In human gut microbiome.The bacterial caseinolytic protease B (ClpB) is host peptide which acts as a conformational mimetic of α-melanocyte-stimulating hormone (a- MSH) which regulates energy homeostasis in humans
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Does the Microbiome Interact with the Human Endocrine System?
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Hidaya Aliouche, B.Sc.
By Hidaya Aliouche, B.Sc.
Skip to:
What are the different metabolites produced?
Can microbiota control brain function?
Microbial components – a role as endocrine effectors?
Whilst the effect of the microbiome on the digestive system has been studied over the past decade, the understanding of its effect on the endocrine system is less well understood.
The endocrine system synthesizes and secrete hormones to regulate physiological processes. Interestingly the gut microbiome is an endocrine organ itself; metabolomic and metagenomic studies have revealed bacterial metabolites and components that affect organ function and subsequently, physiological outcomes. Bacterial- derived metabolites and components may act locally with the host, activating cell receptors or neural terminations, as well as distally through circulatory dissemination. Their mechanism of action is varied- paracrine, endocrine and nervous - yet all converge on influencing endocrine function.
Bacteria Lactobacillus, 3D illustration. Image Credit: Kateryna Kon / Shutterstock
Bacteria Lactobacillus, 3D illustration. Image Credit: Kateryna Kon / Shutterstock
What are the different metabolites produced?
The human gastrointestinal system is unable to digest all carbohydrates. Typically, these indigestible carbohydrates are referred to as dietary fiber, and reach the gut microbiota in the lower GI tract where they are subject to enzymic breakdown. This yields several classes of compounds, the most well studied of which, are the short chain fatty acids (SCFAs). The impact of SCFAs on human health is very well documented in the literature; they act both locally and in an endocrine manner, reaching distal sites such as the liver, adipose tissue, muscle and brain. Subsequently their physiological effects are wildly variable, effecting energy regulation, inflammation and the modulation of cancer.
Beginning with the digestive system, studies have demonstrated that changes in gut peptide production can occur following modification of dietary fiber intake or gut microbiome modification. For example, studies have implicated nondigestible carbohydrate intake in gut microbiome modulation to increase satiety and reduce food intake to reduce energy intake. Oligofructose-induced modulation of the gut microbiome produces this effect and were noncommittal with higher blood GLP-1 and PYY levels, key anti-obesity regulators.
Other than carbohydrates, amino acids (particularly branched chain amino acids (BCAAs)) have been correlated with physiological occurrences, namely insulin resistance. BCAAs have been shown in several studies, to originate endemically from the gut microbiota. In insulin resistant individuals, the with enzymes for BCAAs biosynthesis are enriched.
A pioneering study by F. Backhed demonstrated that the metabolization of histidine by microbiota to imidazole propionate directly contributes to glucose dysregulation via activation of the p38g/p62/mTORC1 pathway. This culminates in inhibition of IRS, the insulin receptor substrate that binds insulin and instigates cell signaling in response to this. However, not all amino acid derived microbial metabolites are correlated with insulin resistance or glucose sensitivity; for example, microbiota metabolize tryptophan to produce molecules such as indoles and their derivatives. These have been shown to act as endocrine molecules and activate the aryl hydrocarbon receptor (AhR). Indole propionic acid (IPA) for example, has been shown to improve metabolism by strengthening the gut barrier function and immune response as well as producing anti-inflammatory effects.
Related Stories
Whole body vibration helps reduce inflammation, thanks to the gut microbiome
Genetically tweaking gut bacteria reduces risk of colorectal cancer in mice finds study
Common antibacterial agent may be bad news for bone health
Recent studies have shown IPA lowers the risk of type II diabetes onsets by protecting the β cell function and increasing insulin release. Like SCFAs, indole and its derivative indole-3 acetate (I3A), modulate host metabolism by stimulating GLP-1 secretion from specialized enteroendocrine L-cells.
Can microbiota control brain function?
Gut microbes can produce the classical neurotransmitters of the brain. Their effect is communicated via the enteric nervous system, which is connected to the autonomic nervous system (ANS). The effect of the neurotransmitters can be localized i.e. affecting motility and intestinal hormone release, or centralized, affecting mood and cognition. Examples include histamine; this is derived from histidine and has been shown to increase asthma in humans, suggesting its role in immune modulation. Another neurotransmitter produced is serotonin and this has been implicated in several physiological processes including gut motility and immunity. Moreover, the microbiota has been shown to affect mood; germ free mice have an overactive hypothalamic-pituitary-adrenergic (HPA) axis which is associated with negative emotion.
Synapse concept degenerative disease neurological disease Alzheimer
Synapse concept degenerative disease neurological disease Alzheimer's, dementia, cognitive process. Image Credit: CI Photos / Shutterstock
Corroborating this finding is a study which demonstrated that administration of the probiotic B. infantis reduced serotonin breakdown in the brain, suggesting this probiotic species possesses antidepressant properties.
Other neurotransmitters produced by the microbiota include gamma-aminobutyric acid (GABA), and catecholamines, such as norepinephrine and dopamine, all of which are key modulators of the neuroendocrine system.
The microbiota may also release gases which act as neurotransmitters. These include nitric oxide (NO) and hydrogen sulfide (H2S). These produce a physiological effect on the gut; NO is derived from Nitric Oxide Synthase (bNOS) enzyme, whilst H2S is derived from bacterial metabolism of cystine. Both inhibit smooth muscle cells, and so researchers have speculated that this effect could aid in the control of glycemia as inhibition of proximal gut motility has been shown to improve this condition.
Microbial components – a role as endocrine effectors?
Aside from bacterial metabolites, specific bacterial components may also act as factors modulating host endocrine functions. They act by interacting with receptors expressed locally or distally by the host. The bacterial caseinolytic protease B (ClpB) is host peptide which acts as a conformational mimetic of α-melanocyte-stimulating hormone (a- MSH) which regulates energy homeostasis in humans.
ClpB is associated with increased food intake; concomitantly, mice with strains of E. coli lacking ClpB synthesis show altered food behaviors compared to control mice. This confirms the role of ClpB in the modulation of host food intake.
Another bacterial protein capable of affecting host metabolism has been discussed in a study in which administration of the outer membrane protein Amuc_1100 of A. muciniphila was shown to improve the gut barrier function and shows some of the beneficial effects in the gut seen in the case of live bacterium.
The role of the gut microbiome as an endocrine organ itself as well as a partner to the human endocrine system is supported by several studies. However, the exact role that each microbial species plays and the full complement of the molecules they produce remains to be determined. Nonetheless, as the research continues to culminate, the ability to harness this bacterial power for the purposes of therapeutic application becomes possible.
Sources
Plovier, H. et al. (2017) A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nature Medicine. DOI: https://doi.org/10.1038/nm.4236
Nohr, M.K. et al. (2013) GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology. DOI: https://doi.org/10.1210/en.2013-1142
Cani, P.D. et al. (2006) Oligofructose promotes satiety in healthy human: a pilot study. European Journal of Clinical Nutrition. DOI: https://doi.org/10.1038/sj.ejcn.1602350
Koh, A. et al. (2018) Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell. DOI: https://doi.org/10.1016/j.cell.2018.09.055
De Mello, V.D. et al. (2017) Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study. Scientific Reports. DOI: https://doi.org/10.1038/srep46337
Chimerel, C. et al. (2014) Bacterial Metabolite Indole Modulates Incretin Secretion from Intestinal Enteroendocrine L Cells. Cell Reports. DOI: https://doi.org/10.1016/j.celrep.2014.10.032
Smolinska, S. et al. (2014) Histamine and gut mucosal immune regulation. Allergy. DOI: https://doi.org/10.1111/all.12330
Barcik, W. et al. (2016) Histamine-secreting microbes are increased in the gut of adult asthma patients. The Journal of Allergy and Clinical Immunology. DOI: https://doi.org/10.1016/j.jaci.2016.05.049
Sudo, N. et al. (2004) Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. The Journal of Physiology. DOI: https://doi.org/10.1113/jphysiol.2004.063388
Asano, Y. et al. (2012) Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. The American Journal of Physiology-Gastrointestinal and Liver Physiology. DOI: https://doi.org/10.1152/ajpgi.00341.2012
Adak, S. et al. (2002) Direct evidence for nitric oxide production by a nitric-oxide synthase-like protein from Bacillus subtilis. Journal of Biological Chemistry. DOI: https://doi.org/10.1074/jbc.M201136200
Blachier, F. et al (2019) Cysteine-derived hydrogen sulfide and gut health: a matter of endogenous or bacterial origin. Current Opinion in Clinical Nutrition & Metabolic Care. DOI: https://doi.org/10.1097/MCO.0000000000000526
Further Reading
Download PDF Copy
Hidaya Aliouche, B.Sc.
By Hidaya Aliouche, B.Sc.
Skip to:
What are the different metabolites produced?
Can microbiota control brain function?
Microbial components – a role as endocrine effectors?
Whilst the effect of the microbiome on the digestive system has been studied over the past decade, the understanding of its effect on the endocrine system is less well understood.
The endocrine system synthesizes and secrete hormones to regulate physiological processes. Interestingly the gut microbiome is an endocrine organ itself; metabolomic and metagenomic studies have revealed bacterial metabolites and components that affect organ function and subsequently, physiological outcomes. Bacterial- derived metabolites and components may act locally with the host, activating cell receptors or neural terminations, as well as distally through circulatory dissemination. Their mechanism of action is varied- paracrine, endocrine and nervous - yet all converge on influencing endocrine function.
Bacteria Lactobacillus, 3D illustration. Image Credit: Kateryna Kon / Shutterstock
Bacteria Lactobacillus, 3D illustration. Image Credit: Kateryna Kon / Shutterstock
What are the different metabolites produced?
The human gastrointestinal system is unable to digest all carbohydrates. Typically, these indigestible carbohydrates are referred to as dietary fiber, and reach the gut microbiota in the lower GI tract where they are subject to enzymic breakdown. This yields several classes of compounds, the most well studied of which, are the short chain fatty acids (SCFAs). The impact of SCFAs on human health is very well documented in the literature; they act both locally and in an endocrine manner, reaching distal sites such as the liver, adipose tissue, muscle and brain. Subsequently their physiological effects are wildly variable, effecting energy regulation, inflammation and the modulation of cancer.
Beginning with the digestive system, studies have demonstrated that changes in gut peptide production can occur following modification of dietary fiber intake or gut microbiome modification. For example, studies have implicated nondigestible carbohydrate intake in gut microbiome modulation to increase satiety and reduce food intake to reduce energy intake. Oligofructose-induced modulation of the gut microbiome produces this effect and were noncommittal with higher blood GLP-1 and PYY levels, key anti-obesity regulators.
Other than carbohydrates, amino acids (particularly branched chain amino acids (BCAAs)) have been correlated with physiological occurrences, namely insulin resistance. BCAAs have been shown in several studies, to originate endemically from the gut microbiota. In insulin resistant individuals, the with enzymes for BCAAs biosynthesis are enriched.
A pioneering study by F. Backhed demonstrated that the metabolization of histidine by microbiota to imidazole propionate directly contributes to glucose dysregulation via activation of the p38g/p62/mTORC1 pathway. This culminates in inhibition of IRS, the insulin receptor substrate that binds insulin and instigates cell signaling in response to this. However, not all amino acid derived microbial metabolites are correlated with insulin resistance or glucose sensitivity; for example, microbiota metabolize tryptophan to produce molecules such as indoles and their derivatives. These have been shown to act as endocrine molecules and activate the aryl hydrocarbon receptor (AhR). Indole propionic acid (IPA) for example, has been shown to improve metabolism by strengthening the gut barrier function and immune response as well as producing anti-inflammatory effects.
Related Stories
Whole body vibration helps reduce inflammation, thanks to the gut microbiome
Genetically tweaking gut bacteria reduces risk of colorectal cancer in mice finds study
Common antibacterial agent may be bad news for bone health
Recent studies have shown IPA lowers the risk of type II diabetes onsets by protecting the β cell function and increasing insulin release. Like SCFAs, indole and its derivative indole-3 acetate (I3A), modulate host metabolism by stimulating GLP-1 secretion from specialized enteroendocrine L-cells.
Can microbiota control brain function?
Gut microbes can produce the classical neurotransmitters of the brain. Their effect is communicated via the enteric nervous system, which is connected to the autonomic nervous system (ANS). The effect of the neurotransmitters can be localized i.e. affecting motility and intestinal hormone release, or centralized, affecting mood and cognition. Examples include histamine; this is derived from histidine and has been shown to increase asthma in humans, suggesting its role in immune modulation. Another neurotransmitter produced is serotonin and this has been implicated in several physiological processes including gut motility and immunity. Moreover, the microbiota has been shown to affect mood; germ free mice have an overactive hypothalamic-pituitary-adrenergic (HPA) axis which is associated with negative emotion.
Synapse concept degenerative disease neurological disease Alzheimer
Synapse concept degenerative disease neurological disease Alzheimer's, dementia, cognitive process. Image Credit: CI Photos / Shutterstock
Corroborating this finding is a study which demonstrated that administration of the probiotic B. infantis reduced serotonin breakdown in the brain, suggesting this probiotic species possesses antidepressant properties.
Other neurotransmitters produced by the microbiota include gamma-aminobutyric acid (GABA), and catecholamines, such as norepinephrine and dopamine, all of which are key modulators of the neuroendocrine system.
The microbiota may also release gases which act as neurotransmitters. These include nitric oxide (NO) and hydrogen sulfide (H2S). These produce a physiological effect on the gut; NO is derived from Nitric Oxide Synthase (bNOS) enzyme, whilst H2S is derived from bacterial metabolism of cystine. Both inhibit smooth muscle cells, and so researchers have speculated that this effect could aid in the control of glycemia as inhibition of proximal gut motility has been shown to improve this condition.
Microbial components – a role as endocrine effectors?
Aside from bacterial metabolites, specific bacterial components may also act as factors modulating host endocrine functions. They act by interacting with receptors expressed locally or distally by the host. The bacterial caseinolytic protease B (ClpB) is host peptide which acts as a conformational mimetic of α-melanocyte-stimulating hormone (a- MSH) which regulates energy homeostasis in humans.
ClpB is associated with increased food intake; concomitantly, mice with strains of E. coli lacking ClpB synthesis show altered food behaviors compared to control mice. This confirms the role of ClpB in the modulation of host food intake.
Another bacterial protein capable of affecting host metabolism has been discussed in a study in which administration of the outer membrane protein Amuc_1100 of A. muciniphila was shown to improve the gut barrier function and shows some of the beneficial effects in the gut seen in the case of live bacterium.
The role of the gut microbiome as an endocrine organ itself as well as a partner to the human endocrine system is supported by several studies. However, the exact role that each microbial species plays and the full complement of the molecules they produce remains to be determined. Nonetheless, as the research continues to culminate, the ability to harness this bacterial power for the purposes of therapeutic application becomes possible.
Sources
Plovier, H. et al. (2017) A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nature Medicine. DOI: https://doi.org/10.1038/nm.4236
Nohr, M.K. et al. (2013) GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology. DOI: https://doi.org/10.1210/en.2013-1142
Cani, P.D. et al. (2006) Oligofructose promotes satiety in healthy human: a pilot study. European Journal of Clinical Nutrition. DOI: https://doi.org/10.1038/sj.ejcn.1602350
Koh, A. et al. (2018) Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell. DOI: https://doi.org/10.1016/j.cell.2018.09.055
De Mello, V.D. et al. (2017) Indolepropionic acid and novel lipid metabolites are associated with a lower risk of type 2 diabetes in the Finnish Diabetes Prevention Study. Scientific Reports. DOI: https://doi.org/10.1038/srep46337
Chimerel, C. et al. (2014) Bacterial Metabolite Indole Modulates Incretin Secretion from Intestinal Enteroendocrine L Cells. Cell Reports. DOI: https://doi.org/10.1016/j.celrep.2014.10.032
Smolinska, S. et al. (2014) Histamine and gut mucosal immune regulation. Allergy. DOI: https://doi.org/10.1111/all.12330
Barcik, W. et al. (2016) Histamine-secreting microbes are increased in the gut of adult asthma patients. The Journal of Allergy and Clinical Immunology. DOI: https://doi.org/10.1016/j.jaci.2016.05.049
Sudo, N. et al. (2004) Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. The Journal of Physiology. DOI: https://doi.org/10.1113/jphysiol.2004.063388
Asano, Y. et al. (2012) Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. The American Journal of Physiology-Gastrointestinal and Liver Physiology. DOI: https://doi.org/10.1152/ajpgi.00341.2012
Adak, S. et al. (2002) Direct evidence for nitric oxide production by a nitric-oxide synthase-like protein from Bacillus subtilis. Journal of Biological Chemistry. DOI: https://doi.org/10.1074/jbc.M201136200
Blachier, F. et al (2019) Cysteine-derived hydrogen sulfide and gut health: a matter of endogenous or bacterial origin. Current Opinion in Clinical Nutrition & Metabolic Care. DOI: https://doi.org/10.1097/MCO.0000000000000526
Further Reading
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Aug 14, 2019, 1:40:08 AM8/14/19
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Int J Eat Disord. 2016 Aug;49(8):805-8. doi: 10.1002/eat.22531. Epub 2016 Apr 1.
Elevated plasma concentrations of bacterial ClpB protein in patients with eating disorders.
Breton J1,2, Legrand R1,2, Akkermann K3, Järv A4, Harro J3, Déchelotte P1,2,5, Fetissov SO1,2.
Author information
1
Nutrition, Gut and Brain Laboratory, Inserm UMR1073, Rouen, 76183, France.
2
Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, 76000, France.
3
Department of Psychology, Estonian Centre of Behavioural and Health Sciences, Tartu, 50409, Estonia.
4
Tartu University Clinics, Psychiatric Hospital, University of Tartu, Tartu, 50417, Estonia.
5
CHU Charles Nicolle, Rouen University Hospital, Rouen, 76183, France.
Abstract
OBJECTIVE:
Caseinolytic protease B (ClpB) produced by Enterobacteria, such as Escherichia coli, has been identified as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic and anxiogenic neuropeptide. In mice, ClpB induces α-MSH cross-reactive antibodies and activates anorexigenic brain neurons. In patients with eating disorders (ED), anti-ClpB and anti-α-MSH antibodies correlate with psychopathological traits. However, it is not known if ClpB is present in human plasma including ED patients.
METHODS:
Plasma concentrations of ClpB were measured using a recently developed ClpB immunoassay in female patients with anorexia nervosa, bulimia nervosa, and binge-eating disorder and compared with healthy participants, all characterized by the Eating Disorder Inventory-2 (EDI-2) scale.
RESULTS:
We found that ClpB was readably detectable in plasma of healthy participants and ED patients and that its concentrations were elevated in ED patients, without significant differences in patient's subgroups. Plasma ClpB concentrations correlated with the EDI-2 scores, with α-MSH as well as with plasma levels of anti-ClpB and anti-α-MSH antibodies.
DISCUSSION:
These data revealed that bacterial ClpB is naturally present in human plasma and that its concentrations can be elevated in ED patients and associated with ED-related psychopathological traits. These results support a link between bacterial ClpB and the ED pathophysiology. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:805-808).
© 2016 Wiley Periodicals, Inc.
KEYWORDS:
AdvancedHelp
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Format: AbstractSend to
Int J Eat Disord. 2016 Aug;49(8):805-8. doi: 10.1002/eat.22531. Epub 2016 Apr 1.
Elevated plasma concentrations of bacterial ClpB protein in patients with eating disorders.
Breton J1,2, Legrand R1,2, Akkermann K3, Järv A4, Harro J3, Déchelotte P1,2,5, Fetissov SO1,2.
Author information
1
Nutrition, Gut and Brain Laboratory, Inserm UMR1073, Rouen, 76183, France.
2
Institute for Research and Innovation in Biomedicine (IRIB), Rouen University, Normandy University, Rouen, 76000, France.
3
Department of Psychology, Estonian Centre of Behavioural and Health Sciences, Tartu, 50409, Estonia.
4
Tartu University Clinics, Psychiatric Hospital, University of Tartu, Tartu, 50417, Estonia.
5
CHU Charles Nicolle, Rouen University Hospital, Rouen, 76183, France.
Abstract
OBJECTIVE:
Caseinolytic protease B (ClpB) produced by Enterobacteria, such as Escherichia coli, has been identified as a conformational mimetic of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic and anxiogenic neuropeptide. In mice, ClpB induces α-MSH cross-reactive antibodies and activates anorexigenic brain neurons. In patients with eating disorders (ED), anti-ClpB and anti-α-MSH antibodies correlate with psychopathological traits. However, it is not known if ClpB is present in human plasma including ED patients.
METHODS:
Plasma concentrations of ClpB were measured using a recently developed ClpB immunoassay in female patients with anorexia nervosa, bulimia nervosa, and binge-eating disorder and compared with healthy participants, all characterized by the Eating Disorder Inventory-2 (EDI-2) scale.
RESULTS:
We found that ClpB was readably detectable in plasma of healthy participants and ED patients and that its concentrations were elevated in ED patients, without significant differences in patient's subgroups. Plasma ClpB concentrations correlated with the EDI-2 scores, with α-MSH as well as with plasma levels of anti-ClpB and anti-α-MSH antibodies.
DISCUSSION:
These data revealed that bacterial ClpB is naturally present in human plasma and that its concentrations can be elevated in ED patients and associated with ED-related psychopathological traits. These results support a link between bacterial ClpB and the ED pathophysiology. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:805-808).
© 2016 Wiley Periodicals, Inc.
KEYWORDS:
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In a nutshell, this bacteria can cause anti bodys which attack melanocyte stimulating hormone which may be contributing to obesirty.
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May 1, 2021, 4:12:05 PM5/1/21
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https://www.youtube.com/watch?v=41IfdwLqtkA Gut microbiome gaining importance in understanding the inflammation response. This is shedding light on maybe why in Parkinson's PD that when cutting the Vagus nerve seems to be remedial. (90% of the nerve fibers go from the intestine to the brain in Vagus. Transplant of colon content from humans to mice can transfer obesity. Thousands more bacteria strains in a Amazonian neolithic lifestyle gut then in not from jungle. Hospitals are found to have areas of microbiome.
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Jun 18, 2021, 1:38:17 AM6/18/21
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The Probiotic Strain H. alvei HA4597® Improves Weight Loss in Overweight Subjects under Moderate Hypocaloric Diet: A Proof-of-Concept, Multicenter Randomized, Double-Blind Placebo-Controlled Study
1
Inserm UMR 1073, 76000 Rouen, France
2
Nutrition Department, University Hospital, 76000 Rouen, France
3
Department of Biology, Rouen Normandy University, 76130 Mont-Saint-Aignan, France
4
TargEDys SA, 91160 Longjumeau, France
5
Practice for General Medicine, 12169 Berlin, Germany
6
Analyze & Realize GmbH, 13467 Berlin, Germany
7
Inserm UMR 1239, 76130 Mont-Saint-Aignan, France
*
Author to whom correspondence should be addressed.
Academic Editor: Margarita Aguilera
Nutrients 2021, 13(6), 1902; https://doi.org/10.3390/nu13061902
Received: 23 April 2021 / Revised: 27 May 2021 / Accepted: 30 May 2021 / Published: 1 June 2021
(This article belongs to the Section Prebiotics and Probiotics)
Background: Increasing evidence supports the role of the gut microbiota in the control of body weight and feeding behavior. Moreover, recent studies have reported that the probiotic strain Hafnia alvei HA4597® (HA), which produces the satietogenic peptide ClpB mimicking the effect of alpha-MSH, reduced weight gain and adiposity in rodent models of obesity. Methods: To investigate the clinical efficacy of HA, 236 overweight subjects were included, after written informed consent, in a 12-week prospective, double-blind, randomized study. All subjects received standardized counselling for a −20% hypocaloric diet and were asked to maintain their usual physical activity. Subjects of the HA group received two capsules per day providing 100 billion bacteria per day and subjects in the Placebo (P) group received two placebo capsules. The primary endpoint was the percentage of subjects achieving a weight loss of at least 3% after 12 weeks. Intention-to-treat statistical analysis was performed using exact-Fischer, Mann-Whitney and paired-Wilcoxon tests as appropriate. Results: In the HA group, significantly more subjects (+33%) met the primary endpoint than in the P group (54.9 vs. 41.4%, p = 0.048). In the HA group, an increased feeling of fullness (p = 0.009) and a greater loss of hip circumference (p < 0.001) at 12 weeks were also observed. Fasting glycemia at 12 weeks was significantly lower (p < 0.05) in the HA compared to P group. Clinical and biological tolerance was good in both groups. Conclusions: A 12-week treatment with the probiotic strain H. alvei HA4597® significantly improves weight loss, feeling of fullness and reduction of hip circumference in overweight subjects following moderate hypocaloric diet. These data support the use of H. alvei HA4597® in the global management of excess weight.
1. Introduction
2.2. Study Design and Intervention3.2.2. Secondary and Post-Hoc Endpoints
Excess weight, defined as overweight and obesity, is a global public health concern, with a rapid increase of prevalence and multiple complications [1]. Thus, efficient therapeutic strategies are needed to limit the progression of weight gain. Multifactorial approaches have been proposed, based mainly on dietetic and behavioral changes [2], while pharmacotherapy for obesity or binge eating disorder remains of limited efficacy and poor tolerance for most drugs [3,4]. Over the last decade, intensive effort in gut microbiota’s research allowed to elucidate distinct bacterial signaling pathways related to host energy harvesting, fat deposition, inflammation and insulin resistance in obesity [5,6]. Moreover, a role of gut microbiota in the regulation of host appetite and feeding behavior has been demonstrated in the physiological and pathological situation [7,8]. For instance, gut bacteria-derived proteins interact with host satiety signaling via stimulating the release of intestinal hormones such as glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), and may also activate anorexigenic pathways in hypothalamic and brainstem nuclei [9]. It appears hence interesting to develop new therapeutic strategies for body weight management targeting gut microbial influence on appetite and/or satiety to prevent overeating and progressive overweight and obesity [10]. Therefore, the use of probiotics to achieve anti-obesity effects has been proposed. The potential mechanisms of action of classic probiotics involve the reset of the consequences of gut microbial dysregulations, including reduction of fat storage, promotion of fatty acid oxidation and reduction of low-grade inflammation [11,12,13]. A new way of preventing excess weight gain may rely on the activation of the anorexigenic pathways [8,9,10]. We previously reported that increased production of ClpB by commensal bacteria was associated with increased anorexigenic effects of bacterial proteins administered in normal rats [9].
To achieve such effects in humans, the probiotic strain Hafnia alvei HA4597®(HA) currently seems a promising candidate. Indeed, this new generation precision probiotic produces the caseinolytic protease B (ClpB) protein, identified as a conformational mimetic of the anorexigenic α-melanocyte-stimulating hormone (α-MSH) [6,8,9,14]. Treatment with HA of obese high-fat-diet (HFD)-fed and leptin-deficient ob/ob hyperphagic mice decreased their body weight gain, fat-mass gain and reduced food intake [15,16]. These effects were associated with reduced hyperglycemia, plasma total cholesterol and alanine aminotransferase, suggesting also an improvement in the metabolic consequences of these obesogenic conditions. Moreover, bacterial ClpB directly activates PYY secretion in the intestinal mucosa and the hypothalamic anorexigenic neurons [9,17]. Thus, early intervention in overweight subjects with this probiotic strain may represent an interesting opportunity to limit the evolution of excess weight gain and offer new perspectives for body weight management. Based on this strong preclinical background, the present study investigated the clinical efficacy of HA on weight loss in overweight subjects under moderate hypocaloric diet.
2. Materials and Methods2.1. Study ParticipantsEligible subjects included into the study were overweight (body mass index, BMI: 25–29.9 kg/m2) males and females between 18 and 65 years old, generally in good health with a stable body weight in the last 3 months prior to the study, stable concomitant medications, and, for women of childbearing age, a negative pregnancy test at first study visit as well as commitment to use contraceptive methods. Subjects with known allergy or sensitivity to any component of the investigational product were excluded from the study. Other exclusion criteria included untreated or non-stabilized thyroid gland disorder, hypertension, or type 1 or 2 diabetes, as well as gastrointestinal disorders or gastrointestinal surgery, acute chronic psychotic disorder, immunodeficiency, any other organic or systemic diseases that could influence the conduct and/or outcome of the study, history and/or presence of eating disorders, any electronic medical implant, clinically significant deviations of safety laboratory parameters at first study visit, use of medication or supplementation that could interfere with the study conduct or evaluation or diet/weight loss programs in the last month prior to the first study visit, any restrictive diet such as vegetarian or vegan, pregnancy or nursing, or a history of past or current abuse of drugs, alcohol, medication, participation in another study during the last 30 days prior to enrollment. Smoking itself was not an exclusion criterion. A total of 236 subjects gave written informed consent and were randomly assigned (see flow chart in Figure 1) to “HA” group or “Placebo (P)”, n = 118 for each group. The study protocol was approved by the Ethics Committee of Charité University Berlin and was performed according to the principles of the World Health Organization (Declaration of Helsinki), and of Good Clinical Practice (EMA/CHMP/ICH/135/1995), ICH E6 (R2). The current study has been registered on clinicaltrials.gov (https://clinicaltrials.gov/ct2/show/NCT03657186?term=Hafnia&draw=2& rank=1; (accessed on 4 September 2018)).
Figure 1. Flowchart illustrating the steps of screening, enrollment, assignment and follow-up of study participants for the Intent To Treat (ITT) and Per Protocol (PP) analysis.
This placebo-controlled, randomized, double-blind explorative study design was conducted to evaluate the benefits of Hafnia alvei HA4597® (HA) on weight reduction in the context of a moderate hypocaloric diet in overweight subjects. An estimation of the sample size has been based on data from previous weight management trials with natural products in addition to dietetic counseling [18,19]. In these studies, the proportion of subjects who lost at least 3% of baseline body weight at 12 weeks (named as “3% responders”) for placebo were ranging roughly from 20% to 30% and for the tested verum products from 50% to 75%. Under the assumption for the present study that about 25% of subjects would have been “3% responders” in the placebo group at least 45% in the verum group, the estimated sample size needed per group was 100 subjects, supposing α = 5% (two-sided) and power of 80%. Taking into account the expected drop-out rate of 15%, a total of 236 subjects were randomized. After screening for inclusion and non-inclusion criteria, the investigational staff provided instructions from trained dietitians to subjects on how to maintain a nutritionally balanced and hypocaloric diet according to individual diet plans throughout the study. The individual energy requirements were calculated based on BMI and reported activity levels at screening (Institute of Medicine, Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) The National Academy Press, 2005), and energy intake was then reduced by 20%. Subjects were instructed to record their daily intake in diaries and not to increase their assigned energy intake by more than 10%, but to freely decrease it. They were also instructed to maintain their usual physical activity level. Subjects were then randomized (see flowchart in Figure 1) to receive either the investigational study product (IP) containing Hafnia alvei or placebo capsule twice daily, for a total dose of 100 billion bacteria per day in the HA group. The H. alvei HA4597® strain is manufactured for TargEDys SA by Biodis (Noyant, France).
2.3. Measurements and EndpointsClinical parameters including body weight measurements were collected every 4 w until 12 w after randomization and treatment initiation. Body weight (measured using calibrated weighing scales, BC-420MA, Tanita, la Garenne Colombe, FRANCE la, body fat and fat free mass (assessed by bioelectrical impedance analysis, BIA, Tanita Body Composition Analyzer BC-420-MA), BMI (body weight (kg)/(height [m])²), waist and hip circumferences, blood pressure, pulse, laboratory parameters (lipid and carbohydrate metabolism parameters total cholesterol, HDL- and LDL-cholesterol, fasting glucose, and HbA1c), evaluation of the feeling of satiety, fullness, and craving, general well-being parameters (IWQOL-LITE), and global evaluation of benefit of the investigational product (IP) by subject and investigator were also analyzed. The primary endpoint was the proportion of subjects who lost at least 3% of baseline body weight (“3% responders”) at week 12. The secondary endpoints were the feeling of satiety and fullness, the reduction of waist and hip circumferences, the changes in body composition and IWQOL-LITE. The proportion of subjects who lost at least 4% of baseline body weight (“4% responders”) at week 12 was also analyzed as a post-hoc endpoint.
Safety and tolerability parameters included assessment of adverse events (AE), vital signs (blood pressure, pulse rate), safety laboratory parameters and global evaluation of tolerability of HA or P by subject and investigator. Biological parameters used for safety blood parameters were full blood count parameters (hemoglobin, hematocrit, erythrocytes, thrombocytes, and leucocytes) and liver and renal function parameters (alanine transaminase, aspartate aminotransferase, gamma-GT, alkaline phosphatase, bilirubin, creatinine, urea, and uric acid). Other parameters assessed during the course of the study included stool frequency (assessed in subject diary), global physical activity according to the Global Physical Activity and gastrointestinal symptoms according to the Gastrointestinal Symptom Rating Scale [20], both filled in by the subjects.
2.4. Statistical AnalysisAll endpoints as well as the concurrent and safety variables received an explorative examination and were descriptively assessed. For metric data (continuous data), the statistical characteristics were given (number, mean, standard deviation, median, extremes, quartiles). For ordinal data (discrete data), number, median, interquartile range and extremes were calculated. For nominal data, the frequency distribution was presented in frequency tables.
The following exploratory statistical tests were applied:
- Mann-Whitney-U test for comparison of independent groups (u),
- Paired Wilcoxon test for the pre-post comparisons within groups (wil),
- Exact Fisher’s test for the comparison of frequencies for independent groups (exF).
Because of the exploratory character of the study, no adjustment for multiple testing was accomplished. Data were analyzed according to Intention to treat (ITT), Per Protocol (PP) and safety set.
Safety set included all subjects who were randomized and had consumed the investigational product (IP) at least once. In cases where all dispensed IP was returned, the subject was to be considered “non-treated” and was not to be included in the safety set. The ITT set consisted of all subjects in the safety set for whom main benefit parameter (body weight) was available. The PP set consisted of all subjects in the ITT terminating the study without any important deviation of the protocol and its procedures.
Subjects who had been enrolled in the study according to the inclusion/exclusion criteria, but who were later found to have an important protocol deviation against these criteria at the time point of inclusion in the study (noticed during the study or during the process of data cleaning) were excluded from the ITT, but remained in the Safety population. The protocol deviations were classified as ‘minor’ or ‘major’ in the blinded Data Review Report. Important (‘major’) deviations led to the exclusion of a subject from the PP.
3. Results3.1. SubjectsOf 300 subjects assessed for eligibility, 236 subjects were randomized. Of these, six subjects terminated the study immediately after randomization and were excluded from all analysis populations, leaving a set of 230 subjects for the ITT analysis. Six subjects terminated the study after visits at 4w and two others after visit at 8w; nine subjects had major deviations with respect to compliance with IP intake, and one subject had a major deviation regarding compliance with energy intake. Thus, these eighteen subjects were excluded from the ITT population, leaving a set of 212 subjects for the PP analysis. The age of the subjects ranged between 20 and 65 years in HA group and 23 and 65 years in P group. There were no statistical differences in age, gender or other physical/physiological characteristics between the study groups (Table 1).
3.2. Effects of the Probiotic strain HA4597®3.2.1. Primary EndpointIn both ITT and PP population, the proportion of subjects who lost at least 3% of baseline body weight was significantly higher in the HA group (54.9% and 57.7%), compared to the placebo group (41.4% and 41.7%, for ITT and PP, respectively) after 12 weeks (p = 0.048 and 0.028, respectively), as displayed in Figure 2A,B.
Figure 2. Effect of HA supplementation on the proportion of responders losing at least 3% of body weight. Proportion of overweight subjects losing at least 3% of body weight in ITT (A) and PP (B) populations. (A,B) Exact Fisher’s test P. vs. HA.* p ≤ 0.05.
Similarly to the primary endpoint, a higher proportion of responders with at least 4% of body weight loss was found, both in ITT and PP population, in the HA (44.2% and 46.2%) compared to the P group (29.3% and 30.6%, for ITT and PP, respectively) at week 12 (p = 0.020 and 0.024, respectively), as displayed in Figure 3A,B.
Figure 3. Proportion of responders losing at least 4% of body weight after 12 HA supplementation. Proportion of HA treated subjects losing at least 4% of body weight in ITT (A) and PP (B) populations. Exact Fisher’s test P. vs. HA.* p ≤ 0.05.
Accordingly, the BMI reduction in PP population was significantly higher in HA compared to P groups (0.97 kg/m2 vs. 0.82 kg/m2, pU = 0.048). Absolute weight values at week 12 were not significantly different in the ITT analysis. In both groups, weight loss compared to baseline was significant: 2.89 kg (HA) and 2.49 kg (P). This difference (0.4 kg) was significant in PP (p = 0.046) with a trend in ITT population (0.3 kg; p = 0.10). No significant change was found in ITT population for either male (p = 0.12) or female (p = 0.28) subsets. A moderate, non-significant, increase of lean mass/fat mass ratio was found in both groups (Supplementary Table S1).
A significantly greater reduction of hip circumference at 12w was observed in the HA vs. P group in the ITT and PP population (Figure 4A,B). Waist circumference was not significantly changed in the ITT analysis while, in the PP analysis, a trend toward reduced waist circumference was observed in HA (−2.95 cm) compared to P (−2.76 cm) groups (pu = 0.10).
Figure 4. Changes in hip circumference following 12 weeks of HA supplementation in overweight subjects. Changes in Hip circumference following 12 weeks of HA supplementation compared to week 0 in ITT (A) and PP (B) population. (A,B) Mann-Whitney-U test (w12-w0)P. vs. (w12-w0)HA.*** pU ≤ 0.001.
The feeling of fullness at baseline was low in both groups (Figure 5). It increased significantly at 12 w in the HA (p = 0.01) versus P group (ITT and PP analysis, Figure 5A,B). The change in feeling of fullness from baseline to 12 w (Figure 5C,D) tended also (p = 0.085) to be higher in the HA group (8.24 mm Visual Analogue Scale; VAS) compared to P group (1.92 mm VAS). There were no differences between the groups for the feelings of satiety and craving (data not shown).
Figure 5. Feeling of fullness in overweight subject treated with HA under hypocaloric diet. Feeling of fullness in ITT (A) and PP (B) populations. Changes in the feeling of fullness over 12 weeks of HA supplementation in ITT (C) and PP (D) population. (A,B) Mann-Whitney-U test (w12)P. vs. (w12)HA.** pU ≤ 0.01.*pU ≤ 0.05. (C) Mann-Whitney-U test; (w12-w0)P. vs. (w12-w0)HA.* pU ≤ 0.05. Paired Wilcoxon test; HA(w0) vs. HA(w12).** pwi ≤ 0.01 (D) Mann-Whitney-U test; (w12-w0)P. vs. (w12-w0)HA.* pU ≤ 0.05. Paired Wilcoxon test; HA(w0) vs. HA(w12).* pwi ≤ 0.05.
Gastrointestinal tolerance was good in both groups. Interestingly, a higher proportion of subjects in HA versus P groups reported a reduction of upper gastrointestinal (GI) symptoms at 12 w versus baseline (pHA = 0.003 and pP = 0.16, ITT analysis). Apart from this, no differences between groups were observed in changes of other GI symptoms.
3.2.3. Clinical and Biological Safety EvaluationNo safety concern was observed both for clinical (data not shown) and biological safety parameters (Table 2). In ITT analysis, fasting glycemia was significantly lower at week 12 in the HA versus P group (pU = 0.027). There were no significant differences between groups regarding haemoglobin, haematocrit, erythrocytes, thrombocytes, leukocytes, ALAT, ASAT AP, gGT, bilirubin, creatinine, urea, uric acid, HbAc1, cholesterol and triglycerides. There were no difference in physical function domain of the IWQOL-LITE (pU = 0.637), systolic or diastolic blood pressure or pulse rates between the study groups, according to inclusion criteria, at the screening visit. Quality of life was not different between groups at 12w (ITT analysis) for the global IWQOL-LITE score and for any of the domains.
3.2.4. Global Evaluation of Efficacy and Tolerability and Adverse Events (AE)In the HA group, benefit of treatment (Figure 6) was rated as “very good” or “good” by 67.9% of subjects compared to 53.1% of subjects in the placebo group (pU = 0.019). The blinded investigators rated the benefit as “very good” or “good” for 64.2% of subjects in the HA group compared to 51.3% of subjects in the placebo group (pU = 0.035). Rating was “poor” by 5% of the HA subjects versus 14.2% of the P group. Tolerability was assessed by subjects and investigators as “very good/good” in 98.2% of cases in both groups (1.8% ratings were “moderate”).
Figure 6. Global assessment of the treatment by the blinded subjects and investigators in the HA and P groups.
Regarding AE, 43 out of 236 subjects (18.2%) reported a total of 55 AE: 25 in the HA group (21.2%) and 18 in the P group (15.3%, no statistical difference, pexF = 0.312). None of the AE was classified as “serious adverse event”. The causal relationship of AE to IP was classified as “unlikely” in all cases, excepted 2 AE classified as “not assessable”, one in each group. The intensity of AE was “mild” for 33 AE (22 subjects in the HA group, 11 subjects in the placebo group) and “moderate” in 22 AE (eight in the HA group and 14 in the P group). No AE was classified as “severe”.
4. DiscussionThe present study investigated in overweight subjects the clinical efficacy of H. alvei HA4597®, a probiotic strain expressing ClpB, an α-MSH mimetic protein, and the main endpoint confirmed a higher rate of significant weight loss in subjects receiving HA in addition to hypocaloric diet. Increasing evidence has accumulated on the capacity of the gut microbiota to contribute to the regulation of body weight, body composition as well as host feeding behavior [6,21,22,23]. Accordingly, dietary interventions, including pre- and probiotics have been used to influence these parameters via modulation of gut microbiota composition in overweight and obese individuals, as well as in malnourished patients [24,25,26,27].
Several conventional probiotics have been proposed for obesity, including Lactobacillus (L. casei, L. gasseri, L. plantarum, L. rhamnosus) and Bifidobacterium (B. infantis and B. longum) species [11,28,29,30]. However, until now, the mechanisms by which these strains may reduce excess weight remain unclear and their clinical efficacy has not yet been demonstrated convincingly [11,28,29]. More specifically, none of these probiotics have been reported to stimulate satietogenic pathways. In contrast, in the present study, we show that the supplementation with H. alvei HA4597® increased significantly the proportion of overweight subjects losing at least 3% and even 4% of baseline body weight while following a hypocaloric diet over 12 weeks. Recent expert guidelines underline that aiming to lose 3–5% of body weight is a meaningful objective for overweight patients, since this change has been associated with clinically significant improvements such as reduced blood glucose, reduction of type-2 diabetes and cardiovascular risks [2]. Thus, our main finding of a better rate of weight loss at the level of 3% (ITT) and even 4% should be considered as clinically relevant to reduce the risk of later complications [2]. In addition, it was associated with reduced hip circumference, and a slight yet significant reduction of blood glucose. In previous studies in overweight or obese patients with full dose treatment (120 mg tid) of orlistat, the increase of percentage of patients achieving 5% weight loss after one year ranged 18–24% [31]. Thus, our finding of a 32% increase of 3% weight loss responders over 12 weeks (primary endpoint) and 50% increase of 4% weight loss responders (post-hoc endpoint) competes well with results with orlistat. It is common finding with drugs targeting overweight and obesity to report responders and non-responders [3], which reflects the heterogeneity of the underlying mechanisms and the different mechanisms of action of the drugs, and a high “placebo effect”.
In our study, the placebo effect was a combination of the dietetic received by both groups and the placebo itself; despite a high response rate in the P group (41.4% at the 3% level and 29.3% at the 4% level), we were able to detect a marked, significant, increase in response rate. This specific benefit of HA supplementation was observed in addition to the effect of the hypocaloric diet followed by subjects in both groups. This may be related to the increased feeling of fullness in the HA group, that is likely to have made it easier for subjects to follow the diet and led to a greater global satisfaction. Accordingly, Figure 6 indicates a marked difference of perception of efficacy between the HA and P groups, both for subjects and for physicians. Thus, three months of HA supplementation may help for developing durable and healthy dietary habits.
The observed improved rate of body weight reduction was most likely due to the effect of HA on eating behavior through the production of ClpB by HA. Indeed, the new-generation probiotic used in the present study has been technically developed to overproduce the ClpB protein and ultimately enhance the activation of peripheral and central satiating pathways through the activation of melanocortin receptor [15]. Indeed, the melanocortin system is a key regulator of energy metabolism via transmission of anorexigenic signals and also by enhancing energy expenditure and lipolytic effects [32]. Melanocortin receptors are also present in intestinal mucosa, i.e., directly accessible to gut bacteria-derived products such as ClpB [33]. Thus, although food intake estimated from patients’ diary did not allow to detect a significant difference, the achievement of the main endpoint of this double-blind study is likely to be related to the satietogenic effect of the probiotic supplementation. Nevertheless, we cannot exclude that a better reduction of body weight and hip circumference in the HA group may also involve some direct lipolytic and/or thermogenic effect of ClpB. It seems unlikely that such reduction was related to physical activity because it was asked to be maintained at a similar level in both groups.
The present clinical results are well in line with our previous demonstrations of the efficacy of HA supplementation in mouse models of obesity (HFD-fed and ob/ob hyperphagic mice). Indeed, obese mice supplemented with HA showed a significant reduction in body weight gain associated with reduced food intake as well as reduced fat mass gain [15,16]. Accordingly, in the present study, HA supplementation increased the feeling of fullness in subjects of the HA as compared to placebo-group. We did not observe a difference for the feeling of “satiety”; this may be related to the fact that “satiety” is less well defined and easy to identify for lay people than fullness. The effect on the feeling of fullness (i.e., enhancing satiation) is likely to have facilitated the compliance of the subjects to the hypocaloric diet limiting the risk of compensatory compulsive behavior, and it is in accordance with known effects of alpha-MSH and other melanocortin receptor agonists [34].
The rationale for supplementation of subjects with weight excess with ClpB-producing probiotic is further reinforced by the data showing a significant decrease of Enterobacterales ClpB gene richness in the fecal microbiota of obese patients [15]. An independent study also demonstrated that ClpB-like gene function in fecal microbiota correlated negatively with BMI and fat mass and that obese subjects displayed low prevalence of bacterial taxa expressing ClpB with alpha-MSH homology [35]. These recent findings are in agreement with an earlier observation of lower abundance of Enterobacteriaceae in obese subjects [36]. In contrast to obesity, bacterial ClpB production was increased in mice with the activity-based anorexia and in food-restricted rats [37,38]. Altogether, these findings suggest that a high abundance of bacteria expressing the ClpB gene such as HA4597® in the intestinal microbiota is associated with an enhanced satiety and reduced body weight.
In addition to a better weight loss response, HA supplementation significantly improved the reduction of hip circumference compared to placebo, and tended to decrease the waist circumference. The effects on waist circumference were, however, expected to be modest since the overweight subjects included in the present study did not exhibit a clinical pattern of excess visceral fat with metabolic syndrome features, but rather a subcutaneous fat accumulation. Therefore a combination of HA with physical activity able to reduce visceral fat needs to be addressed in a different study design, including obese patients with a visceral fat phenotype associated with insulin resistance, diabetes and related increased cardiovascular risk [39,40]. In line with the type of fat distribution observed in the subjects of this study, metabolic parameters were within the normal range at screening visit, without criteria for metabolic syndrome. After 12w of HA supplementation, plasma levels of fasting glucose were significantly lower in the HA group, however still in the normal range. This interesting result is in line with our preclinical findings in obese rodents [15] and warrants further investigations in prediabetes patients to evaluate a metabolic benefit of HA4597®. Recently, a probiotic approach targeting insulin resistance has been developed to compensate the depletion of Akkermansia muciniphila in the microbiota of obese and overweight patients with insulin resistance [41]. In this pilot study, Depommier and colleagues observed that A. muciniphila supplementation over 3 months improved insulin sensitivity, insulinemia, total cholesterol as well as other metabolic markers including hepatic enzymes (γ-glutamyl transferase and aspartate-aminotransferase). However, no significant changes in anthropometric parameters were observed, with only a trend toward decreased body weight (p = 0.09), fat mass (p = 0.09) and hip circumference (p = 0.09) compared to placebo, while no difference in waist circumference was reported among groups [41]. It is tempting to speculate that a combination of H. alvei HA4597®, A. muciniphila and eventually other probiotics may provide beneficial additive or synergistic anti-obesity and metabolic effects in obese patients.
Quality of life improved in both groups of the present study, without any differences between groups. Indeed, it has been previously reported that body weight loss was associated with improvement of quality of life in obese patients [42]. A longer duration of HA supplementation would be probably needed to result in a greater improvement of quality of life in treated than placebo subjects. Gastrointestinal tolerance was good and no specific adverse events have been reported by overweight subjects supplemented with HA. This underlines the commensal nature of HA and its wide safety margin [43,44]. The safety of our precision probiotic approach with H. alvei is worth to be underlined since many of the single or combined drugs proposed for the treatment of overweight or obesity have a poor tolerance profile [3,4]. Ex. appetite suppressing drugs sibutramine and rimonabant which targeted the central control of food intake have been withdrawn from the market, due to unacceptable serious side effects [3,31].
Due to technical constraints, a limitation of this study is the lack of data about intestinal satiety hormone production and fecal microbiota composition in subjects before and after HA supplementation. Such analysis would allow to see if the ClpB gene enrichment in the HA-supplemented subjects may correlate with the clinical efficacy of HA4597® and to determine its impact on other beneficial gut bacteria.
5. ConclusionsIn conclusion, this study demonstrates the efficacy of HA on body weight loss associated with a reduction of hip circumference and a greater feeling of fullness in overweight subjects. To the best of our knowledge, this is the first clear demonstration of the efficacy of a probiotic strain on weight loss and satiation in a prospective randomized placebo-controlled study. Supplementation with HA4597® represents an innovative and well-tolerated strategy to enhance the efficacy of dietary advice for the control of excess body weight; the “precision probiotic” HA4597® [45] paves the way to the precision medicine and nutrition by identifying responders thanks to a gut microbial-based personalized approach. Our probiotic should be further evaluated in conditions of excess fat accumulation and related metabolic disorders, as it may offer a safe and economically affordable alternative to the drugs recently licensed for the treatment of obesity.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/nu13061902/s1.
Author ContributionsConception of the technology: S.O.F., J.B., P.D., G.L., C.T.-P. Conception of the study protocol: P.D., C.T.-P., C.E., G.B., S.O.F., G.L. Inclusions, statistical analysis and report: B.G., C.E., G.B., G.L. Writing of the manuscript: J.B., P.D. All authors contributed to the revision of the manuscript and approved the final version. All authors have read and agreed to the published version of the manuscript.
FundingThis research was funded by TargEDys SA. Recruitment was performed under the supervision of Analyze & Realize.
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GUT CHECK
The condition has confounded scientists. Do bacteria in the gut hold any answers?
11 HOURS AGO
Multiple sclerosis still baffles scientists. Theories exist, but researchers still don’t understand what triggers the immune system to attack healthy nerves.
In a new study, researchers found that the microbiomes — the ecosystem of viruses, bacteria, and fungi that reside in our guts — of people with MS are distinct from those without the disease. Understanding why this difference exists could help researchers better understand and treat the condition.
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WHAT’S NEW — In a study published last month in the journal EBioMedicine, researchers found that a group of people with MS had markedly different bacterial ecosystems in their guts compared to a similar cohort without MS.
In multiple sclerosis, the immune system attacks the protective sheaths of nerve fibers, disrupting the communication between those nerves and our brains. Researchers do not know why people develop the condition and have been left with a baffling list of risk factors: Caucasians are more likely to develop MS, and women are more likely to develop one type. MS is more prevalent in colder climates, and a history of certain infections might play a role in triggering the condition.
To examine the disease from another angle, a team of researchers, led by Washington University School of Medicine and the University of Connecticut’s clinical health unit, looked at the eating habits and digestive and metabolic characteristics of 24 people newly diagnosed with the condition. MS patients enrolled in the study had markedly different blood metabolites and microbiome contents than people without MS. They also, on average, ate more than twice as much meat.
Further research is needed to determine the significance (if any) of these correlations and how they might contribute to an understanding of MS.
WHY IT MATTERS — Multiple sclerosis afflicts 2.3 million people globally and can be debilitating, sometimes causing severe handicaps.
Many treatments are available, but there is no cure, and scientists have been stifled by the enduring mystery of why the immune system mounts this attack on healthy nerves. So every new angle could help.
The gut microbiome helps train and develop the immune system. Researchers know that diet plays a crucial role in shaping what species reside in the gut and in what amounts, so perhaps there are insights to be taken from looking at the digestive and metabolic health of people with MS.
Yanjiao Zhou, one of the coauthors, tells Inverse that this small study is a first crack at examining MS from a new perspective — with the technology that allows scientists to sequence gut bacteria from a stool sample and identify the telling aftereffects of metabolism as seen in the bloodstream, plus the knowledge that all these facets are connected.
“This paper is really just to try to leverage all this technology together, and try [to] review the association between all these components,” she says.
Zhou says that some of the bacteria lacking in MS patients have anti-inflammation properties. Inflammation is correlated with a host of chronic conditions, particularly autoimmune ones.
Also, there were differences in the gut microbiomes between those with mild and severe symptoms, which “suggest[s] that specific gut microbes may be associated with the degree of disability in MS patients,” according to the paper.
The most significant dietary difference between the 24 MS patients and 25 healthy people recruited as a control group was meat consumption. The MS patients ate 2.7 servings of meat for every serving eaten by the control group.
Previous research into MS and meat consumption have had inconclusive results. One study showed a higher prevalence of MS among people with high animal fat intake and a lower prevalence in vegetarians. But another study found that people with increased consumption of non-processed red meat had a reduced risk for neurological activity associated with MS. The authors noted that red meat is high in vitamin D and other components that have a neuroprotective effect.
Investigating this further, the researchers behind the new paper used the microbiome data to determine that, in their pool of participants, high meat consumption was correlated with a lack of B. thetaiotaomicron, a gut bacteria that helps the stomach digest carbohydrates.
Interestingly, the presence of that same bacteria “was strongly negatively correlated” with high circulation of an immune system component called T helper 17 cells. Scientists have thought T helper 17 cells play a role in the immune system’s haywire behavior in MS.
But all of that is inconclusive. As for what this means for one of medicine’s most frustrating conditions, only time and further research will tell.
Study participants with MS ate twice as much red meat as those who did not have MS. Research on MS and meat consumption has largely been inconclusive.Shutterstock
HOW THEY DID IT — The researchers recruited 24 newly diagnosed patients with as-yet untreated MS.
They also recruited 25 healthy people and populated that group to match approximately the age, gender, race, and body mass index of the MS group. They used this control group to tabulate what was standard.
The researchers had both groups complete food diaries and submit blood and stool samples.
WHAT’S NEXT — Zhou and her collaborates would like to do another study with more people to test the consistency of these findings. They would also like to include people with more severe MS to investigate the finding further that the microbiome deviates even further from the norm depending on the severity of the disease.
GUT WEEK
WHY THE GUT MAY BE HUMANS’ “FIRST BRAIN”This is not science fiction.
11.26.2021 12:00 PM
WHETHER IT’S DIVING OFF A PIER into the salty waves below or stepping up to the podium to address a room full of people, you likely know what “butterflies in your stomach” feel like when they start fluttering away inside. In truth, of course, you are not full of literal butterflies — it’s just your brain talking. But this brain isn’t the one in your head: This brain is the one that runs all the way through your body from your mouth to your butt.
Humans have two brains (stay with us): Sometimes nicknamed the “mini-brain,” your gut has its own nervous system made up of more than 100 million neurons working autonomously from the brain in your head to regulate the digestive system.
INVERSE is counting down the ten most-surprising discoveries about your wondrous gut in 2021. This is #2. Read the original story here.
But like the brain in your skull, the enteric system isn’t a one-trick pony: It regulates the immune system, blood flow, and secretes hormones. It’s also in constant communication with the central nervous system, helping to regulate your emotions and mood. But for all we’ve learned about the enteric nervous system, a dozen more questions remain unanswered.
One question stems from the classic “chicken or the egg” problem.
WHICH CAME FIRST: THE CEREBRAL BRAIN OR THE GUT BRAIN?That the enteric nervous system evolved to function independently from the brain causes some researchers to argue that the so-called mini-brain came first — Nick Spencer, a professor at Flinders University in Australia, is one of them.
WHAT’S NEW — Earlier this year, Spencer and his colleagues published a study in support of the “first brain” theory. They showed how gut neurons evolved independently to communicate and control gut muscle movement — a key piece of evidence for that the gut’s nervous system may be our “first brain.”
In the study, Spencer and his colleagues find that neurons from the enteric nervous system send and receive messages to coordinate gut muscle movement. The firing of messages is synchronized to other neurons. Doing so is necessary to move items down for digestion, absorb nutrients from food, and expel waste products.
HERE’S THE BACKGROUND — Support for the ‘first brain’ theory ironically comes from animals without brains.
Freshwater creatures belonging to the genus Hydra have roamed the Earth for over 600 million years and yet, their tube-shaped bodies function without a brain.
How did Hydra survive for so long? According to Spencer, the hydra evolved a nervous system similar to today’s “gut brain.”
Hydra may be key to understanding how our own enteric nervous system evolved.CHOKSAWATDIKORN / SCIENCE PHOTO LIBRARY/Science Photo Library/Getty Images
“Despite the lack of a formal brain, as we know it, their intrinsic nervous system allows them to swim and feed and ingest food,” he says.
The enteric nervous system plays multiple roles but its main one involves moving food and other items in and out of the gut. The neurons cause muscles in the GI tract to contract and relax, allowing for digestion to take place.
WHY IT MATTERS — The study adds to the mountain of evidence for the gut’s starring role in your metabolism, brain function, and longevity. One recent study has even found that a diet feeding healthy gut bacteria could reduce multiple sclerosis symptoms.
And for better or for worse, increasing evidence has demonstrated the gut’s influence on your personality — it all depends on the diversity of your microbiome.
But like any other organ in the body, the enteric nervous system isn’t perfect. Studies like Spencer’s can help shift the needle on developing treatments that take this overlooked nervous system into account.
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GUT SCIENCE
SQUIRREL GUT STUDY COULD HELP TREAT A PAINFUL HUMAN CONDITIONBehold the wonders of the microbiome.
1.27.2022 1:17 PM
THE THIRTEEN-LINED SQUIRREL, aptly named for the thirteen stripes on its back, spends much of its time above ground dodging angry humans. But for several months of the year, it gets a reprieve: Like many mammals, this furry rodent spends the winter months hibernating away in its burrows. But rather unlike other hibernating creatures, it reemerges from its long slumber just as brawny as before. Now, scientists may have figured out how it maintains its muscular build without working out — and these findings could help doctors treat muscle wasting diseases in humans, too.
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