The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
Gastrointestinal (GI) microbial populations are important in maintaining normal functioning of the GI by preventing disorders. Dysbiotic microbiota may increase the likelihood of small intestinal ...bacterial overgrowth (SIBO), a syndrome associated with significant morbidity. We aimed to investigate the microbiota populations of patients with SIBO. Patients with symptoms of SIBO were consecutively enrolled; they underwent a SIBO hydrogen breath test and stool was collected for microbiome analysis by sequencing of the 16S rRNA. Of the 55 patients recruited, 42 (76.4%) were positive for SIBO. When visualizing the bacterial β-diversity, a sub-cluster of patients was identified. Further examination of these patients' records revealed previous treatment for Helicobacter pylori (HP). Microbiome analysis of these patients demonstrated a significant decrease in β-diversity (p-value<0.001) compared to patients without previous HP therapy. Furthermore, β-diversity was significantly different in this subgroup, and several bacterial taxa were differentially expressed, including one from the genus Methanobrevibacter, which was reduced in patients that previously underwent HP treatment. Our findings suggest that while symptoms associated with SIBO may cause dysbiosis, there was no differentiation in fecal microbiome composition based on SIBO diagnosis. Furthermore, our results support previous observations regarding antibiotic-altered microbiota with effects extending two and three years post-treatment.
Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1β (IL-1β). However, the role of IL-1β in ...intestinal defense against Salmonella remains unclear. Here, we show that IL-1β production is detrimental during Salmonella infection. Mice lacking IL-1β (IL-1β -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1β -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1β induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1β loss prevented mortality in Salmonella-infected IL-1β -/- mice. Finally, we found that IL-1β expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1β signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1β signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.
Symbiotic microbial colonization through the establishment of the intestinal microbiome is critical to many intestinal functions, including nutrient metabolism, intestinal barrier integrity, and ...immune regulation. Recent studies suggest that education of intestinal immunity may be ongoing in utero. However, the drivers of this process are unknown. The microbiome and its byproducts are one potential source. Whether a fetal intestinal microbiome exists is controversial, and whether microbially derived metabolites are present in utero is unknown. Here, we aimed to determine whether bacterial DNA and microbially derived metabolites can be detected in second trimester human intestinal samples. Although we were unable to amplify bacterial DNA from fetal intestines, we report a fetal metabolomic intestinal profile with an abundance of bacterially derived and host-derived metabolites commonly produced in response to microbiota. Though we did not directly assess their source and function, we hypothesize that these microbial-associated metabolites either come from the maternal microbiome and are vertically transmitted to the fetus to prime the fetal immune system and prepare the gastrointestinal tract for postnatal microbial encounters or are produced locally by bacteria that were below our detection threshold.
The immune system matures throughout childhood to achieve full functionality in protecting our bodies against threats. The immune system has a strong reciprocal symbiosis with the host bacterial ...population and the two systems co-develop, shaping each other. Despite their fundamental role in health physiology, the ontogeny of these systems is poorly characterized. In this study, we investigated the development of the BCR repertoire by analyzing high-throughput sequencing of their receptors in several time points of young C57BL/6J mice. In parallel, we explored the development of the gut microbiome. We discovered that the gut IgA repertoires change from birth to adolescence, including an increase in CDR3 lengths and somatic hypermutation levels. This contrasts with the spleen IgM repertoires that remain stable and distinct from the IgA repertoires in the gut. We also discovered that large clones that germinate in the gut are initially confined to a specific gut compartment, then expand to nearby compartments and later on expand also to the spleen and remain there. Finally, we explored the associations between diversity indices of the B cell repertoires and the microbiome, as well as associations between bacterial and BCR clusters. Our results shed light on the ontogeny of the adaptive immune system and the microbiome, providing a baseline for future research.
Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells ...control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn’s-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.
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•ER stress controls mucus secretion from colonic goblet cells•Autophagy relieves ER stress to facilitate proper mucus secretion•ER-stress-mediated control of mucus secretion is dependent on the microbiota and NOD2•Excess mucus secretion reshapes the microbiota and protects from colitis
Mutations in autophagy genes and NOD2 predispose individuals to the development of inflammatory bowel diseases; yet, the reason(s) is not clear. Naama et al. show that autophagy regulates mucus secretion from goblet cells and offers protection from colitis by alleviating ER stress in a microbiota- and Nod2-dependent manner.
Ptosis Shmosis Kinori, Michael, MD; Ben Simon, Guy J., MD; Zehavi-Dorin, Tzukit, MD ...
Survey of ophthalmology,
03/2017, Volume:
62, Issue:
2
Journal Article
Peer reviewed
Abstract A 10-year-old girl presented with painless unilateral left upper lid ptosis. A nontender hard mass was palpated in the left upper lid. Blood smear was compatible with the diagnosis of ...leukemia. The cause of ptosis was now thought to be a mass composed of myeloid blast cells (myeloid sarcoma).
BACKGROUNDUpper eyelid blepharoplasty surgery is one of the most common plastic surgeries. Khat is used topically to reduce tissue edema. OBJECTIVESTo evaluate the effect of topical khat ...administration after eyelid surgery on postoperative healing. METHODSOur prospective comparative study included 24 patients who underwent upper eyelid blepharoplasty or ptosis surgery between 2019 and 2020. Patients were randomly assigned to 48 hours of cold dressing with frozen khat leaves and frozen peas dressing (common practice). Postoperative photographs of the eyes were evaluated for the degree of ecchymosis and edema on postoperative days (PODs) 1, 3, and 7 by three blinded observers. Measures included tissue swelling and hemorrhage on PODs 1, 3, and 7. RESULTSThe mean age of the cohort was 67 ± 7 years; 17 females (71%). Khat application was associated with lower postoperative ecchymosis at each time point. Females had lower levels of postoperative ecchymosis on POD 7 (P = 0.07). Eyelid edema was more pronounced in the khat group on PODs 1 and 3, but this was reversed on POD 7. There was good agreement among all three observers in grading ecchymosis and edema (P < 0.001). CONCLUSIONSThe use of khat was associated with less tissue ecchymosis after oculoplastic surgery, although this was not statistically significant even following sub-population analysis. The outcome can be attributed to the active ingredients of cathinone and cathine, which cause vasoconstriction and lipolysis, and to the anti-inflammatory and anti-oxidative flavonoids and phenolic compounds. These encouraging preliminary findings warrant additional studies on a biochemical/cellular level.
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