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Hafnia alvei HA4597™ – a new clinically validated solution in weight management

Probiotics

Hyperphagia is a common underlying cause of overweight and obesity. However, the dieting approaches towards weight loss are usually ineffective due to a persistent increase in appetite. Most of the current products in weight management are based on the principle of sugar/fat blockers and binders which has proven to be rather short-term solution.

More importantly, this approach doesn’t address the hyperphagia. On the contrary, people using these products often eat more to compensate for the smaller calorie intake which reinforces their bad eating behaviour.

The role of microbiota in appetite regulation

Recently, the role of the gut microbiota in the regulation of appetite has been shown suggesting that it can be targeted to combat obesity.1 In particular, identification of the caseinolytic protease B (ClpB) protein produced by certain gut bacteria as a conformational mimetic of the a-MSH – an anorexigenic melanocortin peptide – suggested that ClpB-producing bacteria can be used for appetite control.

After a meal, gut bacteria multiply and enterobacteria begin to produce ClpB, which directly acts on existing receptors in the gut to induce the production of the human satietogenic hormone peptide YY (PYY) by enteroendocrine cells (EEC). Other bacterial components from the exponential growth phase may induce glucagon-like peptide-1 (GLP-1) release in the bloodstream.2 ClpB is also found in the systemic circulation, suggesting that the protein is able to directly or indirectly trigger anorexigenic POMC neurons in the hypothalamus, and may influence the meal pattern via a systemic route. 2

Figure 1: Appetite regulation via the microbiome, adapted from Breton, J. et al., 2016. Cell Metab. 23, 324–34. 2

This research was the origin of the unique partnership between the University of Rouen Normandy, the University Hospital of Rouen and INSERM and a French biotech TargEDys which took these findings to the next step and start the development of a new product.

Hafnia alvei HA4597™ – a unique candidate in appetite regulation

Hafnia alvei, belonging to the Enterobacteriaceae family, was first identified in 1954 in raw milk and has since been found in traditional cheeses with strong flavours such as Camembert and Livarot. Dairy product contamination during the 1990s led industrialists to pasteurize their milk, which meant losing the typical aromas appreciated by cheese lovers. Hafnia alvei is now added to pasteurized cheese as a lactic ferment to restore its original flavour.

Hafnia alvei HA4597™ has also been used for decades by the dairy industry in the lactic ferment mix added in the cheeses ripening process after milk pasteurization. Hafnia alvei HA4597™ is one of the strains responsible for the typical “French” cheese taste and smell. Hafnia alvei HA4597™ can also be considered as a commensal strain since some studies on the METAHIT cohort also showed that the strain is found in the microbiota of 3% to 5% of the population.

Promising preclinical data showing anti-obesity effects

TargEDys has identified and selected this particular Enterobacteriaceae strain for its ability to influence the microbiome-gut-brain axis appetite regulation pathway. Like other Enterobacteriaceae, Hafnia alvei HA4597 is able to produce the ClpB protein which carries in its sequence the specific α-MSH-like pattern allowing molecular mimicry between this bacterial protein and the human satiety hormone.

Three models of obesity were used for evaluating the efficacy of a daily administration of 1.4×1010 CFU H.alvei (Hafnia alvei HA4597): Ob/Ob mice3, High-fat diet (HFD) mice3 and a hybrid model, High-fat diet (HFD)-fed hyperphagic Ob/Ob mice. In the hybrid model, the effects of H.alvei were compared with a lipase inhibitor Orlistat (80 mg/kg daily) and with a vehicle (NaCl 0.9%) in HFD-fed Ob/Ob mice.5

Overall, the administration of H.alvei HA4597™ has shown to have beneficial anti-obesity effects characterized by a reduction in cumulative food intake and body weight associated with reduced glycemia and total plasma cholesterol.3,5

Clinical confirmation of the efficacy of Hafnia alvei HA4597™ in weight loss

After several promising preclinical data, TargEDys has decided to test Hafnia alvei HA4597™ in a large randomized, double-blind, placebo-controlled clinical trial to evaluate its efficacy in the weight loss by appetite regulation.

The study was carried out on 229 overweight subjects characterized by a body mass index between 25 and 30 kg/m2. The two arms underwent a hypocaloric diet associated either with the Hafnia alvei HA4597™ (1.1011 cells/day = 2 capsules/day) or with a placebo.

The primary endpoint related to weight loss has been achieved: there is a statistically significant difference in favour of the probiotic in the proportion of subjects who lost at least 3% of their body weight at 12 weeks. 

Amongst other secondary endpoints, the proposed mechanism of action is confirmed by a statistically significant increase in the feeling of fullness. The probiotic effect is also higher than the placebo in the reduction of hip circumference. Only Hafnia alvei HA4597™ had a significant effect on cholesterol levels (total cholesterol and LDL cholesterol) and induced a higher decrease in glycemia than the placebo. Finally, Hafnia alvei HA4597™ has shown to be significantly superior to the placebo through the overall evaluation of the benefits perceived by both the investigating physicians and the subjects.

The effect on weight loss was significant already at 12 weeks compared to other probiotic strain studied in weight management that often validated their efficacy only after 6 months. Moreover, on certain endpoints such as hip circumference or feeling of fullness the results were significant already at 8 weeks showing an early offset of the efficacy.

A new generation probiotic

The combination of preclinical and clinical results establishes a strong body of evidence confirming the efficacy of Hafnia alvei HA4597™ in weight management through appetite regulation. According to Gregory Lambert, CEO and vice-president of Research and Development in TargEDys, “It is the first product of a new generation of probiotics, single strain, endowed with a scientifically established mechanism of action in the microbiome-gut-brain axis and with a proven clinical efficacy”.

The company has already started the commercialization of its first product using Hafnia alvei HA4597™ in France as a dietary supplement under the name EnteroSatys®. Moreover, the first results from consumer survey are further confirming the preclinical and clinical data also in real-life settings. 

The company is now looking for partners and distributors to get this unique solution to other markets worldwide.

TargEDys® is a commercial-stage French biotech, specialized in the development of nutraceutical and therapeutic solutions for appetite regulation and weight management via microbiome interventions.

The 7th Microbiome and Probiotics R&D and Business Collaboration Forum offers a unique opportunity to build new partnerships and explore effective business and commercialisation strategies. Click here to see the full range of speakers.

References:

[1] Fetissov SO, 2017. Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour. Nat Rev Endocrinol. 13, 11–25.

[2] Breton J et al., 2016. Gut Commensal E. coli Proteins Activate Host Satiety Pathways following Nutrient-Induced Bacterial Growth. Cell Metab. 23, 324–34.

[3] Legrand R et al., 2020. Commensal Hafnia alvei strain reduces food intake and fat mass in obese mice—a new potential probiotic for appetite and body weight management. Int J Obes. 9, 1476-5497.

[4] Mogren L et al. 2018 The hurdle approach—a holistic concept for controlling food safety risks associated with pathogenic bacterial contamination of leafy green vegetables. A Review. Front Microbiol.9:1965. 

[5] Lucas N et al. 2020. 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. Microorganisms. 8, 35. 

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