GPR43 stimulation on TCRαß+ intraepithelial colonic lymphocytes inhibits the recruitment of encephalitogenic T-cells into the central nervous system and attenuates the development of autoimmunity.

INTRODUCTION: Gut microbiota plays a critical role in the regulation of immune homeostasis. Accordingly, several autoimmune disorders have been associated with dysbiosis in the gut microbiota. Notably, the dysbiosis associated with central nervous system (CNS) autoimmunity involves a substantial reduction of bacteria belonging to Clostridia clusters IV and XIVa, which constitute major producers of short-chain fatty acids (SCFAs). Here we addressed the role of the surface receptor-mediated effects of SCFAs on mucosal T-cells in the development of CNS autoimmunity. METHODS: To induce CNS autoimmunity, we used the mouse model of experimental autoimmune encephalomyelitis (EAE) induced by immunization with the myelin oligodendrocyte glycoprotein (MOG)-derived peptide (MOG35-55 peptide). To address the effects of GPR43 stimulation on colonic TCRαß+ T-cells upon CNS autoimmunity, mucosal lymphocytes were isolated and stimulated with a selective GPR43 agonist ex vivo and then transferred into congenic mice undergoing EAE. Several subsets of lymphocytes infiltrating the CNS or those present in the gut epithelium and gut lamina propria were analysed by flow cytometry. In vitro migration assays were conducted with mucosal T-cells using transwells. RESULTS: Our results show a sharp and selective reduction of intestinal propionate at the peak of EAE development, accompanied by increased IFN-γ and decreased IL-22 in the colonic mucosa. Further analyses indicated that GPR43 was the primary SCFAs receptor expressed on T-cells, which was downregulated on colonic TCRαß+ T-cells upon CNS autoimmunity. The pharmacologic stimulation of GPR43 increased the anti-inflammatory function and reduced the pro-inflammatory features in several TCRαß+ T-cell subsets in the colonic mucosa upon EAE development. Furthermore, GPR43 stimulation induced the arrest of CNS-autoreactive T-cells in the colonic lamina propria, thus avoiding their infiltration into the CNS and dampening the disease development. Mechanistic analyses revealed that GPR43-stimulation on mucosal TCRαß+ T-cells inhibits their CXCR3-mediated migration towards CXCL11, which is released from the CNS upon neuroinflammation. CONCLUSIONS: These findings provide a novel mechanism involved in the gut-brain axis by which bacterial-derived products secreted in the gut mucosa might control the CNS tropism of autoreactive T-cells. Moreover, this study shows GPR43 expressed on T-cells as a promising therapeutic target for CNS autoimmunity.

Gut Microbiome Profiles and Associated Metabolic Pathways in HIV-Infected Treatment-Naïve Patients.

The normal composition of the intestinal microbiota is a key factor for maintaining healthy homeostasis, and accordingly, dysbiosis is well known to be present in HIV-1 patients. This article investigates the gut microbiota profile of antiretroviral therapy-naive HIV-1 patients and healthy donors living in Latin America in a cohort of 13 HIV positive patients (six elite controllers, EC, and seven non-controllers, NC) and nine healthy donors (HD). Microbiota compositions in stool samples were determined by sequencing the V3-V4 region of the bacterial 16S rRNA, and functional prediction was inferred using PICRUSt. Several taxa were enriched in EC compared to NC or HD groups, including Acidaminococcus, Clostridium methylpentosum, Barnesiella, Eubacterium coprostanoligenes, and Lachnospiraceae UCG-004. In addition, our data indicate that the route of infection is an important factor associated with changes in gut microbiome composition, and we extend these results by identifying several metabolic pathways associated with each route of infection. Importantly, we observed several bacterial taxa that might be associated with different viral subtypes, such as Succinivibrio, which were more abundant in patients infected by HIV subtype B, and Streptococcus enrichment in patients infected by subtype C. In conclusion, our data brings a significant contribution to the understanding of dysbiosis-associated changes in HIV infection and describes, for the first time, differences in microbiota composition according to HIV subtypes. These results warrant further confirmation in a larger cohort of patients.

Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women.

Given the increasing evidence that the oral microbiome is involved in obesity, diabetes, and cancer risk, we investigated baseline oral microbiota profiles in relation to all-cancer incidence among nonsmoking women enrolled in a Texas cohort of first- and second-generation immigrants of Mexican origin. We characterized the 16Sv4 rDNA microbiome in oral mouthwash samples collected at baseline from a representative subset of 305 nonsmoking women, ages 20-75 years. We evaluated within- (alpha) and between-sample (beta) diversity by incident cancer status and applied linear discriminant analysis (LDA) effect size analysis to assess differentially abundant taxa. Diversity and candidate taxa in relation to all-cancer incidence were evaluated in multivariable-adjusted Cox regression models. Over 8.8 median years of follow-up, 31 incident cancer cases were identified and verified. Advanced age, greater acculturation, and cardiometabolic risk factors were associated with all-cancer incidence. Higher alpha diversity (age-adjusted P difference < 0.01) and distinct biological communities (P difference = 0.002) were observed by incident cancer status. Each unit increase in the Shannon diversity index yielded >8-fold increase in all-cancer and obesity-related cancer risk [multivariable-adjusted HR (95% confidence interval), 8.11 (3.14-20.94) and 10.72 (3.30-34.84), respectively] with similar findings for the inverse Simpson index. Streptococcus was enriched among women who did not develop cancer, while Fusobacterium, Prevotella, Mogibacterium, Campylobacter, Lachnoanaerobaculum, Dialister, and Atopobium were higher among women who developed cancer (LDA score ≥ 3; q-value < 0.01). This initial study of oral microbiota and overall cancer risk in nonsmoking Mexican American women suggests the readily accessible oral microbiota as a promising biomarker. PREVENTION RELEVANCE: Mexican American women suffer a disproportionate burden of chronic health conditions that increase cancer risk. Few investigations of the microbiome, a key determinant of host health, have been conducted among this group. Oral microbiota profiles may provide early and accessible cancer biomarker data on invasive bacteria or community disruptions.

Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes.

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.

Oral microbiota reveals signs of acculturation in Mexican American women.

The oral microbiome has been linked to a number of chronic inflammatory conditions, including obesity, diabetes, periodontitis, and cancers of the stomach and liver. These conditions disproportionately affect Mexican American women, yet few studies have examined the oral microbiota in this at-risk group. We characterized the 16S rDNA oral microbiome in 369 non-smoking women enrolled in the MD Anderson Mano a Mano Mexican American Cohort Study. Lower bacterial diversity, a potential indicator of oral health, was associated with increased age and length of US residency among recent immigrants. Grouping women by overarching bacterial community type (e.g., "Streptococcus," "Fusobacterium," and "Prevotella" clusters), we observed differences across a number of acculturation-related variables, including nativity, age at immigration, time in the US, country of longest residence, and a multi-dimensional acculturation scale. Participants in the cluster typified by higher abundance of Streptococcus spp. exhibited the lowest bacterial diversity and appeared the most acculturated as compared to women in the "Prevotella" group. Computationally-predicted functional analysis suggested the Streptococcus-dominated bacterial community had greater potential for carbohydrate metabolism while biosynthesis of essential amino acids and nitrogen metabolism prevailed among the Prevotella-high group. Findings suggest immigration and adaption to life in the US, a well-established mediator of disease risk, is associated with differences in oral microbial profiles in Mexican American women. These results warrant further investigation into the joint and modifying effects of acculturation and oral bacteria on the health of Mexican American women and other immigrant populations. The oral microbiome presents an easily accessible biomarker of disease risk, spanning biological, behavioral, and environmental factors.

A Lachnospiraceae-dominated bacterial signature in the fecal microbiota of HIV-infected individuals from Colombia, South America.

HIV infection has a tremendous impact on the immune system's proper functioning. The mucosa-associated lymphoid tissue (MALT) is significantly disarrayed during HIV infection. Compositional changes in the gut microbiota might contribute to the mucosal barrier disruption, and consequently to microbial translocation. We performed an observational, cross-sectional study aimed at evaluating changes in the fecal microbiota of HIV-infected individuals from Colombia. We analyzed the fecal microbiota of 37 individuals via 16S rRNA gene sequencing; 25 HIV-infected patients and 12 control (non-infected) individuals, which were similar in body mass index, age, gender balance and socioeconomic status. To the best of our knowledge, no such studies have been conducted in Latin American countries. Given its compositional nature, microbiota data were normalized and transformed using Aitchison's Centered Log-Ratio. Overall, a change in the network structure in HIV-infected patients was revealed by using the SPIEC-EASI MB tool. Genera such as Blautia, Dorea, Yersinia, Escherichia-Shigella complex, Staphylococcus, and Bacteroides were highly relevant in HIV-infected individuals. Differential abundance analysis by both sparse Partial Least Square-Discriminant Analysis and Random Forest identified a greater abundance of Lachnospiraceae-OTU69, Blautia, Dorea, Roseburia, and Erysipelotrichaceae in HIV-infected individuals. We show here, for the first time, a predominantly Lachnospiraceae-based signature in HIV-infected individuals.

Fecal microbiota imbalance in Mexican children with type 1 diabetes.

Dysbiosis of the intestinal microbiota affecting the gut barrier could be triggering Type 1 Diabetes (T1D), the second most frequent autoimmune disease in childhood. This study compared the structure of the fecal microbiota in 29 mestizo children aged 7-18 years, including 8 T1D at onset, 13 T1D after 2 years treatment, and 8 healthy controls. Clinical information was collected, predisposing haplotypes were determined; the fecal DNA was extracted, the V4 region of the 16S rRNA gene amplified and 454-pyrosequenced. The newly diagnosed T1D cases had high levels of the genus Bacteroides (p < 0.004), whereas the control group had a gut microbiota dominated by Prevotella. Children with T1D treated for ≥2 years had levels of Bacteroides and Prevotella compared to those of the control group. The gut microbiota of newly diagnosed T1D cases is altered, but whether it is involved in disease causation or is a consequence of host selection remains unclear.