Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/lpr mice

Commensal bacteria and the immune system have a close and strong relationship that maintains a balance to control inflammation. Alterations of the microbiota, known as dysbiosis, can direct reactivity to self-antigens not only in the intestinal mucosa but also at the systemic level. Our laboratory previously reported gut dysbiosis, particularly lower abundance of bacteria in the family Lactobacillaceae, in lupus-prone MRL/lpr mice, a model of systemic autoimmunity. Restoring the microbiota with a mix of 5 different Lactobacillus species (spp.), L. reuteri, L. oris, L. johnsonii, L. gasseri and L. rhamnosus, attenuated lupus-liked clinical signs, including splenomegaly and lymphadenopathy. However, our understanding of the mechanism was limited. In this study, we first investigated the effects of individual species. Surprisingly, none of the species individually recapitulated the benefits of the mix. Instead, Lactobacillus spp. acted synergistically to attenuate splenomegaly and renal lymphadenopathy through secreted factors and a CX3CR1-dependent mechanism. Interestingly, oral administration of MRS broth exerted the same benefits likely through increasing the relative abundance of endogenous Lactobacillus spp. Mechanistically, we found increased percentages of FOXP3-negative type 1 regulatory T cells with administration of the mix in both spleen and mesenteric lymph nodes. In addition, oral gavage of Lactobacillus spp. decreased the percentage of central memory T cells while increasing that of effector memory T cells in the lymphoid organs. Furthermore, a decreased percentage of double negative T cells was observed in the spleen with the mix. These results suggest that Lactobacillus spp. might act on T cells to attenuate splenomegaly and lymphadenopathy. Together, this study advances our understanding of how Lactobacillus spp. attenuate lupus in MRL/lpr mice. The synergistic action of these bacteria suggests that multiple probiotic bacteria in combination may dampen systemic autoimmunity and benefit lupus patients

The Glucagon-Like Peptide-1 Receptor Regulates Endogenous Glucose Production and Muscle Glucose Uptake Independent of Its Incretin Action

Glucagon-like peptide-1 (GLP-1) diminishes postmeal glucose excursions by enhancing insulin secretion via activation of the β-cell GLP-1 receptor (Glp1r). GLP-1 may also control glucose levels through mechanisms that are independent of this incretin effect. The hyperinsulinemic-euglycemic clamp (insulin clamp) and exercise were used to examine the incretin-independent glucoregulatory properties of the Glp1r because both perturbations stimulate glucose flux independent of insulin secretion. Chow-fed mice with a functional disruption of the Glp1r (Glp1r−/−) were compared with wild-type littermates (Glp1r+/+). Studies were performed on 5-h-fasted mice implanted with arterial and venous catheters for sampling and infusions, respectively. During insulin clamps, [3-3H]glucose and 2[14C]deoxyglucose were used to determine whole-body glucose turnover and glucose metabolic index (Rg), an indicator of glucose uptake. Rg in sedentary and treadmill exercised mice was determined using 2[3H]deoxyglucose. Glp1r−/− mice exhibited increased glucose disappearance, muscle Rg, and muscle glycogen levels during insulin clamps. This was not associated with enhanced muscle insulin signaling. Glp1r−/− mice exhibited impaired suppression of endogenous glucose production and hepatic glycogen accumulation during insulin clamps. This was associated with impaired liver insulin signaling. Glp1r−/− mice became significantly hyperglycemic during exercise. Muscle Rg was normal in exercised Glp1r−/− mice, suggesting that hyperglycemia resulted from an added drive to stimulate glucose production. Muscle AMP-activated protein kinase phosphorylation was higher in exercised Glp1r−/− mice. This was associated with increased relative exercise intensity and decreased exercise endurance. In conclusion, these results show that the endogenous Glp1r regulates hepatic and muscle glucose flux independent of its ability to enhance insulin secretion

Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders