Gut Bacteria Metabolites Reveal New Intestinal Inflammation Treatment
Nowadays, melatonin, previously considered only as a pharmaceutical product for rhythm regulation and sleep aiding, has shown its potential as a co-adjuvant treatment in intestinal diseases, however, its mechanism is still not very clear. A firm connection between melatonin at a physiologically relevant concentration and the gut microbiota and inflammation has recently established. Herein, we summarize their crosstalk and focus on four novelties. First, how melatonin is synthesized and degraded in the gut and exerts potentially diverse phenotypic effects through its diverse metabolites. Second, how melatonin mediates the activation and proliferation of intestinal mucosal immune cells with paracrine and autocrine properties. By modulating T/B cells, mast cells, macrophages and dendritic cells, melatonin immunomodulatory involved in regulating T-cell differentiation, intervening T/B cell interaction and attenuating the production of pro-inflammatory factors, achieving its antioxidant action via specific receptors. Third, how melatonin exerts antimicrobial action and modulates microbial components, such as lipopolysaccharide, amyloid-β peptides via nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or signal transducers and activators of transcription (STAT1) pathway to modulate intestinal immune function in immune-pineal axis. The last, how melatonin mediates the effect of intestinal bacterial activity signals on the body rhythm system through the NF-κB pathway and influences the mucosal epithelium oscillation via clock gene expression. These processes are achieved at mitochondrial and nuclear levels to control the host immune cell development. Considering unclear mechanisms and undiscovered actions of melatonin in gut-microbiome-immune axis, it's time to reveal them and provide new insight for the outlook of melatonin as a potential therapeutic target in the treatment and management of intestinal diseases.
Gut bacteria metabolites reveal new intestinal inflammation treatment
An initial report in 2020 mapped out the effects of bile acids on mouse gut immunity, but left some key questions unanswered: First, just how do bile acids get gut immune cells to perform their immune-regulatory work? Second, which bacteria and bacterial enzymes produce these bile acids? Third, do these bile acids play a role in human intestinal inflammation?
The studies identify three bile acid metabolites and corresponding bacterial genes that produce molecules that affect the activity of inflammation-regulating immune cells. The work also demonstrates that the presence and activity of these bacteria and the immune molecules they produce are notably reduced in patients with inflammatory bowel disease (IBD).
The research, published in Nature Biomedical Engineering in December 2022, demonstrates that these polymers, called micelles, can be designed to release a payload of butyrate, a short chain fatty acid that is known to help prevent food allergies, directly in the small and large intestines. When given to mice, these micelles increased the abundance of butyrate-producing Clostridia bacteria, protected the mice from an anaphylactic reaction to peanuts, and reduced the severity of symptoms in a model of ulcerative colitis. The micelle technology can be adapted to deliver other metabolites and molecules, making it a potential platform for treating other allergies and inflammatory gastrointestinal diseases.
According to current estimates, approximately 1014 microbes are residing in the human body and the number of microbial cells is outnumbering the human cells . In humans, the gastrointestinal tract is a huge, populous, and intricate microbial ecological community that mainly contains bacteria, archaea, fungi, protozoa, and viruses. Alteration of gut microbiota or unexpected exposure to specific bacteria in the intestine can regulate the peripheral and central nervous systems (CNS), leading to the change of brain function and illustrating the existence of the microbiota-gut-brain axis. It is now commonly believed that interaction in the microbiota-gut-brain axis is bidirectional. Excitingly, the interactive signal transmission has been proved to be involved in different kinds of diseases. Abundant work indicated that gut microbiota indeed plays a predominant role in the appearance of visceral pain and provides an infusive research interest in pathological pain linked to gut dysbiosis. The emerging role of gut microbiota in neurological diseases, including chronic pain, has attracted ever more traction recently.
The alteration of gut microbiota and its metabolites is related to intestinal dysfunction and systemic immune responses that are generally accompanied the release of numerous pro-inflammatory mediators by immune and glial cells. Pathogen-associated molecular patterns (PAMPs) derived from gut microbiota contain a remarkable array of components, including lipopolysaccharides (LPS) and peptidoglycan (PGN), which are released locally, enter the bloodstream and interact with pattern recognition receptors (PRRs) [24, 25]. Also, PAMPs are key mediators of peripheral sensitization of chronic pain . Clinically, chemotherapy-induced destruction of the intestinal epithelial barrier causes intestinal flora to translocate and release harmful endogenous substances. These substances stimulate PAMPs and PRRs of host antigen-presenting cells and provoke the generation of pro-inflammatory mediators, which constitute an important component of the pathogenesis of CIPN . Shen et al. revealed that the aggregation of macrophages and cytokines in dorsal root ganglion (DRG) are considerably reduced after the administration of oxaliplatin compared with water, demonstrating that the inflammatory response caused by gut microbiota was suppressed in mice treated with antibiotics . Of note, Lactobacillus fermentum KBL374 and KBL375 can prominently increase the production of the anti-inflammatory cytokine IL-10, with subsequently inhibiting the expression of other pro-inflammatory cytokines and chemokines [28,29,30] (Table 1). Also, results from other strains of lactobacillus suggested that these bacteria mediate immunosuppression by decreasing the production of pro-inflammatory cytokines. These results documented that alteration of gut microbiota could lead to the up-regulation and down-regulation of cytokines and chemokines at the same time, which may affect the occurrence of NP. Due to the absence of specific biomarkers for diagnosing NP to date, further studies are needed to research gut microbiota dysbiosis and determine whether gut microbiota influences the development of NP via the induction of immune responses with these pro-inflammatory mediators. In addition, studies also could identify microbiota subgroups that play the greatest role to obtain better efficacy.
Pain perception involves a variety of neurotransmitters, which can be mainly divided into inflammatory mediators and noninflammatory mediators . The most specific of these neurotransmitters are glutamate and GABA, which are the most widely distributed excitatory and inhibitory neurotransmitters in the body, respectively. Both host and bacteria can convert glutamate to GABA . Some previous studies reported that agents promote the release of GABA by activating GABA receptors, thus effectively relieving trigeminal and diabetic-related NP [72, 73]. Braz et al. demonstrated that GABAergic precursor cell transplantation can reverse allodynia in a mouse NP model and propose transplantation as a therapeutic option in various NP-related models [74, 75]. Furthermore, both the increase of glutamate and the administration of glutamate release inhibitors are sufficient to affect hyperalgesia in animal models [76, 77]. Recently, it has been confirmed that some environmental bacteria strains employed in food fermentation can produce glutamate [47,48,49]. Also, several strains of bacteria, such as Escherichia coli , and Lactobacillus , synthesize GABA (Table 1, Fig. 2). Excitingly, the probiotic Escherichia coli strain Nissle 1917 (EcN) can generate a GABA-related analgesic lipopeptide that inhibits downstream responses caused by nociceptor activation after crossing the intestinal epithelial barrier . In summary, glutamate and GABA in the gut are linked to abundant signaling pathways that modulate pain conditions, regulate the release of pro-inflammatory cytokines, and sense or inhibit afferent innervation of the gastrointestinal tract . However, the host itself also produces GABA. Thus, which of these two sources of GABA predominantly stimulates intestinal neurons and the vagus nerve and ultimately plays a greater role in NP remains unknown.
Serotonin (5-HT), as an important neurotransmitter, could effectively modulate the nociceptive response and serve as a special regulator in NP. When 5-HT acts on its receptors, 5-HT1 receptor activation create a hyperpolarizing effect; while 5-HT2 and 5-HT3 activation leads to primary nociceptive neurons depolarized in DRG  (Fig. 2). Ji et al. found the activation of the 5-HT2c receptor in the basolateral amygdala facilitates activities in NP-associated central nucleus . Correspondingly, 5-HT2c receptor knockdown contributes to the reduction of NP-related behaviors . More than 90% of 5-HT in the body is synthesized by enteroendocrine cells (EECs) and a growing body of literature reveals that the microbiota is correlated with the host level of 5-HT. Notably, 5-HT can be generated by several strains of bacteria, including Escherichia coli, Streptococcus spp., and Enterococcus spp.  (Table 1), but whether gut microbiota can produce 5-HT by de novo remains unknown. Interestingly, 5-HT is reported to be a structural analog of auxins of Escherichia coli, Rhodospirillum rubrum, and Enterococcus faecalis, and activates the growth of these bacteria. Therefore, it might be a hot spot to investigate whether the microbes are able to influence the host 5-HT biosynthesis, and thereby reverse the colonization and development of special microbiota in the intestine . In a word, these findings suggest that the alteration of the microbes may make a difference in the nociception, which is potentially involved in the progression of NP. Though the mechanisms of these neuroactive molecules referred to NP induction and the production of neurotransmitters affected by gut microbiota being far from explicit, it is no denying that gut microbiota is concerned with NP pathogenesis through neurotransmitter routes.