Commensal Hafnia alvei strain reduces food intake and fat mass in obese mice—a new potential probiotic for appetite and body weight management

Abstract

Background/objectives Based on the recent identification of E.coli heat shock protein ClpB as a mimetic of the anorexigenic α-melanocyte stimulating hormone (α-MSH), the objective of this study was to preclinically validate Hafnia alvei, a ClpBproducing commensal bacterium as a potential probiotic for appetite and body weight management in overweight and obesity. Methods The involvement of enterobacterial ClpB in the putative anti-obesity effects was studied using ClpB-deficient E.coli. A food-grade H. alvei HA4597 strain synthetizing the ClpB protein with an α-MSH-like motif was selected as a candidate probiotic to be tested in ob/ob and high-fat diet (HFD)-fed obese and overweight mice. The relevance of the enterobacterial ClpB gene to human obesity was studied by in silico analysis of fecal metagenomes of 569 healthy individuals from the "MetaHIT" database. Results Chronic per os administration of native but not ClpB-deficient E.coli strain reduced body weight gain (p < 0.05) and daily meal frequency (p < 0.001) in ob/ob mice. Oral gavage of H.alvei for 18 and 46 days in ob/ob and HFD-fed obese mice, respectively, was well tolerated, reduced body weight gain and fat mass in both obesity models (p < 0.05) and decreased food intake in hyperphagic ob/ob mice (p < 0.001). Elevated fat tissue levels of phosphorylated hormone-sensitive lipase were detected in H.alvei-treated ob/ob mice (p < 0.01). Enterobacterial ClpB gene richness was lower in obese vs. non-obese humans (p < 0.0001) and correlated negatively with BMI in genera of Enterobacter, Klebsiella and Hafnia. Conclusions H.alvei HA4597 strain reduces food intake, body weight and fat mass gain in hyperphagic and obese mice. These data combined with low enterobacterial ClpB gene abundance in the microbiota of obese humans provide the rationale for using H.alvei as a probiotic for appetite and body weight management in overweight and obesity.

Hafnia alvei HA4597 Strain Reduces Food Intake and Body Weight Gain and Improves Body Composition, Glucose, and Lipid Metabolism in a Mouse Model of Hyperphagic Obesity

“…The lack of leptin in ob/ob mice results in strong hyperphagia underlying development of obesity even on a standard diet [13]. On the other hand, WT mice fed HFD develop diet-induced obesity (DIO), which is typically accompanied by a decreased total (but not caloric) food intake, a phenomenon which was also observed in our previous study, representing an obstacle for the evaluation of a potential H. alvei anorexigenic effect in palatable HFD [11]. An animal model of obesity based on HFD-fed ob/ob mice may represent a good alternative most closely reflecting hyperphagia and diet-induced obesity in humans.…”

“…Indeed, traditional probiotic bacteria belonging to the genera of Lactobacillus, Bifidobacterium, and Enterococcus, alone or in various combinations, have been tested in humans, resulting typically in minor health-positive effects, without significant changes in food intake and body weight [6][7][8][9]. Nevertheless, existence of the functional link between gut microbiota and host regulation of appetite and energy metabolism indicates that some gut commensal bacteria can be potentially identified and developed as new-generation anti-obesity probiotics based on the understanding of their mechanisms of action [10].We have recently demonstrated that a Hafnia alvei (H. alvei) HA4597™ strain of commensal bacteria of the Hafniaceae family (formerly Enterobacteriaceae) belonging to the order of Enterobacteriales displays anti-obesity properties in two animal models of obesity, standard-diet-fed leptin-deficient ob/ob and high-fat-diet (HFD)-fed wild-type (WT) mice [11]. The choice of H. alvei as a potential anti-obesity probiotic was based on its production of the caseinolytic protease B (ClpB) protein, which was previously identified as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), a key anorexigenic peptide involved in the regulation of appetite [11,12].In the present study, we aimed to test the anti-obesity efficacy of the H. alvei HA4597™, in a mouse model of obesity characterized by both hyperphagia and HFD-induced adiposity.…”

“…Nevertheless, existence of the functional link between gut microbiota and host regulation of appetite and energy metabolism indicates that some gut commensal bacteria can be potentially identified and developed as new-generation anti-obesity probiotics based on the understanding of their mechanisms of action [10].We have recently demonstrated that a Hafnia alvei (H. alvei) HA4597™ strain of commensal bacteria of the Hafniaceae family (formerly Enterobacteriaceae) belonging to the order of Enterobacteriales displays anti-obesity properties in two animal models of obesity, standard-diet-fed leptin-deficient ob/ob and high-fat-diet (HFD)-fed wild-type (WT) mice [11]. The choice of H. alvei as a potential anti-obesity probiotic was based on its production of the caseinolytic protease B (ClpB) protein, which was previously identified as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), a key anorexigenic peptide involved in the regulation of appetite [11,12].In the present study, we aimed to test the anti-obesity efficacy of the H. alvei HA4597™, in a mouse model of obesity characterized by both hyperphagia and HFD-induced adiposity. In fact, such forms of obesity may most closely reflect the obesity phenotypes in many humans (compulsive eating behavior combined with hypercaloric diet and accompanied by functional leptin resistance), while ob/ob and HFD models used separately display some limitations.…”

An Updated Overview on Nanonutraceuticals: Focus on Nanoprebiotics and Nanoprobiotics

“…Some of the reported beneficial effects of probiotics in human health include anticancer [99][100][101][102][103][104][105][106][107][108][109][110][111], anti-allergic [112,113], anti-diabetic [114][115][116], anti-obesity [117][118][119][120], anti-pathogenic [121,122], immunomodulatory [123], and anti-inflammatory [124][125][126][127] activities [128], as reported in Table 1.…”

“…The body weight and abdominal fat content were decreased in mouse models fed a modified diet through the administration of L. plantarum LMT1-48 at a density of 10 6 CFU/mL [117] Hafnia alvei Anti-obesity effect Fat mass, food intake, and body weights were reduced in the mouse model of obesity and hyperphagia [118]…”