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EP-4366750-B1 - SPECIES, STRAINS AND COMPOSITIONS OF LACTIC ACID BACTERIA CAPABLE OF MODULATING BODY OXYGENATION BY INCREASING HIF-1ALPHA LEVELS

EP4366750B1EP 4366750 B1EP4366750 B1EP 4366750B1EP-4366750-B1

Inventors

  • DE SIMONE, CLAUDIO

Dates

Publication Date
20260506
Application Date
20220617

Claims (10)

  1. Strain of Lactobacillus acidophilus deposited with the accession number CNCM I-5567 capable of increasing cellular levels of the hypoxia-inducible factor HIF-1α associated with the reduction of cellular oxygen consumption for use in the treatment of hypoxia-inducing conditions selected from the group consisting of chronic fatigue, oxygen deprivation, neurodegenerative diseases, neonatal hypoxia-ischemia, myocardial ischemia, metabolic disorders, chronic cardiac and renal diseases, reproductive disorders such as pre-eclampsia and endometriosis, exacerbation of postural and kinetic tremors, and cerebral hypoxia.
  2. A composition comprising Lactobacillus acidophilus according to claim 1 and optionally one or more pharmaceutically acceptable excipients for use according to claim 1.
  3. Composition according to claim 2 for use according to claim 1, further comprising the strain of Streptococcus thermophilus deposited with the access number CNCM I-5570, and the strain of Bifidobacterium animalis subsp. lactis deposited with the access number CNCM I-5571 and/or the strain of Bifidobacterium animalis subsp. lactis deposited with the access number CNCM I-5572.
  4. Composition according to claim 2 or 3 for use according to claim 1, comprising from 30% to 50% by weight of Lactobacillus acidophilus, from 25% to 35% by weight of Streptococcus thermophilus, and from 25% to 35% by weight of Bifidobacterium animalis subsp. lactis, depending on the weight of the composition.
  5. Composition according to any of claims 2 to 4 for use according to claim 1, further comprising the strain of Levilactobacillus brevis deposited with the accession number CNCM I-5566, the strain of Lactiplantibacillus plantarum subsp. plantarum deposited with the accession number CNCM I-5569, the strain of Lacticaseibacillus paracasei subsp. paracasei deposited with the accession number CNCM I-5568, and the strain of Lactobacillus helveticus deposited with the accession number CNCM I-5573.
  6. Composition according to claim 5 for use according to claim 1, which comprises from 30% to 50% by weight Lactobacillus acidophilus, 1% to 10% by weight Streptococcus thermophilus, from 1% to 20% by weight Bifidobacterium animalis subsp. lactis, from 1% to 10% by weight Levilactobacillus brevis (formerly known as Lactobacillus brevis), from 1% to 10% by weight Lactiplantibacillus plantarum subsp. plantarum (formerly known as Lactobacillus plantarum ), from 1% to 10% by weight of Lacticaseibacillus paracasei subsp. paracasei (formerly known as Lactobacillus paracasei subsp. paracasei ), and from 1% to 10% by weight of Lactobacillus helveticus, based on the weight of the composition.
  7. Composition according to any one of claims 2 to 6 for use according to claim 1, suitable for oral administration, such as in the form of powders, capsules or granules or sprays.
  8. Composition according to claim 7 for use according to claim 1 having a high concentration of bacteria, to the extent of at least 10 billion in the adult and at least 100 million in the infant.
  9. Composition for use according to claim 7, wherein said composition is suitable for administration to animals reared and/or maintained under oxygen-deficient conditions.
  10. Probiotic bacterial strains or compositions according to any of the preceding claims for use according to claim 1, wherein the bacteria used are viable, non-viable, sonicated, tindalized or lyophilized.

Description

Field of invention The invention relates to particular species, strains, and compositions of lactic acid bacteria capable of increasing cellular levels of the hypoxia-inducible factor HIF-1 α for the treatment of hypoxia in hypoxia-inducing conditions such as chronic fatigue, oxygen deficiency, neurodegenerative diseases, pulmonary implications associated with respiratory failure, neonatal hypoxia-ischemia, myocardial ischemia, metabolic disorders, chronic cardiac and renal diseases, reproductive disorders such as pre-eclampsia and endometriosis, exacerbation of postural and kinetic tremors, and cerebral hypoxia. Background of the invention Oxygen (O2) is an essential nutrient that serves as a key substrate in cellular metabolism and energy production by aerobic organisms. In a variety of physiological and pathological states, organisms experience limited/insufficient O2 disponibility, a condition referred to as hypoxia. O2 deprivation creates significant stress in living cells. This condition is related to the inappropriate accumulation of free radicals, which cause further stress on the protein component of cells and the genetic material they contain. To cope with the hypoxic stress condition, cells activate a series of adaptive responses to match O2 supply with metabolic, bioenergetic, and redox demands. In particular, they temporarily arrest the cell cycle, reduce energy consumption, and secrete survival and pro-angiogenic factors. The intestinal mucosa receives between 10% and 35% of the total cardiac output, and the estimated surface area of the gastro-intestinal tract is about 250-300 m2 under normal conditions (Lundquist et al., 2016). The gut is characterized by a peculiar oxygenation profile resulting from a combination of different factors, including massive fluctuations in blood perfusion as a result of food ingestion (Matheson et al., 2000). Changes in the amount of blood reaching the gut greatly affect the amount of O2 available to the remaining body districts. The gut, therefore, plays a key role in determining the distribution of total O2 available to the organism. In the small intestine, increased oxygen availability sustains intense energy expenditure by highly proliferative stem cells and differentiated post-mitotic cells with high energy demand due to digestive, secretory and absorption processes (Rangel-Huerta et al., 2017; Van Der Schoor et al., 2002). The characteristics of oxygenation and oxygen consumption in the small intestine allow us to hypothesize that their modulation may have a major impact on the redistribution of globally available O2 to the body. Under basal physiological conditions, intestinal mucosal epithelial cells are subject to relatively low O2 levels, previously described as "physiological hypoxia" (Karhausen et al., 2005). To this condition, intestinal epithelial cells continuously adapt (Shepherd, 1982; Albenberg et al., 2014). Hypoxia-inducible factors (HIFs) constitute key mediators of intestinal epithelial adaptation to its O2-poor microenvironment (Ramakrishnan et al., 2016). These mediators are responsible for the reduction of oxygen consumption in mitochondria through inhibition of pyruvate to acetyl CoA conversion, suppression of mitochondrial biogenesis, and activation of mitochondria autophagy (Goda and Kanai, 2012). The reduction in cellular oxygen consumption associated with HIFs and the subsequent redistribution of oxygen in the peri-cellular microenvironment are supported by evidence produced using PHD inhibitors (Susser et al., 2020). HIFs are heterodimers composed of two subunits termed alpha and beta, respectively, the second of which is constitutively expressed by eukaryotic cells. The HIF-α subunit belongs to the helix-loop-helix Per-Arnt-Sim (bHLH-PAS) family of basic transcription factors (Schito et al., 2016). Vertebrates possess three subunits α: HIF-1α, HIF-2α and HIF-3α. The N-terminal region of these subunits contains a domain required for DNA binding and heterodimerization (Wu et al., 2015). The HIF-α subunits possess a highly conserved oxygen-dependent degradation (ODD) domain. The ODD domain contains two hydroxylated prolines, in both HIF-1α and HIF-2α (Chan et al., 2005). Hydroxylation of HIF-α leads to proteosomal degradation. The HIF-α subunits are hydroxylated by specific enzymes PHD1 (EGLN2), PHD2 (EGLN1) and PHD3 (EGLN3) belonging to the group of prolyl hydroxylase domain (PHD) enzymes that represent the main oxygen sensors in a cell. Under normoxic conditions, PHDs use O2 to hydroxylate HIF-α subunits at the proline level present in the ODD. Hydroxylation allows the binding of the Von Hippel-Lindau oncosuppressor protein (VHL), which acts as an E3 ubiquitin ligase enabling the degradation of HIF-α (Ivan et al., 2001). Under conditions of low oxygen disponibility, PHD enzymes are unable to perform hydroxylation of HIF-α which are stabilized by heterodimerization with an HIF-β subunit (Wang et al., 1995). The generated heterodimer