Integration of antibiotic and probiotic therapy has the potential to lessen the public health burden of antimicrobial-associated diseases. infection (CDI) represents an important example where the rational design of next-generation probiotics is being actively pursued to prevent disease recurrence. Because intrinsic resistance to clinically relevant antibiotics used to treat CDI (vancomycin, metronidazole, and fidaxomicin) is a desired trait in such probiotic species, we screened several bacteria and identified to be a promising candidate for adjunct therapy. Human-derived bacteria convert glycerol to the broad-spectrum antimicrobial compound reuterin. When supplemented with glycerol, strains carrying the gene locus were potent reuterin producers, with 17938 inhibiting growth at a level on par with the level of growth inhibition by vancomycin. Targeted mutations and complementation studies identified reuterin to be the precursor-induced antimicrobial agent. Pathophysiological relevance was demonstrated when the codelivery of with glycerol was effective against colonization in complex human fecal microbial communities, whereas treatment with either glycerol or alone was ineffective. A global unbiased microbiome and metabolomics analysis independently confirmed that glycerol precursor delivery with elicited changes in the composition and function of the human microbial community that preferentially targets outgrowth and toxicity, a finding consistent with glycerol fermentation and reuterin production. Antimicrobial resistance has thus been successfully exploited in the natural design of human microbiome evasion of , and this method may provide a prototypic precursor-directed probiotic approach. Antibiotic resistance and substrate bioavailability may therefore represent critical new determinants of probiotic efficacy in clinical trials.

When expressed in NOD, but not C57BL/6 (B6) genetic background mice, the common class I variants encoded by the H2g7 MHC haplotype aberrantly lose the ability to mediate the thymic deletion of autoreactive CD8+ T cells contributing to type 1 diabetes (T1D). This indicated some subset of the T1D susceptibility (Idd) genes located outside the MHC of NOD mice interactively impair the negative selection of diabetogenic CD8+ T cells. In this study, using both linkage and congenic strain analyses, we demonstrate contributions from a polymorphic gene(s) in the previously described Idd7 locus on the proximal portion of Chromosome 7 predominantly, but not exclusively, determines the extent to which H2g7 class I molecules can mediate the thymic deletion of diabetogenic CD8+ T cells as illustrated using the AI4 TCR transgenic system. The polymorphic Idd7 region gene(s) appears to control events that respectively result in high vs low expression of the AI4 clonotypic TCR α-chain on developing thymocytes in B6.H2g7 and NOD background mice. This expression difference likely lowers levels of the clonotypic AI4 TCR in NOD, but not B6.H2g7 thymocytes, below the threshold presumably necessary to induce a signaling response sufficient to trigger negative selection upon Ag engagement. These findings provide further insight to how susceptibility genes, both within and outside the MHC, may interact to elicit autoreactive T cell responses mediating T1D development in both NOD mice and human patients.

One of the major lessons learned in the World War II experience with liver injuries was that bile peritonitis was a major factor in morbidity and mortality; the nearly uniform drainage of liver injuries in the subsequent operative era prevented this problem. In the era of nonoperative management, patients who do not require operative treatment for hemodynamic instability may develop large bile and/or blood collections that are often ignored or inadequately drained by percutaneous methods. These inadequately treated bile collections may cause systemic inflammatory response syndrome and/or respiratory distress. We present an experience with laparoscopic evacuation of major bile/blood collections that may prevent the inflammatory sequelae of bile peritonitis. Patients usually underwent operation between 3 and 5 days postinjury (range, 2–18) if CT demonstrated large fluid collections throughout the abdomen/pelvis not amenable to percutaneous drainage. Most patients had signs of systemic inflammatory response syndrome, respiratory compromise, or elevated bilirubin. The bile and retained hematoma was evacuated from around the liver and closed-suction drainage was placed. Twenty-eight patients underwent laparoscopic evacuation/lavage of bile collections (about 4% of total blunt liver injuries). The majority (75%) had Grade IV or V injury. The amount of evacuated fluid ranged from 300 to 3800 mL. Other adjunctive procedures (endoscopic retrograde pancreaticocholangiography, angiography, and laparotomy) were occasionally required. There were no complications related to the procedure. Most patients had a dramatic decline in tachycardia, temperature, white blood cell count, serum bilirubin, and pain. Respiratory failure also resolved in most patients. Large bile and/or blood accumulations are present in a subset of patients with severe liver injuries treated nonoperatively. Delayed laparoscopic evacuation of these collections prevents bile peritonitis and decreases inflammatory response and avoiding early operation, which has been implicated in increased death from hemorrhage.

Lifeway® kefir, a fermented milk product containing 12 probiotic organisms, is reported to show promise as an alternative to fecal microbiota transplantation for recurrent Clostridium difficile infection (CDI). We employed a murine CDI model to study the probiotic protective mechanisms and unexpectedly determined that kefir drastically increased disease severity. Our results emphasize the need for further independent clinical testing of kefir as alternative therapy in recurrent CDI.