The relationship between dietary patterns and blood mineral concentration among children in Hunan Province of China.

BACKGROUND: Minerals have crucial biological functions in metabolism and are primarily obtained through diet. As a result, various dietary patterns can impact blood mineral levels. The aim of this study was to investigate the correlation between dietary patterns and the concentration of calcium, magnesium, iron, zinc, and copper in the bloodstream. METHODS: Three hundred eighty healthy children (53.7% male) were recruited in a region of Hunan Province in September 2019. We gathered basic information and measured physical proportions, along with completing a food frequency questionnaire (FFQ). Using principal component analysis (PCA), we determined dietary patterns. To analyze mineral levels in the blood, we used flame atomic absorption spectrometry (FAAS). We utilized linear regression models to investigate if certain dietary patterns are related to mineral concentration. RESULTS: Three dietary patterns were identified: 'Vegetables/Nuts,' 'Snacks/Beverages,' and 'Cereal/Beans.' Children from high-income families (annual average income > 50,000 yuan) prefer the 'Vegetables/Nuts' dietary pattern (P = 0.004). In comparison, those from low-income families (annual average income < 20,000 yuan) prefer the 'Snacks/Beverages' dietary pattern (P = 0.03). Following adjustment for age, gender, guardian's identity, education level, and annual household income. We found that an increase in the 'Vegetables/Nuts' pattern score (ß = 0.153, CI: 0.053 ~ 0.253; P = 0.003) and 'Snacks/Beverages' pattern score (ß = 0.103, CI: 0.002 ~ 0.204; P = 0.033) were significantly associated blood copper concentration. CONCLUSIONS: Household income was found to be associated with dietary behavior. Furthermore, higher blood copper concentration was significantly correlated with the 'Vegetables/Nuts' dietary pattern and 'Snacks/Beverages' dietary pattern, but the correlation is extremely low.

Exploring the effects of formula feeding on infant immune development in China: A prospective cohort study.

BACKGROUND AND OBJECTIVES: The worldwide exclusive breastfeeding rate is suboptimal and this study aims to evaluate effects on infant immune development of formula feeding. METHODS AND STUDY DESIGN: A prospective study including 221 infants fed with breast milk or formula was conducted. At 3-month and 9-month, the concentrations of total immunoglobulin (Ig)G, IgM, IgA, IgG1, IgG2, interleukin (IL)-4, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were measured by using enzyme-linked immunosorbent assay (ELISA). Natural killer (NK) cell activity and lymphocyte transformation testing were conducted. Furthermore, the occurrence of infantile diarrhea, respiratory infections and allergic diseases were questioned. RESULTS: The levels of total IgG (Z=-3.21, p=0.001), IgG1 (Z=-2.12, p=0.034), IFN-γ (t=-2.09, p=0.039) and NK cell activity (t=-2.14, p=0.034) were significant higher in formula-fed infants compared to breast-fed after 3 months. At 9-month, the levels of total IgG (Z=-4.34, p<0.001), IgA (Z=-2.05, p=0.041) and TNF-α (t=-2.10, p=0.037) of formula-fed infants were higher, but the lymphocyte stimulation index (t=2.76, p=0.007) was lower than breast-fed infants. While, no significant differences were found in the incidences of diarrhea and respiratory tract infection (p>0.05). CONCLUSIONS: This investigation suggested that formula- and breast-feeding have different contributions to infant immune development, but the formula feeding would not cause significantly increase of diarrhea and respiratory infections.

The role of NO-cGMP pathway inhibition in vascular endothelial-dependent smooth muscle relaxation disorder of AT1-AA positive rats: protective effects of adiponectin.

Angiotensin II type 1 receptor autoantibodies (AT1-AA) cause endothelial-dependent smooth muscle relaxation disorder. It is well understood that impairment of the NO-cGMP signaling pathway is one of the mechanisms of endothelial-dependent smooth muscle relaxation disorder. However, it is still unclear whether AT1-AA induces endothelial-dependent smooth muscle relaxation disorder via the impairment of the NO-cGMP signaling pathway. In addition, adiponectin exerts vascular endothelial protection through the NO-cGMP signaling pathway. Therefore, the purpose of this investigation was to assess the mechanism of vascular endothelial-dependent smooth muscle relaxation disorder induced by AT1-AA and the role of adiponectin in attenuating this dysregulation. Serum endothelin-1 (ET-1), adiponectin and AT1-AA were detected by enzyme-linked immunosorbent assay. In preeclamptic patients, there was an increased level of AT1-AA, which was positively correlated with ET-1 and negatively correlated with adiponectin, as elevated levels of ET-1 suggested endothelial injury. AT1-AA-positive animal models were actively immunized with the second extracellular loop of the angiotensin II type 1 receptor (AT1R-ECII) for eight weeks. In thoracic aortas of AT1-AA positive rats, ET-1 was elevated, endothelium-dependent vasodilation was decreased. Paradoxically, as the upstream element of the NO-cGMP signaling pathway, NO production was not decreased but increased, and the ratio of p-VASP/VASP, an established biochemical endpoint of NO-cGMP signaling pathway, was reduced. Moreover, the levels of nitrotyrosine and gp91phox which indicate the presence of peroxynitrite (ONOO-) and superoxide anion (O2·-) were increased. Pretreatment with the ONOO- scavenger FeTMPyP or O2·-scavenger Tempol normalized vasorelaxation. Key enzymes responsible for NO synthesis were also assessed. iNOS protein expression was increased, but p-eNOS(Ser1177)/eNOS was reduced. Preincubation with the iNOS inhibitor 1400 W or eNOS agonist nebivolol restored vasorelaxation. Further experiments showed levels of p-AMPKα (Thr172)/AMPKα, which controls iNOS expression and eNOS activity, to have been reduced. Furthermore, levels of the upstream component of AMPK, adiponectin, was reduced in sera of AT1-AA positive rats and supplementation of adiponectin significantly decreased ET-1 contents, improved endothelial-dependent vasodilation, reduced NO production, elevated p-VASP/VASP, inhibited protein expression of nitrotyrosine and gp91phox, reduced iNOS overexpression, and increased eNOS phosphorylation at Ser1177 in the thoracic aorta of AT1-AA positive rats. These results established that impairment NO-cGMP pathway may aggravate the endothelial-dependent smooth muscle relaxation disorder in AT1-AA positive rats and adiponectin improved endothelial-dependent smooth muscle relaxation disorder by enhancing NO-cGMP pathway. This discovery may shed a novel light on clinical treatment of vascular diseases associated with AT1-AA.

Multiple regulatory effects of angiotensin II on the large-conductance Ca2+- and voltage-activated potassium channel in vascular smooth muscle cells.

Renin-angiotensin system (RAS) is involved in the regulation of vascular smooth muscle cell (VSMC) tension. Angiotensin II (Ang II) as the main effector molecule of RAS can increase the intracellular Ca2+ concentration and cause VSMCs contraction by activating angiotensin II type 1 receptor (AT1R). The large-conductance Ca2+- and voltage-activated potassium (BK) channel is an essential potassium channel in VSMCs, playing an important role in maintaining membrane potential and intracellular potassium-calcium balance. The BK channel in VSMCs mainly consists of α and ß1 subunits. Functional BKα subunits contain voltage-sensors and Ca2+ binding sites. Hence, increase in the membrane potential or intracellular Ca2+ concentration can trigger the opening of the BK channel by mediating transient K+ outward current in a negative regulatory manner. However, increasing evidence has shown that although Ang II can raise the intracellular Ca2+ concentration, it also inhibits the expression and function of the BK channel by activating the PKC pathway, internalizing AT1R-BKα heterodimer, or dissociating α and ß1 subunits. Under some specific conditions, Ang II can also activate the BK channel, but the underlying mechanism remains unknown. In this review, we summarize the potential mechanisms underlying the inhibitory or activating effect of Ang II on the BK channel, hoping that it could provide a theoretical basis for improving intracellular ion imbalance.

Active immunization using hand-push emulsification method increases the operator's risk of transcutaneous immunization.

Setting up an animal model by using active immunization methods is a common means of studying immune-related diseases or producing antibodies with high titer and high activities. However, the security during the process of pathogen emulsification remains unclear. In a physical examination, we unexpectedly noticed high levels of angiotensin II type 1 receptor autoantibody (AT1-AA) specific to the immunizing antigen in the sera of some researchers who had participated in setting up active immunization animal models, and we were puzzled about the cause of AT1-AA production. In this study, we intended to investigate whether the emulsified antigen was the source of infection in these researchers, and if so, how to prevent it from occurring. AT1-AA was detected by advanced ELISA method. The participants presented higher levels of AT1-AA compared with non-participants of the same laboratory. This phenomenon remained that some factors during the process of rat model establishment may contribute to AT1-AA production. Animal and glove penetration studies indicated the emulsified antigen infection was attributed to neither aerosol or fur touch nor penetrating through gloves. However, AT1-AA level was largely decreased in the participants after they used an automatic emulsification device. Because of the strong permeability of the adjuvant, we speculated that emulsified antigen might get access to the unprotected skin of the participants accidentally during the immunization process. These results demonstrated that accidental contacts of emulsified antigens may infect researchers during the process of traditional hand-push emulsification, resulting in high specific autoantibody levels, which can be prevented by using appropriate tools.

The inhibitory effect of BKCa channels induced by autoantibodies against angiotensin II type 1 receptor is independent of AT1R.

Autoantibodies against angiotensin II Type 1 receptor (AT1-AA) are routinely detected in the serum of preeclampsia patients, which results in an increase in vascular tone and an elevation in intracellular calcium concentration of rat vascular smooth muscle (VSM). The big conductance calcium-activated potassium channels (BKCa channels) account for the dominant outward currents in VSMCs, contributing to membrane hyperpolarization and vasodilation. In the present study, we investigated the effect of AT1-AA on BKCa channels. A preeclampsia model was established by passively immunizing healthy pregnant BALB/c mice with AT1-AA extracted from hybridoma culture supernatant. Blood pressure, serum AT1-AA levels, and urinary protein were measured in the immunized mice. BKCa channel expression was detected using qRT-PCR and immunohistochemical technique. The patch-clamp technique was used to record the single currents of BKCa channels in the HEK293T cells that had been transfected. AT1-AA immunized mice exhibited elevated AT1-AA and urinary protein levels compared with mice of the vehicle group. Systolic blood pressure was also increased in the immunized group. BKCa channel ß1-subunit expression was reduced in the mesenteric arteries of immunized mice. AT1-AA could inhibit the BKCa currents and the inhibitory effects were not completely reversed following the application of valsartan, an inhibitor of AT1 receptor. In conclusion, AT1-AA could decrease BKCa expression and inhibit BKCa activity independent of AT1R. These inhibitory effects are likely to be contributory factors in the promotion of increased vascular tone caused by AT1-AA in preeclampsia.

[Angiotensin II type 1 receptor autoantibody induces myocardial fibrosis by activating cardiac fibroblasts].

Myocardial fibrosis (MF) is an important pathological process of cardiac remodeling in patients with heart failure; however its etiology has not been clear. It has been known that the angiotensin II type 1 receptor autoantibody (AT1-AA) is present in patients with heart failure, but it is unclear whether this antibody directly causes MF. In this study, we investigated the role of AT1-AA in MF and its effects on cardiac fibroblasts (CFs). The AT1-AA positive rat model was established by active immunization method, and the measurement of indexes were made in the 8th week after active immunity. The results of heart echocardiography showed that the cardiac systolic and diastolic functions of AT1-AA positive rats were impaired with reduced left ventricular wall thickness and enlarged heart chambers. HE staining results showed that the myocardial fibers were disorganized and ruptured, and Masson staining revealed that the area of collagen fibers around the myocardium and coronary arteries was significantly increased in AT1-AA positive group compared with that of the control group (P < 0.05). Moreover, primary CFs isolated from neonatal rats were cultured and treated with AT1-AA for 48 h. CCK-8 and immunofluorescence staining results showed that AT1-AA enhanced proliferation rate of CFs (P < 0.001), and Western blot results showed that AT1-AA significantly increased expressions of collagen I (Col I), Col III, matrix metalloproteinase-2 (MMP-2) and MMP-9 in CFs (all P < 0.05). Taken together, these results suggest that AT1-AA may induce MF and cardiac dysfunction via activating CFs.

Correction to: Seasonal variations of PCDD/Fs in fishes: inferring a hidden exposure route from Na-PCP application for schistosomiasis control.

The original version of this article unfortunately contained an error in the affiliation section.

Seasonal variations of PCDD/Fs in fishes: inferring a hidden exposure route from Na-PCP application for schistosomiasis control.

Japanese schistosomiasis was endemic in Dongting Lake, the second largest freshwater lake in China. The technical sodium pentachlorophenate (Na-PCP) was widely used during the period between the early 1960s and early 1990s to kill oncomelania, the intermediate host of Schistosomes. However, polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) also contaminated the environment of Dongting Lake due to trace impurities of Na-PCP. In this study, 13 species of freshwater fish were collected from Dongting Lake and analyzed in wet and dry seasons. Temporal (wet and dry season) variations in PCDD/Fs in fishes from Dongting Lake were observed. The concentration of PCDD/Fs was considerably higher in the wet season than in the dry season and in areas in China where Na-PCP was not applied. The higher level of PCDD/Fs in the wet season may be attributed to the use of Na-PCP in the past and to the increase in the migration of PCDD/Fs from sediments to water in the wet season. The results indicate that the risk of PCDD/Fs contamination is connected with prior consumption of fishes that live in the Na-PCP application area. However, there was no difference in the concentrations of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) between the wet and dry seasons.

Attenuation of Colitis by Lactobacillus casei BL23 Is Dependent on the Dairy Delivery Matrix.

The role of the food delivery matrix in probiotic performance in the intestine is not well understood. Because probiotics are often provided to consumers in dairy products, we investigated the contributions of milk to the health-benefiting performance of Lactobacillus casei BL23 in a dextran sulfate sodium (DSS)-induced murine model of ulcerative colitis. L. casei BL23 protected against the development of colitis when ingested in milk but not in a nutrient-free buffer simulating consumption as a nutritional supplement. Consumption of (acidified) milk alone also provided some protection against weight loss and intestinal inflammation but was not as effective as L. casei and milk in combination. In contrast, L. casei mutants deficient in DltD (lipoteichoic acid d-alanine transfer protein) or RecA (recombinase A) were unable to protect against DSS-induced colitis, even when consumed in the presence of milk. Mice fed either L. casei or milk contained reduced quantities of colonic proinflammatory cytokines, indicating that the L. casei DltD(-) and RecA(-) mutants as well as L. casei BL23 in nutrient-free buffer were effective at modulating immune responses. However, there was not a direct correlation between colitis and quantities of these cytokines at the time of sacrifice. Identification of the cecal microbiota by 16S rRNA gene sequencing showed that L. casei in milk enriched for Comamonadaceae and Bifidobacteriaceae; however, the consumption of neither L. casei nor milk resulted in the restoration of the microbiota to resemble that of healthy animals. These findings strongly indicate that probiotic strain efficacy can be influenced by the food/supplement delivery matrix.

IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic.

IL-22 is a good candidate to play a critical role in regulating gut microbiota because it is an important inducer of antimicrobial peptides and mucins in the gut. However, whether IL-22 participates in immune homeostasis by way of modulating gut microbiota remains to be elucidated. In this study, we find, through 16S rRNA gene-pyrosequencing analysis, that healthy IL-22-deficient mice had altered colonic microbiota, notably with decreased abundance of some genera, including Lactobacillus, and increased levels of others. Mice harboring this altered microbiota exhibited more severe disease during experimentally induced colitis. Interestingly, this altered gut microbiota can be transmitted to cohoused wild-type animals along with the increased susceptibility to this colitis, indicating an important role for IL-22 in shaping the homeostatic balance between immunity and colonic microbiota for host health.

Short communication: effect of milk and milk containing Lactobacillus casei on the intestinal microbiota of mice.

BALB/c mice were fed milk or Lactobacillus casei BL23 in milk for 14d and fecal samples were collected at d 0, 4, and 7 as well as 1 and 8d after the last administration. According to high-throughput DNA sequencing of the 16S rRNA genes extracted from the fecal microbiota, the bacterial diversity in the fecal samples of all mice increased over time. After 14d of administration, the consumption of milk and milk containing L. casei BL23 resulted in distinct effects on the microbial composition in the intestine. Specifically, the proportions of bacteria in the Lactobacillaceae, Porphyromonadaceae, and Comamonadaceae were significantly higher in mice fed the L. casei BL23-milk culture compared with one or more of the other groups of mice. The relative amounts of Lachnospiraceae were higher and Streptococcaceae were lower in mice fed milk alone. The changes were not found at d 4 and 7 during milk and L. casei feeding and were no longer detected 8d after administration was stopped. This study shows that consumption of milk or probiotic L. casei-containing milk results in non-overlapping, taxa-specific effects on the bacteria in the distal murine intestine.

Microbiome and cancer immunotherapies.

Here, we present 3 different perspectives on how the microbiome has impacted cancer patients, treatment, and clinical studies. We hear about the challenges of implementing microbiome analyses into the clinics, the impact these analyses might have on patients' care, and treatment in the future, specifically for gastric cancer treatment. These are a few of the many voices that are highlighting the role of the microbiome in cancer development, treatment, and clinical outcomes.

The associations of fatty acids related dietary patterns with overweight and obesity among Chinese children.

BACKGROUND: Childhood overweight and obesity is becoming an emerging face of malnutrition. The aims of this study were to develop fatty acid (FAs) related dietary patterns and explored the associations of FAs related dietary patterns with overweight and obesity among Chinese children. METHODS: An observational study was conducted on 435 children aged 4 to 7 years old in South Central China. Erythrocyte FAs composition was analyzed by gas chromatography-mass spectrometry. Diet was collected by food frequency questionnaires and dietary patterns were evaluated by reduced rank regression. The logistic regression analysis was used to exploring the association of dietary patterns with overweight and obesity. RESULTS: The prevalence of overweight, obesity, and overweight or obesity were 6.52, 4.59, and 11.11% in Chinese children, respectively. Twenty five types of FAs were detected in erythrocyte of children and four FAs related dietary patterns were identified. The dietary pattern positively correlated with n-3 PUFAs, but negatively with SFAs,was characterized by high intake of fish, shrimp, crab and shellfish, leaf-off vegetable, nuts, and tubers, which have a significantly decreased overweight risk (OR = 0.580, 95%CI: 0.375 ∼ 0.895, P = 0.014).The pattern positively strong associated with n-6 PUFAs, but negatively strong with n-3 PUFAs, had high intake of snacks, leaf-off vegetable, fresh beans, and coarse cereals, which have a significantly decreased obesity risk (OR = 0.518, 95%CI: 0.325 ∼ 0.827, P = 0.006). CONCLUSION: Four FAs related dietary patterns were identified. The dietary pattern with high intake of fish, shrimp, crab and shellfish decreased overweight risk by increasing n-3 PUFAs, and decreasing SFAs. The dietary pattern with high intake of plant food, decreased obesity risk by providing an balanced n-6/n-3 PUFAs ratio.

Eubacterium rectale is a potential marker of altered gut microbiota in psoriasis and psoriatic arthritis.

Previous studies have profiled the gut microbiota among psoriatic patients compared to that among healthy individuals. However, a comprehensive understanding of the magnitude, direction, and detailed compositional and functional profiles remains limited. Additionally, research exploring the gut microbiota in the context of both plaque psoriasis (PsO) and psoriatic arthritis (PsA) is lacking. To assess the taxonomic and functional characteristics of the gut microbiota in PsO and PsA patients and investigate potential links between the gut microbiota and disease pathogenesis. We collected fecal samples from 70 psoriatic patients (44 PsO and 26 PsA) and 25 age- and gender-matched healthy controls (HC) and employed deep metagenomic sequencing to characterize their gut microbiota. We noted significant alternations in the gut microbiota compositions of both PsO and PsA patients compared to those of HC. Despite limited effect sizes in alpha diversity (12.3% reduction of microbial richness but unchanged evenness in psoriatic patients) and beta diversity (disease accounts for 3.5% of total variations), we consistently observed substantial reductions of Eubacterium rectale in both PsO and PsA patients, with PsA patients exhibiting even lower levels of E. rectale than PsO patients. Additionally, two Alistipes species were also depleted in psoriatic patients. These microorganisms are known to play crucial roles in carbohydrate metabolism pathways, mainly producing short-chain fatty acids with anti-inflammatory effects. Overall, our observations supplemented the profiling of altered gut microbiota in patients with PsO and PsA at the species level and described a link between the dominant short-chain fatty acid-producing bacterial species and systemic immunity in psoriatic patients. IMPORTANCE: In this observational clinical study with sufficient sample size and metagenomic sequencing to profile the gut microbiota, we identified consistent signals of the depleted abundance of Eubacterium rectale and related functional genes among psoriatic patients, including those with psoriatic arthritis. E. rectale may serve as an ecologically important functional unit in the gut microbiota, holding potential as a diagnostic marker and target for therapeutic interventions to achieve lasting effects. Our findings provide comprehensive gut microbiota profiling in psoriasis, resolving previous contradictions and generating new hypotheses for further investigation. These insights may significantly impact psoriasis management and related conditions.

Chemical Synthesis of a Branched Nonasaccharide Fragment from Helicobacter pylori Lipopolysaccharide.

A chemical synthesis of a unique nanosaccharide fragment from Helicobacter pylori lipopolysaccharide was achieved via a convergent glycosylation method. Challenges involved in the synthesis include the highly stereoselective construction of ß-3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) and two 1,2-cis-glycosidic linkages, as well as the formation of a branched 2,7-disubstituted heptose subunit. Hydrogen-bond mediated aglycone delivery strategy and benzoyl-directing remote participation effect were employed, respectively, for the efficient generation of the desired ß-Kdo glycoside and 1,2-cis-α-l-fucoside/d-glucoside. Moreover, the key branched framework was successfully established through a [(7 + 1) + 1] assembly approach involving the stepwise glycosylation of the heptasaccharide alcohol with two monosaccharide donors. The synthesized 1 containing a propylamine linker at the reducing end can be covalently bound to a carrier protein for further immunological studies.

Multi-omics of the gut microbial ecosystem in patients with microsatellite-instability-high gastrointestinal cancer resistant to immunotherapy.

Despite the encouraging efficacy of anti-PD-1/PD-L1 immunotherapy in microsatellite-instability-high/deficient mismatch repair (MSI-H/dMMR) advanced gastrointestinal cancer, many patients exhibit primary or acquired resistance. Using multi-omics approaches, we interrogate gut microbiome, blood metabolome, and cytokines/chemokines of patients with MSI-H/dMMR gastrointestinal cancer (N = 77) at baseline and during the treatment. We identify a number of microbes (e.g., Porphyromonadaceae) and metabolites (e.g., arginine) highly associated with primary resistance to immunotherapy. An independent validation cohort (N = 39) and mouse model are used to further confirm our findings. A predictive machine learning model for primary resistance is also built and achieves an accuracy of 0.79 on the external validation set. Furthermore, several microbes are pinpointed that gradually changed during the process of acquired resistance. In summary, our study demonstrates the essential role of gut microbiome in drug resistance, and this can be utilized as a preventative diagnosis tool and therapeutic target in the future.

Topic modeling for multi-omic integration in the human gut microbiome and implications for Autism.

While healthy gut microbiomes are critical to human health, pertinent microbial processes remain largely undefined, partially due to differential bias among profiling techniques. By simultaneously integrating multiple profiling methods, multi-omic analysis can define generalizable microbial processes, and is especially useful in understanding complex conditions such as Autism. Challenges with integrating heterogeneous data produced by multiple profiling methods can be overcome using Latent Dirichlet Allocation (LDA), a promising natural language processing technique that identifies topics in heterogeneous documents. In this study, we apply LDA to multi-omic microbial data (16S rRNA amplicon, shotgun metagenomic, shotgun metatranscriptomic, and untargeted metabolomic profiling) from the stool of 81 children with and without Autism. We identify topics, or microbial processes, that summarize complex phenomena occurring within gut microbial communities. We then subset stool samples by topic distribution, and identify metabolites, specifically neurotransmitter precursors and fatty acid derivatives, that differ significantly between children with and without Autism. We identify clusters of topics, deemed "cross-omic topics", which we hypothesize are representative of generalizable microbial processes observable regardless of profiling method. Interpreting topics, we find each represents a particular diet, and we heuristically label each cross-omic topic as: healthy/general function, age-associated function, transcriptional regulation, and opportunistic pathogenesis.

The gut microbiome affects response of treatments in HER2-negative advanced gastric cancer.

BACKGROUND: Common treatments for metastatic/unresectable HER2-negative gastric cancer include chemotherapy, immune checkpoint inhibitor monotherapy and chemotherapy plus immune checkpoint inhibitor. However, significant drug resistance exists regardless of the treatment regimen. METHODS: Patients with metastatic/unresectable HER2-negative gastric/gastroesophageal junction adenocarcinoma were enrolled. All patients were divided into three groups according to the treatment regimen and were further divided into responders and non-responders according to efficacy evaluation. Metagenomics sequencing were performed to analyze gut microbiome signature of patients receiving different treatments at baseline and throughout treatment. RESULTS: One hundred seventeen patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma receiving chemotherapy alone, anti PD-1/PD-L1 immunotherapy alone or combined regimen were included in this study. Microbiome signatures related to clinical response are distinct among the three treatment groups. Among which, 14, 8 and 13 species were significantly different between responders and non-responders in immunotherapy, immunotherapy plus chemotherapy and chemotherapy group, respectively. Patients with higher relative abundance of Lactobacillus possessed higher microbiome diversity and significantly better response to anti-PD-1/PD-L1 immunotherapy and had a trend to achieve better progression-free survival. Another cohort of 101 patients has been used as an external validation set to confirm the stability and reliability of these findings. CONCLUSIONS: Gut microbiome affects response of treatments in HER2-negative advanced gastric cancer in a treatment-specific way, immunotherapy plus chemotherapy did not equal to a simple superposition of immunotherapy and chemotherapy. Lactobacillus is expected to become a novel choice as an adjuvant agent in promoting the efficacy of immunotherapy in gastric cancer.

Correlation of the gut microbiome and immune-related adverse events in gastrointestinal cancer patients treated with immune checkpoint inhibitors.

Introduction: The wide application of immune checkpoint inhibitors has significantly improved the survival expectation of cancer patients. While immunotherapy brings benefits to patients, it also results in a series of immune-related adverse events (irAEs). Increasing evidence suggests that the gut microbiome is critical for immunotherapy response and the development of irAEs. Methods: In this prospective study, we recruited 95 patients with advanced/unresectable gastrointestinal cancers treated with immunotherapy and report a comprehensive analysis of the association of the gut microbiome with irAEs. Metagenome sequencing was used to analyze the differences in bacterial composition and metabolic pathways of baseline fecal samples. Results: In summary, we identified bacterial species and metabolic pathways that might be associated with the occurrence of irAEs in gastric, esophageal, and colon cancers. Ruminococcus callidus and Bacteroides xylanisolvens were enriched in patients without severe irAEs. Several microbial metabolic pathways involved in the urea cycle, including citrulline and arginine biosynthesis, were associated with irAEs. We also found that irAEs in different cancer types and toxicity in specific organs and the endocrine system were associated with different gut microbiota profiles. These findings provide the basis for future mechanistic exploration.