Clinical utility of anti-Ro52 antibody confirmation in anti-MDA5 antibody-positive dermatomyositis: A Case Report.

This case report highlights dermatomyositis (DM) characterized by the concurrent presence of anti-melanoma differentiation-associated protein 5 (anti-MDA5) and anti-Ro52 antibodies. A 64-year-old woman initially presented with erythema on the palms, which later spread to the dorsum of the hands, followed by involvement of the face, forehead, and upper eyelids. The patient reported joint pain, fatigue, and dyspnea. Physical examination revealed characteristic cutaneous manifestations, including heliotrope rash and Gottron's sign, accompanied by skin ulceration and muscle weakness. Blood tests showed elevated levels of creatine phosphokinase and C-reactive protein. A high-resolution computed tomography (HRCT) scan revealed interstitial lung disease (ILD) with an organizing pneumonia (OP) pattern. Magnetic resonance imaging (MRI) confirmed the presence of myositis. Autoantibody analysis revealed concurrent positivity for both anti-MDA5 and anti-Ro52 antibodies. At the time of diagnosis, she had no respiratory impairment, but had an elevated C-reactive protein and high levels of anti-MDA5 antibody. She was started on triple combination therapy with glucocorticoids, cyclophosphamide, and tacrolimus. She had worsening oxygenation and elevated ferritin during the first weeks of treatment, but then her symptoms improved. Early detection of a co-positive anti-Ro52 antibody led to early initiation of triple combination therapy and a good prognosis.

Extracellularly secreted cysteine derived from cystine regulates oxidative and electrophilic stress in HepG2 cells.

While cysteine (CysSH) is known to be exported into the extracellular space, its biological significance is not well understood. The present study examined the movement of extracellular CysSH using stable isotope-labeled cystine (CysSSCys), which is transported into cells and reduced to CysSH. Exposure of HepG2 cells to 100 µM stable isotope-labeled CysSSCys resulted in 70 µM labeled CysSH in cell medium 1 h after CysSSCys exposure. When the cell medium was collected and incubated with either hydrogen peroxide (H2O2) or atmospheric electrophiles, such as 1,2-naphthoquinone, 1,4-naphthoquinone and 1,4-benzoquinone, CysSH in the cell medium was almost completely consumed. In contrast, extracellular levels of CysSH were unaltered during exposure of HepG2 cells to H2O2 for up to 2 h, suggesting redox cycling of CysSSCys/CysSH in the cell system. Experiments with and without changing cell medium containing CysSH from HepG2 cells revealed that oxidative and electrophilic modifications of cellular proteins, caused by exposure to H2O2 and 1,2-naphthoquinone, were significantly repressed by CysSH in the medium. We also examined participation of enzymes and/or antioxidants in intracellular reduction of CysSSCys to CysSH. These results provide new findings that extracellular CysSH derived from CysSSCys plays a role in the regulation of oxidative and electrophilic stress.

[Supersulfides to Regulate Electrophilic Stress].

Environmental electrophiles modify thiol groups of proteins in organs, disrupting cellular functions carried out by the modified proteins and increasing the risk of various diseases. The transcription factor NF-E2-related factor 2 (Nrf2) plays a crucial role in detoxifying electrophiles by forming glutathione adducts and subsequently excreting them into extracellular spaces. Supersulfides such as cysteine persulfides (CysSSH) produced by cystathionine γ-lyase (CSE) capture environmental electrophiles through sulfur adduct formation. However, the Nrf2 and CSE contributions to blocking environmental electrophile-mediated toxicity have yet to be evaluated. Therefore, we assessed the individual and combined roles of Nrf2 and CSE in suppressing toxicity induced by environmental electrophiles using Nrf2 knockout (KO), CSE KO, and Nrf2/CSE double KO (DKO) mice. Our findings indicate that CSE/Nrf2 DKO mice are more sensitive to environmental electrophiles compared to their single KO counterparts, highlighting the distinct mechanisms through which both pathways mitigate the toxic effects of reactive electrophiles. Moreover, diverse metabolites produced by symbiotic gut bacteria in the human body are known to exert various effects on host organ functions beyond the intestinal tract. We observed reduced blood supersulfide levels in mice lacking gut microflora compared to normal mice. Furthermore, we identified intestinal bacteria belonging to the families Ruminococcaceae and Lachnospiraceae as high CysSSH-producing bacteria. This suggests that the gut microbiota serves as a source of in vivo supersulfide molecules. These findings suggest that supersulfide derived from gut bacteria may act protectively against environmental electrophilic exposure in the host.

Potential Association between Methylmercury Neurotoxicity and Inflammation.

Methylmercury (MeHg) is the causal substrate of Minamata disease and a major environmental toxicant. MeHg is widely distributed, mainly in the ocean, meaning its bioaccumulation in seafood is a considerable problem for human health. MeHg has been intensively investigated and is known to induce inflammatory responses and neurodegeneration. However, the relationship between MeHg-induced inflammatory responses and neurodegeneration is not understood. In the present review, we first describe recent findings showing an association between inflammatory responses and certain MeHg-unrelated neurological diseases caused by neurodegeneration. In addition, cell-specific MeHg-induced inflammatory responses are summarized for the central nervous system including those of microglia, astrocytes, and neurons. We also describe MeHg-induced inflammatory responses in peripheral cells and tissue, such as macrophages and blood. These findings provide a concept of the relationship between MeHg-induced inflammatory responses and neurodegeneration, as well as direction for future research of MeHg-induced neurotoxicity.

Capture of Electrophilic Quinones in the Extracellular Space: Evidence for a Phase Zero Reaction.

Electrophilic quinones are produced during the combustion of gasoline in the atmosphere. Although these reactive species covalently bind to protein-based nucleophiles in cells, resulting in the formation of protein adducts involved in the modulation of redox signaling pathways and cytotoxicity, the extracellular regulation of quinones is not understood. In this study, incubation of 1,2-naphthoquinone (1,2-NQ) with the low-molecular-weight fraction of mouse plasma resulted in the consumption of cysteine (CysSH) in the plasma in a concentration-dependent manner. Covalent modification of albumin was markedly repressed by the addition of either the low-molecular-weight fraction of mouse plasma or CysSH, suggesting that CysSH protects by forming a conjugate with 1,2-NQ. Similar phenomena also occurred for other atmospheric quinones 1,4-NQ and 1,4-benzoquinone (1,4-BQ). The addition of cystine to a culture medium without amino acids enhanced the release of CysSH from A431 cells and blocked 1,2-NQ-mediated arylation of intracellular proteins, suggesting that 1,2-NQ interacts with extracellular CysSH. Liquid chromatography-tandem mass spectrometry analysis revealed that 1,2-NQ and 1,4-BQ undergoes nucleophilic attack by CysSH, yielding a 1,2-NQH2-SCys adduct and 1,4-BQH2-SCys adduct, respectively. Unlike 1,2-NQ and 1,4-BQ, the authentic 1,2-NQH2-SCys adduct and 1,4-BQH2-SCys adduct had little effect on the covalent modification of cellular proteins and viability of A431 cells. These results suggest that electrophilic quinones are readily trapped by CysSH released from A431 cells, forming less-toxic CysSH adducts and thereby repressing covalent modification of cellular proteins. These findings provide evidence for the existence of a "phase zero" reaction of electrophiles prior to their uptake by cells.

SCIATIC DENERVATION-INDUCED SKELETAL MUSCLE ATROPHY IS ASSOCIATED WITH PERSISTENT INFLAMMATION AND INCREASED MORTALITY DURING SEPSIS.

ABSTRACT: Background: Patients with underlying skeletal muscle atrophy are likely to develop aggravated sepsis. However, no study has experimentally verified the association between the prognosis of sepsis and muscle atrophy, and the mechanism of aggravation of sepsis under muscle atrophy remains unclear. In this study, we investigated the effect of skeletal muscle atrophy induced by sciatic denervation (DN), an experimental muscle atrophy model, on sepsis prognosis. Methods: Skeletal muscle atrophy was induced by DN of the sciatic nerve in C57BL/6J male mice. Cecal ligation and puncture (CLP) was performed to induce sepsis. Results: The survival rates of the sham and DN groups 7 days after CLP were 63% and 35%, respectively, wherein an approximately 30% reduction was observed in the DN group ( P < 0.05, vs. sham-CLP). The DN group had a higher bacterial count in the blood 48 h after CLP ( P < 0.05, vs. sham-CLP). Notably, NOx (a metabolite of nitric oxide) concentrations in DN mice were higher than those in sham mice after CLP ( P < 0.05, vs. sham-CLP), whereas serum platelet levels were lower 48 h after CLP ( P < 0.05, vs. sham-CLP). In organ damage analysis, DN mice presented increased protein expression of the kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), a kidney injury marker, after CLP (NGAL 48 h after CLP, P < 0.05, vs. sham-CLP; KIM-1 24 h after CLP, P < 0.01, vs. sham-CLP). Furthermore, nitro tyrosine levels in the kidneys of DN mice were higher 48 h after CLP compared with those in sham-CLP mice, indicating the accumulation of nitrative stress ( P < 0.05, vs. sham-CLP). Serum cytokine levels were increased in both groups after CLP, but decreased in the sham group 48 h after CLP and remained consistently higher in the DN group (tumor necrosis factor [TNF]-α: P < 0.05, sham-CLP vs. DN-CLP; interleukin (IL)-1ß: P < 0.01, sham-CLP vs. DN-CLP; IL-6: P < 0.05, DN vs. DN-CLP; IL-10: P < 0.05, sham-CLP vs. DN-CLP). Conclusions: We verified that skeletal muscle atrophy induced by DN is associated with poor prognosis after CLP-induced sepsis. Importantly, mice with skeletal muscle atrophy presented worsening sepsis prognosis at late onset, including prolonged infection, persistent inflammation, and kidney damage accumulation, resulting in delayed recovery.

Cystine-dependent antiporters buffer against excess intracellular reactive sulfur species-induced stress.

Reactive sulfur species (RSS) play a role in redox homeostasis; however, adaptive cell responses to excessive intracellular RSS are not well understood. Therefore, in this study, we generated transgenic (Tg) mice overexpressing cystathionine gamma-lyase (CSE) to produce excessive RSS. Contrary to expectations, tissue concentrations of RSS, such as cysteine persulfide (CysSSH), were comparable in both wild-type and CSE Tg mice, but the plasma concentrations of CysSSH were significantly higher in CSE Tg mice than in wild-type mice. This export of surplus intracellular RSS was also observed in primary hepatocytes of CSE Tg mice. Exposure of primary hepatocytes to the RSS generator sodium tetrasulfide (Na2S4) resulted in an initial increase in the intracellular concentration of RSS, which later returned to basal levels after export into the extracellular space. Interestingly, among all amino acids, cystine (CysSSCys) was found to be essential for CysSSH export from primary mouse hepatocytes, HepG2 cells, and HEK293 cells during Na2S4 exposure, suggesting that the cystine/glutamate transporter (SLC7A11) contributes, at least partially, to CysSSH export. We established HepG2 cell lines with knockout and overexpression of SLC7A11 and used them to confirm SLC7A11 as the predominant antiporter of CysSSCys and CysSSH. We observed that the poor efflux of excess CysSSH from the cell enhanced cellular stresses induced by Na2S4 exposure, such as polysulfidation of intracellular proteins, mitochondrial damage, and cytotoxicity. These results suggest the presence of a cellular response to excess intracellular RSS that involves the extracellular efflux of excess CysSSH by a cystine-dependent transporter to maintain intracellular redox homeostasis.

Dietary-protein sources modulate host susceptibility to Clostridioides difficile infection through the gut microbiota.

Clostridioides difficile causes nosocomial antibiotic-associated diarrhea on a global scale. Susceptibility to C. difficile infection (CDI) is influenced by the composition and metabolism of gut microbiota, which in turn are affected by diet. However, the mechanism underlying the interplay between diet and gut microbiota that modulates susceptibility to CDI remains unclear. Here, we show that a soy protein diet increases the mortality of antibiotic-treated, C. difficile-infected mice while also enhancing the intestinal levels of amino acids (aas) and relative abundance of Lactobacillus genus. Indeed, Ligilactobacillus murinus-mediated fermentation of soy protein results in the generation of aas, thereby promoting C. difficile growth, and the process involves the anchored cell wall proteinase PrtP. Thus, mutual interaction between dietary protein and the gut microbiota is a critical factor affecting host susceptibility to CDI, suggesting that dietary protein sources can be an important determinant in controlling the disease.

D-Tryptophan suppresses enteric pathogen and pathobionts and prevents colitis by modulating microbial tryptophan metabolism.

D-Amino acids (D-AAs) have various functions in mammals and microbes. D-AAs are produced by gut microbiota and can act as potent bactericidal molecules. Thus, D-AAs regulate the ecological niche of the intestine; however, the actual impacts of D-AAs in the gut remain unknown. In this study, we show that D-Tryptophan (D-Trp) inhibits the growth of enteric pathogen and colitogenic pathobionts. The growth of Citrobacter rodentium in vitro is strongly inhibited by D-Trp treatment. Moreover, D-Trp protects mice from lethal C. rodentium infection via reduction of the pathogen. Additionally, D-Trp prevents the development of experimental colitis by the depletion of specific microbes in the intestine. D-Trp increases the intracellular level of indole acrylic acid (IA), a key molecule that determines the susceptibility of enteric microbes to D-Trp. Treatment with IA improves the survival of mice infected with C. rodentium. Hence, D-Trp could act as a gut environmental modulator that regulates intestinal homeostasis.

Cooperative action of gut-microbiota-accessible carbohydrates improves host metabolic function.

Microbiota-accessible carbohydrates (MACs) exert health-promoting effects, but how each MAC impacts gut microbiota and regulates host physiology remains unclear. Here, we show that l-arabinose and sucrose cooperatively act on gut microbiota and exert anti-obesogenic effects. Specifically, l-arabinose, a monosaccharide that is poorly absorbed in the gut and inhibits intestinal sucrase, suppresses diet-induced obesity in mice in the presence of sucrose. Additionally, the suppressive effect of l-arabinose on adiposity is abrogated in mice lacking the short-chain fatty acid (SCFA) receptors GPR43 and GPR41. Mechanistically, l-arabinose increases the relative abundance of acetate and propionate producers (e.g., Bacteroides), while sucrose enhances SCFA production. Furthermore, l-arabinose and sucrose activate the glycolytic and pentose phosphate pathways of Bacteroides, respectively, indicating that they synergistically promote acetate production through distinct pathways. These findings suggest that each MAC has a unique property and thus may serve as a precision gut-microbiota modulator to promote host homeostasis.

Potentiation of methylmercury toxicity by combined metal exposure: In vitro and in vivo models of a restricted metal exposome.

Methylmercury (MeHg) is a prevalent toxic metal that readily modifies protein thiols. Reactive persulfides that play a role in redox homeostasis are able to inactivate this metal through sulfur adduct formation. Although humans are exposed to other metals that could consume reactive persulfides on a daily basis, the health effects of combined exposure to MeHg and other metals remain unexplored. This study aimed to examine potential MeHg toxicity during exposure to MeHg with other metals capable of consuming reactive persulfides. We designed a simple system to assess the risk of combined exposure to metals based on reactivity to reactive persulfides and mercury accumulation. Among the metals examined in a cell-free system, copper, cadmium, nickel, and MeHg consumed Na2S2, used as a model of reactive persulfides, whereas zinc, iron, lithium, strontium, tin, and aluminum did not. In HepG2 cells, binary exposure to MeHg and copper, but not aluminum, increased the consumption of extracellular reactive persulfides. Binary exposure exacerbated MeHg-induced cytotoxicity by promoting the modification of intracellular proteins by MeHg. In a mouse model, binary exposure to MeHg and copper resulted in elevated mercury accumulation in the fetuses and placenta of pregnant mice, as well as the brain and liver of non-pregnant mice. Our study suggests that MeHg sensitivity can be increased by combined exposure with other electrophilic metals. In particular, binary exposure to MeHg and copper during pregnancy exacerbated mercury accumulation in offspring.

Gut microbiota reinforce host antioxidant capacity via the generation of reactive sulfur species.

Gut microbiota act beyond the gastrointestinal tract to regulate the physiology of the host. However, their contribution to the antioxidant capacity of the host remains largely understudied. In this study, we observe that gut bacteria increase the steady-state plasma levels of high-antioxidant molecules, reactive sulfur species (RSS), such as hydrogen sulfide and cysteine persulfide (CysSSH), in the host. Moreover, gut bacteria utilize cystine as a substrate to enzymatically produce CysSSH. Administration of cystine to mice increases their plasma levels of RSS and suppresses the concanavalin-A-induced oxidative stress and liver damage in a gut-microbiota-dependent manner. We find that gut bacteria belonging to the Lachnospiraceae and Ruminococcaceae families have a high capacity to produce RSS, requiring pyridoxal 5'-phosphate for their enzymatic reactions. Collectively, our data demonstrate that gut microbiota enhance the antioxidant capacity of the host through the generation of RSS.

Concentrations of nucleophilic sulfur species in small Indian mongoose (Herpestes auropunctatus) in Okinawa, Japan.

Reactive sulfur species (RSS), such as hydrogen per (poly)sulfide, cysteine per (poly)sulfide, glutathione per (poly)sulfide, and protein-bound per (poly)sulfides, can easily react with environmental electrophiles such as methylmercury (MeHg), because of their high nucleophilicity. These RSS are produced by enzymes such as cystathionine ß-synthase (CBS) and cystathionine γ-lyase (CSE) and are found in mammalian organs. Organs of wildlife have not been analyzed for hydrogen sulfide, cysteine, glutathione, and RSS. In this study, low molecular weight nucleophilic sulfur substances, including RSS, were quantified by stable isotope dilution assay-based liquid chromatography-mass spectrometry using ß-(4-hydroxyphenyl)ethyl iodoacetamide to capture the target chemicals in the small Indian mongoose which species possesses high mercury content as same as some marine mammals. Western blotting revealed that the mongoose organs (liver, kidney, cerebrum, and cerebellum) contained proteins that cross-reacted with anti-CBS and CSE antibodies. The expression patterns of these enzymes were similar to those in mice, indicating that mongoose organs contain CBS and CSE. Moreover, bis-methylmercury sulfide (MeHg)2S, which is a low toxic compound in comparison to MeHg, was found in the liver of this species. These results suggest that the small Indian mongoose produces RSS and monothiols associated with detoxification of electrophilic organomercury. The animals which have high mercury content in their bodies may have function of mercury detoxification involved not only Se but also RSS interactions.

Spatio-temporal distribution of reactive sulfur species during methylmercury exposure in the rat brain.

Brain susceptibility to methylmercury (MeHg) is developmentally and regionally specific in both humans and rodents, but the mechanism is not well clarified. Reactive sulfur species (RSS) with high nucleophilicity can react with MeHg, leading to the formation of a less toxic metabolite bismethylmercury sulfide, thus exerting cytoprotection. In this study, we assessed the variation of RSS content in the rat brain and evaluated its relevance in sensitivity to MeHg. Analyses of fetal/juvenile rat brains showed low RSS levels in early developmental stages. Site-specific analysis of adult rat brains revealed that cerebellar RSS levels were lower than those of the hippocampus. Microscopically, RSS levels of the granular cell layer were lower than those of the molecular layer in the cerebellum. Thus, low RSS levels corresponded with age and site of the brain that is vulnerable to MeHg. Taken together with the finding that brain RSS were consumed during MeHg exposure, these results indicate that RSS is a factor that defines the specificity of MeHg vulnerability in the brain.

Seaweed Dietary Fiber Sodium Alginate Suppresses the Migration of Colonic Inflammatory Monocytes and Diet-Induced Metabolic Syndrome via the Gut Microbiota.

Metabolic syndrome (MetS) is a multifactorial chronic metabolic disorder that affects approximately one billion people worldwide. Recent studies have evaluated whether targeting the gut microbiota can prevent MetS. This study aimed to assess the ability of dietary fiber to control MetS by modulating gut microbiota composition. Sodium alginate (SA) is a seaweed-derived dietary fiber that suppresses high-fat diet (HFD)-induced MetS via an effect on the gut microbiota. We observed that SA supplementation significantly decreased body weight gain, cholesterol levels, and fat weight, while improving glucose tolerance in HFD-fed mice. SA changed the gut microbiota composition and significantly increased the abundance of Bacteroides. Antibiotic treatment completely abolished the suppressive effects of SA on MetS. Mechanistically, SA decreased the number of colonic inflammatory monocytes, which promote MetS development, in a gut microbiota-dependent manner. The abundance of Bacteroides was negatively correlated with that of inflammatory monocytes and positively correlated with the levels of several gut metabolites. The present study revealed a novel food function of SA in preventing HFD-induced MetS through its action on gut microbiota.

Gut Microbiota Prevents Sugar Alcohol-Induced Diarrhea.

While poorly-absorbed sugar alcohols such as sorbitol are widely used as sweeteners, they may induce diarrhea in some individuals. However, the factors which determine an individual's susceptibility to sugar alcohol-induced diarrhea remain unknown. Here, we show that specific gut bacteria are involved in the suppression of sorbitol-induced diarrhea. Based on 16S rDNA analysis, the abundance of Enterobacteriaceae bacteria increased in response to sorbitol consumption. We found that Escherichia coli of the family Enterobacteriaceae degraded sorbitol and suppressed sorbitol-induced diarrhea. Finally, we showed that the metabolism of sorbitol by the E. coli sugar phosphotransferase system helped suppress sorbitol-induced diarrhea. Therefore, gut microbiota prevented sugar alcohol-induced diarrhea by degrading sorbitol in the gut. The identification of the gut bacteria which respond to and degrade sugar alcohols in the intestine has implications for microbiome science, processed food science, and public health.

Amino Acid-Based Diet Prevents Lethal Infectious Diarrhea by Maintaining Body Water Balance in a Murine Citrobacter rodentium Infection Model.

Infectious diarrhea is one of the most important health problems worldwide. Although nutritional status influences the clinical manifestation of various enteric pathogen infections, the effect of diet on enteric infectious diseases remains unclear. Using a fatal infectious diarrheal model, we found that an amino acid-based diet (AD) protected susceptible mice infected with the enteric pathogen Citrobacter rodentium. While the mice fed other diets, including a regular diet, were highly susceptible to C. rodentium infection, AD-fed mice had an increased survival rate. An AD did not suppress C. rodentium colonization or intestinal damage; instead, it prevented diarrhea-induced dehydration by increasing water intake. An AD altered the plasma and fecal amino acid levels and changed the gut microbiota composition. Treatment with glutamate, whose level was increased in the plasma and feces of AD-fed mice, promoted water intake and improved the survival of C. rodentium-infected mice. Thus, an AD changes the systemic amino acid balance and protects against lethal infectious diarrhea by maintaining total body water content.

Lipophilic compounds in garlic decrease the toxicity of methylmercury by forming sulfur adducts.

Garlic (Allium sativum L.) contains numerous sulfur compounds. We have previously found that reactive sulfur species such as glutathione persulfide, glutathione polysulfide, protein-bound persulfides, and hydrogen sulfide can bind to methylmercury to give bismethylmercury sulfide, which is less toxic than methylmercury. It was not clear, however, whether such reactive sulfur species are present in garlic. The aim of the study presented here was to determine whether garlic contains reactive sulfur species that can bind to methylmercury. We extracted garlic with organic solvents and then performed silica gel column chromatography to separate constituents that could cause bismethylmercury sulfide to form. We found numerous garlic constituents could bind to methylmercury to form bismethylmercury sulfide. A hexane extract of garlic decreased methylmercury cytotoxicity in vitro and body weight loss in mice. The results suggest that ingesting garlic may decrease methylmercury toxicity by causing the formation of sulfur adducts that inhibit adverse reactions.

Adverse effects of methylmercury on gut bacteria and accelerated accumulation of mercury in organs due to disruption of gut microbiota.

Methylmercury (MeHg), an environmental electrophile, binds covalently to the cysteine residues of proteins in organs, altering protein function and causing cytotoxicity. MeHg has also been shown to alter the composition of gut microbes. The gut microbiota is a complex community, the disturbance of which has been linked to the development of certain diseases. However, the relationship between MeHg and gut bacteria remains poorly understood. In this study, we showed that MeHg binds covalently to gut bacterial proteins via cysteine residues. We examined the effects of MeHg on the growth of selected Lactobacillus species, namely, L. reuteri, L. gasseri, L. casei, and L. acidophilus, that are frequently either positively or negatively correlated with human diseases. The results revealed that MeHg inhibits the growth of Lactobacillus to varying degrees depending on the species. Furthermore, the growth of L. reuteri, which was inhibited by MeHg exposure, was restored by Na2S2 treatment. By comparing mice with and without gut microbiota colonization, we found that gut bacteria contribute to the production of reactive sulfur species such as hydrogen sulfide and hydrogen persulfide in the gut. We also discovered that the removal of gut bacteria accelerated accumulation of mercury in the cerebellum, liver, and lungs of mice subsequent to MeHg exposure. These results accordingly indicate that MeHg is captured and inactivated by the hydrogen sulfide and hydrogen persulfide produced by intestinal microbes, thereby providing evidence for the role played by gut microbiota in reducing MeHg toxicity.

Understanding Host Immunity and the Gut Microbiota Inspires the New Development of Vaccines and Adjuvants.

Vaccinations improve the mortality and morbidity rates associated with several infections through the generation of antigen-specific immune responses. Adjuvants are often used together with vaccines to improve immunogenicity. However, the immune responses induced by most on-going vaccines and adjuvants approved for human use vary in individuals; this is a limitation that must be overcome to improve vaccine efficacy. Several reports have indicated that the symbiotic bacteria, particularly the gut microbiota, impact vaccine-mediated antigen-specific immune responses and promote the induction of nonspecific responses via the "training" of innate immune cells. Therefore, the interaction between gut microbiota and innate immune cells should be considered to ensure the optimal immunogenicity of vaccines and adjuvants. In this review, we first introduce the current knowledge on the immunological mechanisms of vaccines and adjuvants. Subsequently, we discuss how the gut microbiota influences immunity and highlight the relationship between gut microbes and trained innate immunity, vaccines, and adjuvants. Understanding these complex interactions will provide insights into novel vaccine approaches centered on the gut microbiota.