Targeted mobilization of Lrig1+ gastric epithelial stem cell populations by a carcinogenic Helicobacter pylori type IV secretion system.

Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag+H. pylori or an isogenic cagE- mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE- mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.

Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach.

OBJECTIVE: Lrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice. DESIGN: We performed lineage labelling using Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) or R26R-LacZ/+ (Lrig1/LacZ) mice to examine whether the Lrig1-YFP-marked cells are gastric progenitor cells. We studied whether Lrig1-YFP-marked cells give rise to normal gastric lineage cells in damaged mucosa using Lrig1/YFP mice after treatment with DMP-777 to induce acute injury. We also studied Lrig1-CreERT2/CreERT2 (Lrig1 knockout) mice to examine whether the Lrig1 protein is required for regeneration of gastric corpus mucosa after acute injury. RESULTS: Lrig1-YFP-marked cells give rise to gastric lineage epithelial cells both in the gastric corpus and antrum, in contrast to published results that Lgr5 only marks progenitor cells within the gastric antrum. Lrig1-YFP-marked cells contribute to replacement of damaged gastric oxyntic glands during the recovery phase after acute oxyntic atrophy in the gastric corpus. Lrig1 null mice recovered normally from acute gastric mucosal injury indicating that Lrig1 protein is not required for lineage differentiation. Lrig1+ isthmal progenitor cells did not contribute to transdifferentiating chief cell lineages after acute oxyntic atrophy. CONCLUSIONS: Lrig1 marks gastric corpus epithelial progenitor cells capable of repopulating the damaged oxyntic mucosa by differentiating into normal gastric lineage cells in mouse stomach.

Frequency and Characteristics of Patients Prescribed Antibiotics on Admission to Hospice Care.

Background: Little is known about antibiotic prescribing on hospice admission despite known risks and limited evidence for potential benefits. Objective: To describe the frequency and characteristics of patients prescribed antibiotics on hospice admission. Design: Cross-sectional study. Subjects: Adult (age ≥18 years) decedents of a national, for-profit hospice chain across 19 U.S. states who died between January 1, 2017 and December 31, 2019. Measures: The primary outcome was having an antibiotic prescription on hospice admission. Patient characteristics of interest were demographics, hospice referral location, hospice care location, census region, primary diagnosis, and infectious diagnoses on admission. We used multivariable logistic regression to quantify associations between study variables. Results: Among 66,006 hospice decedents, 6080 (9.2%) had an antibiotic prescription on hospice admission. Fluoroquinolones (22%) were the most frequently prescribed antibiotic class. Patients more likely to have an antibiotic prescription on hospice admission included those referred to hospice care from the hospital (adjusted odds ratio [aOR] 1.13, 95% confidence interval [CI] 1.00-1.29) compared with an assisted living facility, those receiving hospice care in a private home (aOR 3.85, 95% CI 3.50-4.24), nursing home (aOR 3.65, 95% CI 3.24-4.11), assisted living facility (aOR 4.04, 95% CI 3.51-4.64), or hospital (aOR 2.43, 95% CI 2.18-2.71) compared with inpatient hospice, and those with a primary diagnosis of liver disease (aOR 2.23, 95% CI 1.82-2.74) or human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (aOR 3.89, 95% CI 2.27-6.66) compared with those without these diagnoses. Conclusions: Approximately 9% of hospice patients had an antibiotic prescription on hospice admission. Patients referred to hospice from a hospital, those receiving care in a noninpatient hospice facility, and those with liver disease or HIV/AIDS were more likely to have an antibiotic prescription. These results may inform future antimicrobial stewardship interventions among patients transitioning to hospice care.