Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine.

Gut microbiota influence anti-tumor immunity, often by producing immune-modulating metabolites. However, microbes consume a variety of metabolites that may also impact host immune responses. We show that tumors grow unchecked in the omenta of microbe-replete mice due to immunosuppressive Tregs. By contrast, omental tumors in germ-free, neomycin-treated mice or mice colonized with altered Schaedler's flora (ASF) are spontaneously eliminated by CD8+ T cells. These mice lack Proteobacteria capable of arginine catabolism, causing increases in serum arginine that activate the mammalian target of the rapamycin (mTOR) pathway in Tregs to reduce their suppressive capacity. Transfer of the Proteobacteria, Escherichia coli (E. coli), but not a mutant unable to catabolize arginine, to ASF mice reduces arginine levels, restores Treg suppression, and prevents tumor clearance. Supplementary arginine similarly decreases Treg suppressive capacity, increases CD8+ T cell effectiveness, and reduces tumor burden. Thus, microbial consumption of arginine alters anti-tumor immunity, offering potential therapeutic strategies for tumors in visceral adipose tissue.

Bacteroidales-Specific Antimicrobial Genes Can Influence the Selection of the Dominant Fecal Strain of Bacteroides vulgatus and Bacteroides uniformis from the Gastrointestinal Tract Microbial Community.

Bacteroides vulgatus and Bacteroides uniformis are known to be abundant in the human fecal microbial community. Although these strains typically remain stable over time in humans, disruption of this microbial community following antibiotics resulted in the transient change to new strains suggesting that a complex, dynamic strain community exists in humans. To further study the selection of dominant fecal microbial strains from the gastrointestinal tract (GIT) community, we analyzed three longitudinal metagenomic sequencing data sets using BLAST+ to identify genes encoding Bacteroidales-specific antimicrobial proteins (BSAP) that have known functions to restrict species-specific replication of B. uniformis (BSAP-2) or B. vulgatus (BSAP-3) and have been postulated to provide a competitive advantage in microbial communities. In the HMP (Human Microbiome Project) data set, we found fecal samples from individuals had B. vulgatus or B. uniformis with either complete or deleted BSAP genes that did not change over time. We also examined fecal samples from two separate longitudinal data sets of individuals who had been given either single or multiple antibiotics. The BSAP gene pattern from most individuals given either single or multiple antibiotics recovered to be the same as the pre-antibiotic strain. However, in a few individuals, we found incomplete BSAP-3 genes at early times during the recovery that were replaced by B. vulgatus with the complete BSAP-3 gene, consistent with the function of the BSAP to specifically restrict Bacteroides spp. The results of these studies provide insights into the fluxes that occur in the Bacteroides spp. GIT community following perturbation and the dynamics of the selection of a dominant fecal strain of Bacteroides spp.

Exploring Gut Microbiota Alterations with Trimethoprim-Sulfamethoxazole and Dexamethasone in a Humanized Microbiome Mouse Model.

Along with the standard therapies for glioblastoma, patients are commonly prescribed trimethoprim-sulfamethoxazole (TMP-SMX) and dexamethasone for preventing infections and reducing cerebral edema, respectively. Because the gut microbiota impacts the efficacy of cancer therapies, it is important to understand how these medications impact the gut microbiota of patients. Using mice that have been colonized with human microbiota, this study sought to examine how TMP-SMX and dexamethasone affect the gut microbiome. Two lines of humanized microbiota (HuM) Rag1-/- mice, HuM1Rag and HuM2Rag, were treated with either TMP-SMX or dexamethasone via oral gavage once a day for a week. Fecal samples were collected pre-treatment (pre-txt), one week after treatment initiation (1 wk post txt), and three weeks post-treatment (3 wk post txt), and bacterial DNA was analyzed using 16S rRNA-sequencing. The HuM1Rag mice treated with TMP-SMX had significant shifts in alpha diversity, beta diversity, and functional pathways at all time points, whereas in the HuM2Rag mice, it resulted in minimal changes in the microbiome. Likewise, dexamethasone treatment resulted in significant changes in the microbiome of the HuM1Rag mice, whereas the microbiome of the HuM2Rag mice was mostly unaffected. The results of our study show that routine medications used during glioblastoma treatment can perturb gut microbiota, with some microbiome compositions being more sensitive than others, and these treatments could potentially affect the overall efficacy of standard-of-care therapy.

A case-control study of the association between the gut microbiota and colorectal cancer: exploring the roles of diet, stress, and race.

BACKGROUND: The gut microbiota is associated with risk for colorectal cancer (CRC), a chronic disease for which racial disparities persist with Black Americans having a higher risk of CRC incidence and mortality compared to other groups. Given documented racial differences, the gut microbiota may offer some insight into previously unexplained racial disparities in CRC incidence and mortality. A case-control analysis comparing 11 women newly diagnosed with CRC with 22 cancer-free women matched on age, BMI, and race in a 1:2 ratio was conducted. Information about participants' diet and perceived stress levels were obtained via 24-h Dietary Recall and Perceived Stress Scale-10 survey, respectively. Participants provided stool samples from which microbial genomic DNA was extracted to reveal the abundance of 26 genera chosen a priori based on their previously observed relevance to CRC, anxiety symptoms, and diet. RESULTS: Significantly lower alpha diversity was observed among cancer-free Black women compared to all other race-cancer status combinations. No group differences were observed when comparing beta diversity. Non-Hispanic White CRC cases tended to have higher relative abundance of Fusobacteria, Gemellaceae, and Peptostreptococcus compared to all other race-cancer combination groups. Perceived stress was inversely associated with alpha diversity and was associated with additional genera. CONCLUSIONS: Our findings suggest that microbiome-CRC associations may differ by racial group. Additional large, racially diverse population-based studies are needed to determine if previously identified associations between characteristics of the gut microbiome and CRC are generalizable to Black women and other racial, ethnic, and gender groups.

A Bacterial-Sourced Protein Diet Induces Beneficial Shifts in the Gut Microbiome of the Zebrafish, Danio rerio.

Background: Bacterial-sourced single-cell proteins (SCPs) offer an alternative protein source for diet formulation for Zebrafish (Danio rerio) and other aquaculture models. In addition, the use of a single-cell bacterial protein source derived from multiple species provides a unique insight into the interplay among nutrients in the diet, microbial populations in the diet, and the gut microbiome in D. rerio. Objective: Our objective in this study was to evaluate the impact of dietary replacement of fish protein hydrolysate in a standard reference (SR) with a single-cell bacterial protein source on D. rerio gut microbiome. Methods: We investigated gut microbial compositions of D. rerio fed an open-formulation standard reference (SR) diet or a bacterial-sourced protein (BP) diet, utilizing microbial taxonomic co-occurrence networks, and predicted functional profiles. Results: Microbial communities in the SR diet were primarily composed of Firmicutes. In contrast, the BP diet was mainly composed of Proteobacteria. Alpha diversity revealed significant differences in microbial communities between the 2 diets, and between the guts of D. rerio fed either of the 2 diets. D. rerio fed with the SR diet resulted in abundance of Aeromonas and Vibrio. In contrast, D. rerio fed with a BP diet displayed a large abundance of members from the Rhodobacteraceae family. Taxonomic co-occurrence networks display unique microbial interactions, and key taxons in D. rerio gut samples were dependent on diet and gender. Predicted functional profiling of the microbiome across D. rerio fed SR or BP diets revealed distinct metabolic pathway differences. Female D. rerio fed the BP diet displayed significant upregulation of pathways related to primary and secondary bile acid synthesis. Male D. rerio fed the BP diet revealed similar pathway shifts and, additionally, a significant upregulation of the polyketide sugar unit biosynthesis pathway. Conclusions: The use of a BP dramatically affects the composition and activity of the gut microbiome. Future investigations should further address the interplay among biological systems and diet and may offer insights into potential health benefits in preclinical and translational animal models.

Long term methionine restriction: Influence on gut microbiome and metabolic characteristics.

The Methionine restriction (MR) diet has been shown to delay aging and extend lifespan in various model organisms. However, the long-term effects of MR diet on the gut microbiome composition remain unclear. To study this, male mice were started on MR and control diet regimens at 6 months and continued until 22 months of age. MR mice have reduced body weight, fat mass percentage, and bone mineral density while having increased lean mass percentage. MR mice also have increased insulin sensitivity along with increasing indirect calorimetry markers such as energy expenditure, oxygen consumption, carbon dioxide production, and glucose oxidation. Fecal samples were collected at 1 week, 18 weeks, and 57 weeks after the diet onset for 16S rRNA amplicon sequencing to study the gut microbiome composition. Alpha and beta diversity metrics detected changes occurring due to the timepoint variable, but no changes were detected due to the diet variable. The results from LEfSe analysis surprisingly showed that more bacterial taxa changes were linked to age rather than diet. Interestingly, we found that the long-term MR diet feeding induced smaller changes compared to short-term feeding. Specific taxa changes due to the diet were observed at the 1 or 18-week time points, including Ileibacterium, Odoribacter, Lachnoclostridium, Marinifilaceae, and Lactobacillaceae. Furthermore, there were consistent aging-associated changes across both groups, with an increase in Ileibacterium and Erysipelotrichaceae with age, while Eubacterium_coprostanoligenes_group, Ruminococcaceae, Peptococcaceae, and Peptococcus decreased with age.