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Disruption of intestinal microbial communities appears to underlie many human illnesses, but the mechanisms that promote this dysbiosis and its adverse consequences are poorly understood. In patients who received allogeneic hematopoietic cell transplantation (allo-HCT), we describe a high incidence of enterococcal expansion, which was associated with graft-versus-host disease (GVHD) and mortality. We found that Enterococcus also expands in the mouse gastrointestinal tract after allo-HCT and exacerbates disease severity in gnotobiotic models. Enterococcus growth is dependent on the disaccharide lactose, and dietary lactose depletion attenuates Enterococcus outgrowth and reduces the severity of GVHD in mice. Allo-HCT patients carrying lactose-nonabsorber genotypes showed compromised clearance of postantibiotic Enterococcus domination. We report lactose as a common nutrient that drives expansion of a commensal bacterium that exacerbates an intestinal and systemic inflammatory disease.

The human microbiome constitutes a complex multikingdom community that symbiotically interacts with the host across multiple body sites. Host-microbiome interactions impact multiple physiological processes and a variety of multifactorial disease conditions. In the past decade, microbiome communities have been suggested to influence the development, progression, metastasis formation, and treatment response of multiple cancer types. While causal evidence of microbial impacts on cancer biology is only beginning to be unraveled, enhanced molecular understanding of such cancer-modulating interactions and impacts on cancer treatment are considered of major scientific importance and clinical relevance. In this review, we describe the molecular pathogenic mechanisms shared throughout microbial niches that contribute to the initiation and progression of cancer. We highlight advances, limitations, challenges, and prospects in understanding how the microbiome may causally impact cancer and its treatment responsiveness, and how microorganisms or their secreted bioactive metabolites may be potentially harnessed and targeted as precision cancer therapeutics.

Bone marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. Recent studies indicate that the intestinal microbiota not only regulates mucosal immunity, but can also contribute to systemic immunity and hematopoiesis. Using antibiotic-mediated microbiota depletion in a syngeneic BMT mouse model, here we describe a role for the intestinal flora in hematopoietic recovery after BMT. Depletion of the intestinal microbiota resulted in impaired recovery of lymphocyte and neutrophil counts, while recovery of the hematopoietic stem and progenitor compartments and the erythroid lineage were largely unaffected. Depletion of the intestinal microbiota also reduced dietary energy uptake and visceral fat stores. Caloric supplementation through sucrose in the drinking water improved post-BMT hematopoietic recovery in mice with a depleted intestinal flora. Taken together, we show that the intestinal microbiota contribute to post-BMT hematopoietic reconstitution in mice through improved dietary energy uptake.

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Background and Aims Regenerating islet-derived protein type 3 [Reg3] lectins are antimicrobial peptides at mucosal surfaces of the gut, whose expression is regulated by pathogenic gut microbes via interleukin-22- or Toll-like receptor signalling. In addition to antimicrobial effects, tissue protection is hypothesized, but has been poorly investigated in the gut. Methods We applied antibiotic-induced microbiota perturbations, gnotobiotic approaches and a dextran-sodium sulfate [DSS] colitis model to assess microbial Reg3 regulation in the intestines and its role in colitis. We also used an intestinal organoid model to investigate this axis in vitro. Results First, we studied whether gut commensals are involved in Reg3 expression in mice, and found that antibiotic-mediated reduction of Clostridia downregulated intestinal Reg3B. A loss in Clostridia was accompanied by a significant reduction of short-chain fatty acids [SCFAs], and knock-out [KO] mice for SCFA receptors GPR43 and GPR109 expressed less intestinal Reg3B/-G. Propionate was found to induce Reg3 in intestinal organoids and in gnotobiotic mice colonized with a defined, SCFA-producing microbiota. Investigating the role of Reg3B as a protective factor in colitis, we found that Reg3B-KO mice display increased inflammation and less crypt proliferation in the DSS colitis model. Propionate decreased colitis and increased proliferation. Treatment of organoids exposed to DSS with Reg3B or propionate reversed the chemical injury with a loss of expression of the stem-cell marker Lgr5 and Olfm4. Conclusions Our results suggest that Clostridia can regulate Reg3-associated epithelial homeostasis through propionate signalling. We also provide evidence that the Reg3–propionate axis may be an important mediator of gut epithelial regeneration in colitis.

<b><i>Background/Aims:</i></b> The gut microbiota is altered in irritable bowel syndrome (IBS), and microbiota manipulations by diet or antibiotics can reduce its symptoms. As fecal microbiota transfer (FMT) in IBS is still controversial, we investigated the clinical and side effects of FMT in a cohort of IBS patients with recurrent, treatment refractory symptoms, and studied gut microbiota signatures. <b><i>Methods:</i></b> Using an observational, prospective study design, we applied FMTs from one unrelated, healthy donor to 13 IBS patients. Fecal samples of patients and the donor were analyzed by 16S ribosomal RNA amplicon sequencing. <b><i>Results:</i></b> On a symptom level, primarily abdominal pain symptoms were reduced after FMT, and no adverse effects were observed. Studying the microbiome, we found an increase in alpha diversity and changes in the composition of the gut microbiota after FMT. Beta diversity changes after FMT were prominent in a subset of 7 patients with microbiota profiles coming very close to the donor. These patients also showed most pronounced visceral pain reduction. The relative abundance of <i>Akkermansia muciniphila</i> was inversely correlated with pain reduction in our cohort. <b><i>Conclusion:</i></b> Although exploratory in nature and with a pilot character, this study highlights the potential role of microbiota manipulations in IBS and describes a novel association of intestinal <i>Akkermansia</i> and pain modulation.

Background At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with Coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict COVID-19 illness. However, the results are not conclusive, as critical illness can drastically alter a patient’s microbiome through multiple confounders. Methods To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multi-center, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate and severe COVID-19 (n=322 participants). Results In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. Conclusion In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.