Lactobacillus acidophilus Induces a Strain-specific and Toll-Like Receptor 2–Dependent Enhancement of Intestinal Epithelial Tight Junction Barrier and Protection Against Intestinal Inflammation

Defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease. To date, no effective therapies that specifically target the intestinal TJ barrier are available. The purpose of this study was to identify probiotic bacterial species or strains that induce a rapid and sustained enhancement of intestinal TJ barrier and protect against the development of intestinal inflammation by targeting the TJ barrier. After high-throughput screening of >20 Lactobacillus and other probiotic bacterial species or strains, a specific strain of Lactobacillus acidophilus, referred to as LA1, uniquely produced a marked enhancement of the intestinal TJ barrier. LA1 attached to the apical membrane surface of intestinal epithelial cells in a Toll-like receptor (TLR)-2–dependent manner and caused a rapid increase in enterocyte TLR-2 membrane expression and TLR-2/TLR-1 and TLR-2/TLR-6 hetero-complex–dependent enhancement in intestinal TJ barrier function. Oral administration of LA1 caused a rapid enhancement in mouse intestinal TJ barrier, protected against a dextran sodium sulfate (DSS) increase in intestinal permeability, and prevented the DSS-induced colitis in a TLR-2– and intestinal TJ barrier–dependent manner. In conclusion, we report for the first time that a specific strain of LA causes a strain-specific enhancement of intestinal TJ barrier through a novel mechanism that involves the TLR-2 receptor complex and protects against the DSS-induced colitis by targeting the intestinal TJ barrier.

Intestinal epithelial tight junctions (TJs) are the apical-most junctional complexes and act as a functional and structural barrier against the paracellular permeation of harmful luminal antigens, which promote intestinal inflammation.¹ The increased intestinal permeability caused by defective intestinal epithelial TJ barrier or a leaky gut is an important pathogenic factor that contributes to the development of intestinal inflammation in inflammatory bowel disease (IBD) and other inflammatory conditions of the gut, including necrotizing enterocolitis and celiac disease.^2,3 Clinical studies in patients with IBD have found that a persistent increase in intestinal permeability after clinical remission is predictive of poor clinical outcome and early recurrence of the disease, whereas normalization of intestinal permeability correlates with a sustained long-term clinical remission.4, 5, 6 Accumulating evidence has found that a defective intestinal TJ barrier plays an important role in exacerbation and prolongation of intestinal inflammation in IBD. Currently, no effective therapies that specifically target the tightening of the intestinal TJ barrier are available.Intestinal microbiota play an important role in modulating the immune system and in the pathogenesis of intestinal inflammation.⁷ Patients with IBD have bacterial dysbiosis in the gut, characterized by a decrease in bacterial diversity and an aberrant increase in some commensal bacteria, which are an important factor in the pathogenesis of intestinal inflammation.^8,9 Normal microbial flora of the gastrointestinal tract consists both of bacteria that are known to have beneficial effects (probiotic bacteria) on intestinal homeostasis and bacteria that could potentially have detrimental effects on gut health (pathogenic bacteria).¹⁰ The modulation of intestinal microflora affects the physiologic and pathologic states in humans and animals. For example, fecal transplantation from healthy, unaffected individuals to patients with refractory Clostridium difficile colitis is curative in up to 94% of the treated patients, and transfer of stool microbiome from obese mice induces obesity in previous lean mice, whereas transfer of microbiome from lean mice preserves the lean phenotype.11, 12, 13 The beneficial effects of gut microbiota are host and bacterial species-specific.¹⁴ Although multiple studies indicate that some commensal bacteria play a beneficial role in gut homeostasis by preserving or promoting the intestinal barrier function, because of conflicting reports, it remains unclear which probiotic species cause a persistent predictable enhancement in the TJ barrier and could be used to treat intestinal inflammation by targeting the TJ barrier. For example, some studies suggest that Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus plantarum, or Lactobacillus rhamnosus cause a modest enhancement in the intestinal epithelial TJ barrier, whereas others have found minimal or no effect of these probiotic species on the intestinal TJ barrier.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 The major aim the current study was to perform a high-throughput screening of Lactobacillus and other bacterial species to identify probiotic species that induce a rapid, predictable, and marked increase in the intestinal epithelial TJ barrier and protect against the development of intestinal inflammation by preserving the intestinal TJ barrier.In the studies described herein, most of the probiotic species tested (>20 species or strains) had a modest or minimal effect on intestinal TJ barrier function. L. acidophilus uniquely caused a rapid and marked increase in intestinal TJ barrier function. Further analysis indicated that the effect of L. acidophilus was strain-specific, limited to a specific strain of L. acidophilus, and did not extend to other L. acidophilus strains. The L. acidophilus enhancement of the intestinal TJ barrier was mediated by live bacterial-enterocyte interaction that involved Toll-like receptor (TLR)-2 heterodimeric complexes on the apical membrane surface of intestinal epithelial cells. Our animal studies also found that L. acidophilus causes a marked enhancement in mouse intestinal barrier function and protects against the dextran sodium sulfate (DSS)–induced colitis by preserving and augmenting the mouse intestinal barrier function in a strain-specific manner.     

Validity of Birth Certificate and Hospital Discharge Data Reporting of Labor Induction

Purpose

To examine the concordance of labor induction measures derived from birth certificate and hospital discharge data with each other and with maternal report.

Osteomyelitis caused by Veillonella

Veillonella parvula and alcalescens are anaerobic gram-negative cocci that, when isolated from anaerobic cultures of clinical specimens, are usually regarded as commensal organisms. Occasionally they play a pathogenic role and require antibiotic therapy. Limited clinical experience and in vitro susceptibility studies suggest that penicillin G is the drug of choice for these organisms and that cephalosporins, clindamycin, chloramphenicol, and metronidazole may be acceptable therapeutic alternatives. Presented herein is a case report of a Veillonella infection, a discussion of the importance of these organisms when they occur in a clinical infection, and a discussion of the appropriate antibiotic therapy.     

Maternal blood pressure and fetal growth

Eleven thousand eighty-two term, singleton pregnancies were analyzed for clues to how different levels of maternal blood pressure affect fetal growth. Birth weights progressively increased with increasing pressures until the hypertensive range was reached when maternal edema and proteinuria were absent. Pressure-associated increases in fetal growth were even more rapid when mothers were edematous, and slower when 2+ or greater proteinuria was present. Birth weights leveled off or decreased when pressures reached the hypertensive range. The pressure threshold at which growth slowed increased from diastolic 75 mm Hg in the lowest maternal pregnancy weight gain category to nearly 100 mm Hg in the highest weight gain category. Decreases in birth weight associated with hypertension were most severe when mothers were thin and had low pregnancy weight gains. Diuretics reduced birth weights in low maternal weight gain pregnancies but not in high weight gain ones.     

Ductus arteriosus aneurysm presenting as pulmonary artery obstruction: diagnosis and management

The occurrence of pulmonary artery obstruction in an 8 day old infant as a complication of an aneurysm of a nonpatent ductus arteriosus is reported, together with the echocardiographic and angiographic findings. To relieve the obstruction, the aneurysm and an intrapulmonary thrombus were successfully removed with the use of cardiopulmonary bypass when the infant was 3 months old.     

Morphology of ventricular premature beats as an aid in the electrocardiographic diagnosis of myocardial infarction

To determine whether morphologic analysis of ventricular premature beats (VPBs) can aid in the electrocardiographic diagnosis of myocardial infarction (MI), 12-lead electrocardiograms were evaluated in 760 consecutive patients who underwent cardiac catheterization, and 2-minute multiple-lead rhythm strips were evaluated in 515 of these patients. VPBs occurred in 58 patients; 21 had prior MI diagnosed by regional akinesia or dyskinesia on left ventricular cineangiography. Standard criteria were used to diagnose prior MI from the sinus beats of the electrocardiogram. Infarction was diagnosed from the morphology of a VPB when it had a QR or QRS pattern with Q wave greater than or equal to 0.04 second. Morphologic analysis of VPBs had a low sensitivity (29%) but high specificity (97%) and high predictive value (86%) for the diagnosis of MI. Sinus beats diagnosed MI with higher sensitivity (52%, and 69% if patients with left bundle branch block and left ventricular hypertrophy were excluded from analysis) than VPB morphologic analysis (p less than 0.05), but with similar specificity (97%) and predictive value (92%). Two patients with angiographic MI had no MI according to standard electrocardiographic criteria, but did have an MI manifest by VPB morphologic analysis. Despite low sensitivity, analysis of the morphology of VPBs may be useful for the diagnosis of MI when the morphology of sinus beats is not diagnostic. Therefore, VPB analysis is complementary to the standard electrocardiographic diagnosis of MI.