ligand may stimulate cellular hyperexcitability, which could represent an important causative and pathogenic aspect of carcinoma⁵¹. Hepatocellular carcinoma as well as liver cancer were frequently related with elevated degrees of oxidative stress with aberrant hepatic lipogenesis, all of that have been considerably linked to obesity along with the metabolic syndrome^49,52.

In an MSG-induced obese mice model, increased activity of the drug-metabolizing enzymes UDP-glucuronosyltransferase 1A as well as NAD(P)H: quinone oxidoreductase 1 led modified kinetics of drugs. Additionally, obese animals with reduced glutathione S-transferase activity suggested decreased antioxidants and chemoprotection^53,54. When contrasted with the primary pathways, the reactive species produced by these enzymes are more reactive. Data from clinical as well as epidemiological research revealed a strong connection between these enzymes and colorectal cancer⁵⁵.

A GI disease known as irritable bowel syndrome (IrBS) is characterised by persistent pain in the abdomen along with alterations in bowel habits that have no recognised biological causes⁵⁶. The altered metabolism of abdominal fat highlights the contribution of obesity to the higher probability of IrBS by affecting GI motility, stimulating the generation of adipokines, and immunologic variables⁵⁷. According to a research, a rise in visceral adiposity has been linked toaugmented visceral sensitivity to luminal spurs, intestinal motility, as well as pain in the abdomen, all of which are common in Ir BS patients. Increased intestine sensitivity to various stimuli is another symptom of IrBS and related illnesses. Normally, intra-luminal lipids improve the way the body perceives contemporaneous intestinal impulses and modify bowel motor responses; in Ir BS patients, their impacts are magnified⁵⁸.

The risk of colonic diverticulosis is further raised by obesity⁵⁹. When colonic mucosa as well as sub-mucosa protrude through holes in the muscular component of the wall of the colon, causes diverticulosis of the colon, an anatomic transformation in the wall of the colon that is marked by an appearance of extroflexions⁶⁰. Diverse conceivable explanations for the link between diverticulosis and obesity have been presented⁶¹. The pathology of colonic diverticulosis could be influenced by differences in the gut microbes among obese versus non-obese persons. Previous research has shown an association between BMI and an elevated level of methane within the colon in obese patients, which is thought to be caused by a change in the microbe population in the gut. The greater methane concentration could raise the pressure in the lumen and eventually cause diverticulosis⁶².

With a projected prevalence of fifteen to forty percent overweight among inflammatory bowel syndrome (IBD) patients, the incidence of IBD is rising concurrently alongside overweight and obesity^63,64. It is well recognised that food can influence host-microbe communications and the makeup of the microbiota, which may contribute to the rising incidence of IBD in the world⁶⁵. This is widely known that some dietary components, including fats and proteins, can lead to a rise in the generation of potentially toxic bacterial metabolites that stimulate inflammatory reactions within the gut. In addition to metabolic and cardiovascular issues, obesity is linked to GI issues, carcinoma, as well as colon polyps⁶⁶.

Figure 2: Monosodium glutamate pathways causing obesity. GH- growth hormone, TNF-α- tumour necrosing factor.

MSG-GUT DYSBIOSIS-INTESTINAL DISORDERS:

More than 100 trillion microbes make up the extensive microbe population known as the gut microbiota⁶⁷. The microbiota has a significant impact on human health and illness. Numerous variables, particularly antibiotic consumption, mental and physical stress, gender, age, race, location, metabolic processes, the immune system, and nutrition, can have an impact on gut microbiota^68,69. Alterations to gut microbiota are therefore thought to represent crucial associations between food habits and chronic diseases⁷⁰. In particular, excessive MSG consumption increases Collinsella while reducing the taxa Faecalibacterium, Megamonas, and Blautia within the gut microbiome⁷¹. A diet low in fibre can alter the gut microbiota as well as its metabolic products, which can cause epithelium injury in intestine, triggering the generation of pro-inflammatory cytokines, as well as increasing the gut permeability^72-74. A high-quality nutrition represents the diversity and abundance of the gut microbiota. A diet high in fibre preserves the gastrointestinal tract's barrier function and mucus layer integrity^75-77. Purified prebiotic fibres cannot reverse the effects of a persistent or intermittent fibre deficit in animal models, which results in dysbiosis, mucosal injury, as well as barrier disorders⁷⁸. The number of bacteria that break down mucin may rise as a result of dysbiosis brought on by a diet low in fibre. Additionally, dysbiosis can drastically reduce generation of short-chain fatty acids as well as their beneficial anti-inflammatory responses^75,79.

Adenomatous colon polyps, colorectal cancer, inflammatory bowel disease, as well as irritable bowel syndrome are all recognised as gastrointestinal disorders that are often detected by changes in the density of particular bacteria^80-88. With a rise in Bacteroidesvulgatus, Ruminococcusgnavus, and Clostridium perfringens and a decrease in Lachnospiraceae genera (Blautia and Roseburia), pouchitis has been linked to a dysbiosis of the gut microbiota⁸⁹. After 8 weeks of faecal microbiota transplantation, persons with mild to moderate ulcerative colitis showed positive results⁹⁰. It has been noted that the enrichment of Fusobacterium nucleatum induces immunosuppressive activity, which is mediated by the suppression of T cells in the development of colorectal cancer⁹¹. The presence of Fusobacterium nucleatum in colorectal cancer tissue is related to the location of the tumour, according to a prospective cohort research involving 1102 individuals with colorectal carcinoma⁹².

The microbiota in patients with cancer linked to colitis is different from that seen in patients with sporadic cancer unrelated to IBD. Colitis-related cancer was associated with lower Firmicutes as well as Bacteroidetes and a considerable rise in Proteobacteria, whereas random cancer patients had lower Bacteriodes along with increased Fusobacteria^93-97. Both the bifidobacterial population and the butyrate-producing bacteria Faecalibacterium, Eubacterium, Roseburia, Lachnospiraceae, and Ruminococcaceae are reduced in patients with Crohn's disease as well as ulcerative colitis⁹⁸. In adenomatous polyps as well as in cancer-causing mucosa, the microbial genera Faecalibacterium, Bacteroides, along with Romboutsia were decreased^99,100. In addition, compared to healthy persons, patients with CRC and adenomatous polyps had increased concentrations of microbes from the Campylobacter genus¹⁰⁰. Comparing American patients with adenomas to controls, some taxa showed a rise like Bilophila, Desulfovibrio, several Bacteroidetes species), while others showed a decrease as in Veillonella, Firmicutes, Clostridia, and Actinobacteria family Bifidobacteriales. Patients with dysbiosis also showed altered carbohydrate, protein, and fat metabolism as well as increased bile acid formation¹⁰¹.

CONCLUSION:

MSG is being extensively used as an food additive in both domestic as well as commercial purposes. There have been many research and meta-analysis doubting the safety of MSG, as well as questioning the agencies of the nations to review the safety profile of MSG. There are countries where the consumption is about 4g/day/person. In this perspective it is necessary to overlook the mechanism involved in the toxicity produced by MSG. The present review elucidated the association of MSG with various intestinal disorders, explaining the possible mechanism. This may be helpful for re-investigate intensively through proper approaches and techniques for deciding the safety of the MSG as food additive.

CONFLICTS OF INTERESTS:

None.

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Received on 11.10.2023 Modified on 06.01.2024

Research J. Pharm. and Tech 2024; 17(8):4103-4109.

DOI: 10.52711/0974-360X.2024.00636