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.     

乳头凹陷矫形方法临床500例研究

目的促进和支持母乳喂养,促进母婴健康。方法是将我院2009年1月—2013年12月就诊孕妇3000例中有乳头凹陷的500例进行乳头矫形。结果 500例行徒手手法矫形,成功300例,成功率60%,为徒手矫形组。剩余200例用20 mL空注射器去掉乳头磨平扣在乳头上,利用负压抽吸方法帮助乳头外突,成功200例,成功率100%,为负压抽吸组,负压抽吸法成功率要明显优于徒手手法矫形,差异明显,具有统计学意义。结论采用20 mL空注射器去掉乳头磨平扣在乳头上,利用负压抽吸方法帮助乳头外突,成功率高,孕妇痛苦少,方便,孕妇自己也可以操作,经济,实惠。深受孕妇及家人的信赖,值得临床大力推广。     

Monitoring recovery from diaphragm paralysis with ultrasound

BACKGROUND: Diaphragmatic paralysis is an uncommon, yet underdiagnosed cause of dyspnea. Data regarding the time course and potential for recovery has come from a few small case series. The methods that have been traditionally employed to diagnose diaphragmatic weakness or paralysis are either invasive or limited in sensitivity and specificity. A new technique utilizing two-dimensional, B-mode ultrasound (US) measurements of diaphragm muscle thickening during inspiration (Deltatdi%) has been validated in the diagnosis of diaphragm paralysis (DP). The purpose of this study was to assess whether serial US evaluation might be utilized to monitor the potential recovery of diaphragm function. METHODS: Twenty-one consecutive patients with clinically suspected DP were referred to the pulmonary physiology laboratory. Sixteen patients were found to have DP by US (unilateral, 10 patients; bilateral, 6 patients). Subjects were followed up for up to 60 months. On initial and subsequent visits, Deltatdi% was measured by US. Additional measurements included upright and supine vital capacity (VC), maximal inspiratory pressure (Pimax), and maximal expiratory pressure. RESULTS: Eleven of 16 patients functionally recovered from DP. The mean (+/- SD) recovery time was 14.9 +/- 6.1 months. No diaphragm thickening was noted in those patients who did not recover. Positive correlations were found between improvement in Deltatdi% and interval changes in VC, Pimax, and end-expiratory measurements of diaphragm thickness. CONCLUSIONS: US may be used to assess for potential functional recovery from diaphragm weakness or DP. As in previous series, recovery occurs in a substantial number of individuals, but recovery time may be prolonged.