Tag Archives: Metabolites

Breast milk microbes shape infant gut health

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A new paper published in the Frontiers in Microbiology explores the contribution of human breast milk to the establishment of the infant gut microbiome.

Study: Human milk-associated bacterial communities associate with the infant gut microbiome over the first year of life. Image Credit: Pavel Ilyukhin / Shutterstock.com Study: Human milk-associated bacterial communities associate with the infant gut microbiome over the first year of life. Image Credit: Pavel Ilyukhin / Shutterstock.com

Introduction

Breastfeeding is encouraged as the first and exclusive food of infants for at least the first six months of life. In addition to its nutritional content, breast milk contributes significantly to the formation of the infant gut microbiome. This is because of its high content of immune cells, oligosaccharides carrying glycosyl residues, fatty acids, and some microbes.

Both breast milk bacteria and skin microbes from the maternal nipple reach and establish themselves in the infant’s gut. Bacteria may be shielded by secretory immunoglobulin A (sIgA) covering the immune system, thus allowing them to enter the gut intact.   

The infant gut microbiome (IGMB) is important for both infant development and immunity, as well as modulating conditions like atopy and body mass composition. However, earlier research on potential associations between the IGMB and breast milk microbiota has been limited to analyzing samples from corresponding time points.

The current study included almost 190 dyads from New Hampshire. Breast milk and infant stool samples were collected at around six weeks, four months, six months, nine months, and one year from birth, which allowed the scientists to identify correlations that developed over time.

What did the study show?

In the study population, with a mean age of 32 years, most were White and had a normal body mass index (BMI) during pregnancy. About 25% of deliveries occurred through Cesarean section (C-section), and antibiotic exposure prior to lactation occurred in over half of mothers.

Most babies were almost full term at birth, with only 3% being exposed to antibiotics by four months of life. By one year, about 30% of infants had been exposed to antibiotics.

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About 75% and 40% of infants did not receive any formula up to six weeks and four months, respectively. Most infants began eating solid food by six months.

Three breast milk microbiome types (BMTs) were identified in the six-week breast milk samples. These could be differentiated by the relative proportions of four bacterial genera, including Streptococcus, Staphylococcus, Pseudomonas, and Acinetobacter, as well as by the microbial diversity.

At six weeks, the gut microbiome in infants exhibited four six-week infant gut microbiome types (6wIGMTs). These had different abundances of Bifidobacterium, Bacteroides, Clostridium, Streptococcus, and Escherichia/Shigella.

The 6wIGMT correlated with the 6wBMT in male infants and those born by C-section. Notably, the same microbe was likely to be the most abundant within the dyads at this point.

By age one, the predominant difference in microbiome composition was due to Bacteroides. There was no association between the 6wBMT and 12mIGMT, which is likely due to the intake of solid foods by infants at this age. The transition to a primarily solid diet causes the infant microbiome to be dominated by other microbes, such as Bifidobacterium and Bacteroidetes, both of which are more abundant in the adult gut.

At six weeks, the BMT was associated with 6wIGMT in all infants but more strongly in male infants born by C-section. Male infants also had a higher proportion of microbes from breast milk present in their stool.

While infants delivered by C-section have a reduced colonization by maternal stool microbiota, their colonization by breast milk microbiota is higher than vaginally delivered infants.”

This could be due to the reduced microbial diversity and Bacteroides depletion in the IGMB of C-section-delivered infants, which makes it easier for breast milk microbes to colonize the gut.

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Male infants appeared to show a greater effect of the breast milk microbes on their gut microbiome. This may be because they exhibit less microbial diversity, with fewer Clostridiales and more Enterobacteriales abundance than is observed in female infants. The male infant’s gut microbiota is also more susceptible to stress and environmental exposures.

Overall, the breast milk microbial communities correlated most strongly with those found in infant stool samples that were collected at a later time point. For example, Pantoea in breast milk at four and six months was correlated with infant stool collected at nine and twelve months, respectively. These findings require further validation in future research.

What are the implications?

The identification of microbial clusters in human milk and infant feces that were shared within the mother-infant pair at six weeks is a striking finding in this study. The delay in cluster sharing and the association with C-section were associated with stronger correlations.

The findings of this study agree with earlier reports on the associations of various microbes in breast milk and the infant gut. Notably, the current study adds to previous data by identifying correlations between different taxa in these two sites.

The scientists postulate that microbes within communities may show direct interactions, such as the transmission of a microbe present in the infant oral cavity to the breast in this case, as well as the intake of breast milk by the infant. In addition, they may show indirect interactions through nutrients like fatty acids and milk sugars or other bacterial metabolites that influence both communities.

With the observed shift in breast milk microbial diversity over time, long-term studies may be needed to understand the breadth of microbial exposures during infancy. The change in IGMTs over time should also be better characterized and their relevance assessed.

These results suggest that milk microbial communities have a long-term effect on the infant gut microbiome both through sharing of microbes and other molecular mechanisms.”

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Journal reference:
  • Lundgren, S. N., Madan, J. C., Karagas, M. R., et al. (2023). Human milk-associated bacterial communities associate with the infant gut microbiome over the first year of life. Frontiers in Microbiology. doi:10.3389/fmicb.2023.1164553.

Can a disrupted gut microbiota contribute to anorexia nervosa pathogenesis?

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In a recent study published in the journal Nature Microbiology, researchers investigated whether intestinal microbial alterations contribute to anorexia nervosa (AN) pathogenesis.

AN, a disorder associated with altered eating, has caused considerable mortality, especially among women. However, therapies based on scientific evidence are scarce. AN pathogenesis likely involves several environmental and genetic factors. Studies have reported intestinal microbial dysbiosis among AN-affected individuals. However, data were obtained from small sample sizes, and genus-level microbial alterations were analyzed by amplicon sequencing.

Study: The gut microbiota contributes to the pathogenesis of anorexia nervosa in humans and mice. Image Credit: Tatiana Shepeleva / ShutterstockStudy: The gut microbiota contributes to the pathogenesis of anorexia nervosa in humans and mice. Image Credit: Tatiana Shepeleva / Shutterstock

About the study

In the present study, researchers assessed the association between the intestinal microbiome and AN.

The team performed metabolomics and shotgun metagenomic analyses on serum and fecal samples, respectively, that were obtained from women with AN (n=77) and age- and sex-matched healthy controls (n=70). Further, the fecal microbiome was transplanted from anorexia nervosa cases to murine animals fed calories-limited diets over three weeks to simulate AN eating behavior for in vivo analysis. In addition, the team explored causal associations in silico by bidirectional mediation analysis. The intestinal microbiome was analyzed at functional, taxonomic, and genetic levels.

The team used the eating disorder inventory-3 (EDI-3) questionnaire to assess eating behaviors and insulin resistance was assessed using the homoeostatic model assessment for insulin resistance (HOMA-IR) tool. The team examined covariations between bacterial abundance at species and genus levels and clinical variables for AN cases and controls. Linear regression modeling was performed, adjusting for confounders such as age, smoking status, medications, and body mass index (BMI).

Further, the team evaluated the growth dynamics of gut bacteria by calculating peak-to-trough ratios (PTR) using the metagenomic dataset. The functional modules of gut bacteria were identified using gut-brain modules (GBMs) and gut metabolic modules (GMMs). Differences in bacterial genomics were explored based on the Canberra distance of bacterial structural variant profiles.

​​​​​​​Graphical abstract of the study workflow and findings.

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Results

Several bacterial organisms (including Clostridium) were altered among individuals with anorexia nervosa and were associated with mental well-being and eating behavior estimates. Bacterial functional-type modules related to neurotransmitter degradation were enriched among those with anorexia nervosa. Further, several structural variants (SVs) in bacterial organisms were associated with the metabolic characteristics of anorexia nervosa.

The findings indicated a probable role of the intestinal microbiome in AN-associated changes concerning satiety and the metabolism of secondary bile acids. The metabolomic analysis indicated an elevation in metabolites linked to lowered food consumption (including taurine-hyodeoxycholic acid, taurine-α-muricholic acid, and indole-3-propionic acid molecules). Causal inference analysis indicated that serological bacterial metabolites probably mediate the effect of gut microbial alterations on anorexia nervosa. At the phylum level, AN microbiome samples showed lowered Actinobacteriota and Bacteroidota counts. Among families of bacteria, Christensenellaceae species, particularly CAG-138, showed the most significant enrichment in AN.

At the genus level, elevated Lactobacillus counts were observed in the AN microbiota. The Ruminococcacea-enterotype was more prevalent in cases of AN. Species-level analysis indicated greater β-diversity among AN-affected women. In AN, Roseburia inulinivorans and Roseburia intestinalis were depleted, whereas those of Erysipelatoclostridium ramosum, Blautia species CAG, and Enterocloster bolteae innocuum (Clostridium) were increased. Clostridium counts correlated positively with eating disorder scores. The abundance of Bifidobacterium and Parasutterella, in absolute terms, showed positive correlations with perfectionism and body dissatisfaction, respectively.

Absolute Brachyspira count showed a positive association with ‘drive for thinness’ markers in anorexia nervosa. Median values for PTR markedly differed between individuals with AN and controls. Women with AN were leaner, had lower fasting serological insulin, glucose, and C-reactive protein (CRP) levels, and were more sensitive to insulin than controls. Bacterial organisms with significant growth retardation, among AN case individuals included Alistipes finegoldii, Akkermansia muciniphila, Eubacterium siraeum, Coprococcus catus, SS3/4, and Odoribacter splanchnicus.

In addition, the intestinal virome was altered among AN-affected individuals, including lowered bacterial-viral interactions, due to attenuated interactions of viruses with short-chain fatty acid (SCFA)-producing bacteria, including Roseburia inulinivorans, Roseburia hominis, and Faecalibacterium prausnitzii. The team observed greater viral richness and Shannon diversity in the fecal samples of AN cases compared to controls. Notably, 25/30 viruses increased in AN were Lactococcus bacteriophages. The abundance of GBMs for serotonin synthesis and degradation of tryptophan, glutamate, and dopamine, were enriched in AN.

The team detected 2,423 and 5,056 variable SVs and deletion SVs, respectively, across 56 species of bacteria, including Bacteroides uniformis, Faecalibacterium prausnitzii, Parabacteroides distasonis, Methanobrevibacter smithii. Individuals with AN lacking the genomic region of B. uniformis had greater scores for self-denial and bulimia. The genetic deletion in B. uniformis could result in the deficiency of thiamine, a vitamin associated with intestinal and mental health. The serotonin synthesis module causally affected BMI through glycoursodeoxycholic acid, which is upregulated by serotonin.

Serum leucine mediated the influence of B. vulgatus counts on glucose homeostasis. Mice receiving AN individuals’ fecal transplants initially lost more weight with a slower gain of weight with time than those receiving fecal transplants of control individuals. The finding was related to greater levels of hypothalamic appetite-suppressing genes and thermogenesis-associated genes in the adipose tissues of mice receiving fecal transplants from individuals with AN.

Based on the study findings, gut microbial disruptions may contribute to the pathogenesis of AN.

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Journal reference:

Study finds sugary beverages increase dementia risk, while natural juices may help prevent it

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In an article published in the journal Current Opinion in Microbiology, scientists have provided a detailed overview of the factors affecting maternal gut microbiota during pregnancy and its impact on maternal and infant health.

Study: Sugary beverages and genetic risk in relation to brain structure and incident dementia: a prospective cohort study. Image Credit: Africa Studio / ShutterstockStudy: Sugary beverages and genetic risk in relation to brain structure and incident dementia: a prospective cohort study. Image Credit: Africa Studio / Shutterstock

Background

Pregnancy is associated with a wide range of hormonal, immunological, and metabolic changes needed for fetal development. The most notable changes include increased cardiac output, higher levels of T regulatory cells, and alteration in gut microbiome composition.

Alteration in gut microbiota composition and diversity is associated with changes in women’s metabolic, immunological, and neurological processes, irrespective of pregnancy status. In addition, changes in gut microbiota composition are known to affect insulin sensitivity. In children with type 1 diabetes, functional and metabolic changes in gut microbiota have been documented.

Alteration in gut microbiota during pregnancy

Only limited evidence is available to thoroughly understand the changes in gut microbiota during pregnancy and its impact on maternal and fetal health. However, according to the available literature, low-grade inflammation at the intestinal mucosa as well as hormonal changes, might be responsible for gut microbiota alteration during pregnancy.

Regarding hormonal changes, pregnancy-related induction in progesterone levels is known to directly associate with increased Bifidobacterium levels in women. Bifidobacterium is a beneficial bacterium that naturally resides in the intestine. Therefore, the gut-to-gut transmission of this bacterium from the mother to the infant is crucial during the neonatal period. In infants, this bacterium helps degrade human milk oligosaccharides coming from maternal milk, in addition to developing infant gut microbiota and immune system.

Factors influencing maternal gut microbiota during pregnancy

Adult human gut microbiota can be influenced by many factors, including body mass index (BMI), medications, diseases, environment, and lifestyle (diet, physical activity, smoking, and drinking habits). Pre-pregnancy exposure to these factors can lead to structural and functional alteration in maternal gut microbiota during pregnancy.

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Animal studies have shown that maternal diet influences maternal and infant gut microbiota composition before and during pregnancy. Both pre-pregnancy body weight and pregnancy-related weight gain have been found to alter the composition and diversity of maternal gut microbiota.

Infant gut microbiota are influenced by the way they are delivered. For example, infants delivered vaginally have been shown to gain beneficial changes in gut microbiota compared to those delivered by c-section.

Functional studies in animals have shown that smoking-related nicotine exposure during pregnancy affects maternal gut microbiota, which in turn alters fetal exposure levels to circulating short-chain fatty acids and leptin during in-utero development.

Certain diseases before pregnancy, such as inflammatory bowel disease, have been found to influence maternal microbiota during pregnancy. The microbiota of the pregnant mother’s gut has also been shown to be affected pre-pregnancy and during pregnancy by certain medications, including antibiotics, proton-pump inhibitors, metformin, laxatives, and probiotics.

Maternal health impact of altered gut microbiota

Studies have found maternal gut microbiota alteration during pregnancy is associated with pregnancy complications, including gestational diabetes and preeclampsia.  

Gestational diabetes

A spontaneous induction in blood glucose levels during pregnancy is medically termed gestational diabetes. Studies have shown that a reduced abundance of beneficial bacteria and an increased abundance of pathogenic bacteria are responsible for the onset of gestational diabetes.

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In the microbiome of gestational diabetes patients, an increased abundance of membrane transport, energy metabolism, lipopolysaccharides, and phosphotransferase system pathways has been observed. Recent evidence indicates that gut microbiota-derived dopamine deficiency in the blood, impaired production of short-chain fatty acids, and excessive metabolic inflammation are collectively responsible for the development of gestational diabetes.

Preeclampsia

Preeclampsia is characterized by new-onset hypertension, proteinuria, and organ dysfunction during pregnancy. Studies involving pregnant women with preeclampsia have found gut microbiota dysbiosis (imbalance in gut microbiota composition) and increased plasma levels of lipopolysaccharide and trimethylamine N-oxide.

Recent evidence indicates that preeclampsia onset is associated with reduced bacterial diversity in gut microbiota. Specifically, the changes in gut microbiota include a depletion in beneficial bacteria and an enrichment in opportunistic bacteria.

Some mechanistic studies have pointed out that gut microbiota dysbiosis induces immune imbalance and intestinal barrier disruption in pregnant women, leading to the translocation of bacteria to the intrauterine cavity, placental inflammation, and poor placentation. All these factors collectively contribute to the development of preeclampsia.

Infant health impact of altered gut microbiota

Alteration in maternal gut microbiota has been found to affect the fetus’s neurodevelopment via signaling microbially modulated metabolites to neurons in the developing brain. These changes can have long-term effects on an infant’s behaviors.

Maternal microbiota-derived metabolites such as short-chain fatty acids are known to shape the metabolic system of infants. Some evidence has also indicated that maternal gut microbiota influences an infant’s susceptibility to allergic diseases.

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Journal reference:

Factors shaping maternal gut microbiome during pregnancy and the impact on infant health

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In an article published in the journal Current Opinion in Microbiology, scientists have provided a detailed overview of the factors affecting maternal gut microbiota during pregnancy and its impact on maternal and infant health.

Study: The maternal gut microbiome during pregnancy and its role in maternal and infant health. Image Credit: Design_Cells / ShutterstockStudy: The maternal gut microbiome during pregnancy and its role in maternal and infant health. Image Credit: Design_Cells / Shutterstock

Background

Pregnancy is associated with a wide range of hormonal, immunological, and metabolic changes needed for fetal development. The most notable changes include increased cardiac output, higher levels of T regulatory cells, and alteration in gut microbiome composition.

Alteration in gut microbiota composition and diversity is associated with changes in women’s metabolic, immunological, and neurological processes, irrespective of pregnancy status. In addition, changes in gut microbiota composition are known to affect insulin sensitivity. In children with type 1 diabetes, functional and metabolic changes in gut microbiota have been documented.

Alteration in gut microbiota during pregnancy

Only limited evidence is available to thoroughly understand the changes in gut microbiota during pregnancy and its impact on maternal and fetal health. However, according to the available literature, low-grade inflammation at the intestinal mucosa as well as hormonal changes, might be responsible for gut microbiota alteration during pregnancy.

Regarding hormonal changes, pregnancy-related induction in progesterone levels is known to directly associate with increased Bifidobacterium levels in women. Bifidobacterium is a beneficial bacterium that naturally resides in the intestine. Therefore, the gut-to-gut transmission of this bacterium from the mother to the infant is crucial during the neonatal period. In infants, this bacterium helps degrade human milk oligosaccharides coming from maternal milk, in addition to developing infant gut microbiota and immune system.

Factors influencing maternal gut microbiota during pregnancy

Adult human gut microbiota can be influenced by many factors, including body mass index (BMI), medications, diseases, environment, and lifestyle (diet, physical activity, smoking, and drinking habits). Pre-pregnancy exposure to these factors can lead to structural and functional alteration in maternal gut microbiota during pregnancy.

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Animal studies have shown that maternal diet influences maternal and infant gut microbiota composition before and during pregnancy. Both pre-pregnancy body weight and pregnancy-related weight gain have been found to alter the composition and diversity of maternal gut microbiota.

Mode of delivery has been found to influence infant gut microbiota. For example, infants delivered vaginally have been shown to gain beneficial changes in gut microbiota compared to those delivered by c-section.

Functional studies in animals have shown that smoking-related nicotine exposure during pregnancy affects maternal gut microbiota, which in turn alters fetal exposure levels to circulating short-chain fatty acids and leptin during in-utero development.

Certain diseases before pregnancy, such as inflammatory bowel disease, have been found to influence maternal microbiota during pregnancy. Similarly, pre-pregnancy and during-pregnancy consumption of certain medications, including antibiotics, proton-pump inhibitors, metformin, laxatives, and probiotics, has been found to influence maternal gut microbiota during pregnancy.

Maternal health impact of altered gut microbiota

Studies have found maternal gut microbiota alteration during pregnancy is associated with pregnancy complications, including gestational diabetes and preeclampsia.  

Gestational diabetes

A spontaneous induction in blood glucose levels during pregnancy is medically termed gestational diabetes. Studies have shown that a reduced abundance of beneficial bacteria and an increased abundance of pathogenic bacteria are responsible for the onset of gestational diabetes.

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In the microbiome of gestational diabetes patients, an increased abundance of membrane transport, energy metabolism, lipopolysaccharides, and phosphotransferase system pathways has been observed. Recent evidence indicates that gut microbiota-derived dopamine deficiency in the blood, impaired production of short-chain fatty acids, and excessive metabolic inflammation are collectively responsible for the development of gestational diabetes.

Preeclampsia

Preeclampsia is characterized by new-onset hypertension, proteinuria, and organ dysfunction during pregnancy. Studies involving pregnant women with preeclampsia have found gut microbiota dysbiosis (imbalance in gut microbiota composition) and increased plasma levels of lipopolysaccharide and trimethylamine N-oxide.

Recent evidence indicates that preeclampsia onset is associated with reduced bacterial diversity in gut microbiota. Specifically, the changes in gut microbiota include a depletion in beneficial bacteria and an enrichment in opportunistic bacteria.

Some mechanistic studies have pointed out that gut microbiota dysbiosis induces immune imbalance and intestinal barrier disruption in pregnant women, leading to the translocation of bacteria to the intrauterine cavity, placental inflammation, and poor placentation. All these factors collectively contribute to the development of preeclampsia.

Infant health impact of altered gut microbiota

Alteration in maternal gut microbiota has been found to affect the fetus’s neurodevelopment via signaling microbially modulated metabolites to neurons in the developing brain. These changes can have long-term effects on an infant’s behaviors.

Maternal microbiota-derived metabolites such as short-chain fatty acids are known to shape the metabolic system of infants. Some evidence has also indicated that maternal gut microbiota influences an infant’s susceptibility to allergic diseases.

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Journal reference:

Study offers novel insights into reducing adverse effects of antibiotics on the gut microbiome

Antibiotics help to fight bacterial infections, but they can also harm the helpful microbes living in the gut, which can have long-lasting health consequences.

Now new research being presented at this year’s European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Copenhagen, Denmark (15-18 April) has identified several protective drugs that may lessen the collateral damage caused by antibiotics without compromising their effectiveness against harmful bacteria.

The unique study by Dr Lisa Maier and Dr Camille V. Goemans from the European Molecular Biology Laboratory, Heidelberg, Germany and colleagues, which analyzed the effects of 144 different antibiotics on the abundance of the most common gut bacteria, offers novel insights into reducing the adverse effects of antibiotic treatment on the gut microbiome.

The trillions of microorganisms in the human gut profoundly impact health by aiding digestion, providing nutrients and metabolites, and working with the immune system to fend off harmful bacteria and viruses.

Antibiotics can damage these microbial communities, resulting in an imbalance that can lead to recurrent gastrointestinal problems caused by Clostridioides difficile infections as well as long-term health problems such as obesity, allergies, asthma and other immunological or inflammatory diseases.

Despite this well-known collateral damage, which antibiotics affect which types of bacterial species, and whether these negative side effects be mitigated has not been studied systematically because of technical challenges.

To find out more, researchers systematically analyzed the growth and survival of 27 different bacterial species commonly found in the gut following treatment with 144 different antibiotics. They also assessed the minimal inhibitory concentration (MIC) – the minimal concentration of an antibiotic required to stop bacteria from growing – for over 800 of these antibiotic-bacteria combinations.

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The results revealed that the majority of gut bacteria had slightly higher MICs than disease-causing bacteria, suggesting that at commonly used antibiotic concentrations, most of the tested gut bacteria would not be affected.

However, two widely used antibiotic classes – tetracyclines and macrolides – not only stopped healthy bacteria growing at much lower concentrations than those required to stop the growth of disease-causing bacteria, but they also killed more than half of the gut bacterial species they tested, potentially altering the gut microbiome composition for a long time.

As drugs interact differently across different bacterial species, the researchers investigated whether a second drug could be used to protect the gut microbes. They combined the antibiotics erythromycin (a macrolide) and doxycycline (a tetracycline) with a set of 1,197 pharmaceuticals to identify suitable drugs that would protect two abundant gut bacterial species (Bacteriodes vulgatus and Bacteriodes uniformis) from the antibiotics.

The researchers identified several promising drugs including the anticoagulant dicumarol, the gout medication benzbromarone, and two anti-inflammatory drugs, tolfenamic acid and diflunisal.

Importantly, these drugs did not compromise the effectiveness of the antibiotics against disease-causing bacteria.

Further experiments showed that these antidote drugs also protected natural bacterial communities derived from human stool samples and in living mice.

This Herculean undertaking by an international team of scientists has identified a novel approach that combines antibiotics with a protective antidote to help keep the gut microbiome healthy and reduce the harmful side effects of antibiotics without compromising their efficiency,” says Dr Ulrike Löber, of the Max-Delbrück-Center for Molecular Medicine in Berlin, Germany who is presenting the research at ECCMID. “Despite our promising findings, further research is needed to identify optimum and personalized combinations of antidote drugs and to exclude any potential long-term effects on the gut microbiome.

Research identifies western diet-induced microbial and metabolic contributors to liver disease

New research from the University of Missouri School of Medicine has established a link between western diets high in fat and sugar and the development of non-alcoholic fatty liver disease, the leading cause of chronic liver disease.

The research, based in the Roy Blunt NextGen Precision Health Building at MU, has identified the western diet-induced microbial and metabolic contributors to liver disease, advancing our understanding of the gut-liver axis, and in turn the development of dietary and microbial interventions for this global health threat.

We’re just beginning to understand how food and gut microbiota interact to produce metabolites that contribute to the development of liver disease. However, the specific bacteria and metabolites, as well as the underlying mechanisms were not well understood until now. This research is unlocking the how and why.”

Guangfu Li, PhD, DVM, co-principal investigator, associate professor in the department of surgery and Department of Molecular Microbiology and Immunology

The gut and liver have a close anatomical and functional connection via the portal vein. Unhealthy diets change the gut microbiota, resulting in the production of pathogenic factors that impact the liver. By feeding mice foods high in fat and sugar, the research team discovered that the mice developed a gut bacteria called Blautia producta and a lipid that caused liver inflammation and fibrosis. That, in turn, caused the mice to develop non-alcoholic steatohepatitis or fatty liver disease, with similar features to the human disease.

“Fatty liver disease is a global health epidemic,” said Kevin Staveley-O’Carroll, MD, PhD, professor in the department of surgery, one of the lead researchers. “Not only is it becoming the leading cause of liver cancer and cirrhosis, but many patients I see with other cancers have fatty liver disease and don’t even know it. Often, this makes it impossible for them to undergo potentially curative surgery for their other cancers.”

As part of this study, the researchers tested treating the mice with an antibiotic cocktail administered via drinking water. They found that the antibiotic treatment reduced liver inflammation and lipid accumulation, resulting in a reduction in fatty liver disease. These results suggest that antibiotic-induced changes in the gut microbiota can suppress inflammatory responses and liver fibrosis.

Li, Staveley-O’Carroll and fellow co-principal investigator R. Scott Rector, PhD, Director of NextGen Precision Health Building and Interim Senior Associate Dean for Research -; are part of NextGen Precision Health, an initiative to expand collaboration in personalized health care and the translation of interdisciplinary research for the benefit of society. The team recently received a $1.2 million grant from the National Institutes of Health to fund this ongoing research into the link between gut bacteria and liver disease.

Source:
Journal reference:

Yang, M., et al. (2023). Western diet contributes to the pathogenesis of non-alcoholic steatohepatitis in male mice via remodeling gut microbiota and increasing production of 2-oleoylglycerol. Nature Communications. doi.org/10.1038/s41467-023-35861-1.

Altered gut microbiome plays a major role in the progression of endometriosis in animal model

About 196 million women worldwide suffer from endometriosis, a condition that typically causes pelvic pain and infertility. Endometriosis develops when lining inside the womb grows attached to surrounding tissues, such as the intestine or the membrane lining the abdominal cavity, causing bleeding, pain and other symptoms. Despite decades of research, little is known about the factors that contribute to the development of endometriosis.

Evidence suggests that the microbiome, a community of microorganisms living inside the body, is altered in women with endometriosis. In this study published in the journal Cell Death & Discovery, researchers at Baylor College of Medicine discovered that an altered gut microbiome plays a pivotal role in endometriosis disease progression in an animal model.

“To investigate the role of the microbiome in endometriosis we first implemented a novel mouse model of the condition in which we eliminated the microbiome using antibiotics,” said lead author Dr. Rama Kommagani, associate professor in the Departments of Pathology and Immunology and of Molecular Virology and Microbiology at Baylor.

The researchers found that mice lacking gut microbiome had smaller endometriotic lesions than mice with a microbiome. Furthermore, when gut microbiome-free mice received gut microbiota from mice with endometriosis, the lesions grew as large as those in mice retaining their microbiome. These findings suggest that altered gut bacteria drive disease progression. On the other hand, the uterine microbiome did not seem to affect disease progression.

The team also discovered a novel signature of microbiome-derived metabolites, products produced by the microbes, that were significantly altered in feces of mice with endometriosis. Supporting the role of microbiome metabolites in disease progression, Kommagani and his colleagues found that treatment of endometriotic cells and mice with the metabolite called quinic acid significantly enhanced the cellular proliferation and endometriotic lesion growth, respectively.

The findings suggest that certain microbiome communities and/or their metabolites can contribute to endometriosis progression and that modifying the composition of these communities could help control the condition in human patients. “We are currently investigating this possibility,” Kommagani said.

The findings also suggested that studying microbiome metabolites in human stool samples could be used as a diagnostic tool. “Endometriosis is typically diagnosed with ultrasound, and an invasive procedure is necessary to characterize the lesion well,” Kommagani said. “We are investigating whether microbiome metabolites in human stool samples could be a useful diagnostic tool and also whether some of these metabolites could be used as a treatment strategy.”

Women with endometriosis also tend to have bowel issues, such as colitis or inflammatory bowel syndrome.

We are interested in determining whether changes in the gut microbiome could affect bowel conditions and the possibility of controlling them by modifying the microbiome or with their metabolites.”

Dr. Rama Kommagani, Lead Author

Source:
Journal reference:

Chadchan, S.B., et al. (2023) Gut microbiota and microbiota-derived metabolites promotes endometriosis. Cell Death Discovery. doi.org/10.1038/s41420-023-01309-0.

Chemicals accumulated in the vagina may contribute to spontaneous preterm birth

Chemicals that accumulate in the vagina, potentially originating from personal care products, may contribute to spontaneous preterm birth, according to a new study by researchers at Columbia University Vagelos College of Physicians and Surgeons.

The study of 232 pregnant women found that a handful of non-biological chemicals previously found in cosmetics and hygiene products are strongly associated with preterm birth.

Our findings suggest that we need to look more closely at whether common environmental exposures are in fact causing preterm births and, if so, where these exposures are coming from. The good news is that if these chemicals are to blame, it may be possible to limit these potentially harmful exposures.”

Tal Korem, PhD, study co-leader, assistant professor in the Program for Mathematical Genomics and the Departments of Systems Biology and Obstetrics and Gynecology at Columbia University

The study was published January 12 in Nature Microbiology.

Preterm birth, childbirth before 37 weeks of pregnancy, is the number one cause of neonatal death and can lead to a variety of lifelong health issues. Two-thirds of preterm births occur spontaneously, but despite extensive research, there are no methods for predicting or preventing spontaneous preterm birth.

Several studies have suggested that imbalances in the vaginal microbiome play a role in preterm birth and other problems during pregnancy. However, researchers have not been able to reproducibly link specific populations of microorganisms with adverse pregnancy outcomes.

The research team, co-led by Korem and Maayan Levy, PhD, of the University of Pennsylvania, decided to take a more expansive view of the vaginal microenvironment by looking at its metabolome. The metabolome is the complete set of small molecules found in a particular biological niche, including metabolites produced by local cells and microorganisms and molecules that come from external sources. “The metabolome can be seen as a functional readout of the ecosystem as a whole,” Korem says. “Microbiome profiling can tell us who the microbes are; metabolomics gets us close to understanding what the microbes are doing.”

In the current study, the researchers measured over 700 different metabolites in the second-trimester metabolome of 232 pregnant women, including 80 pregnancies that ended prematurely.

The study found multiple metabolites that were significantly higher in women who had delivered early than in those who delivered at full term.

“Several of these metabolites are chemicals that are not produced by humans or microbes-;what we call xenobiotics,” says Korem. “These include diethanolamine, ethyl-beta glucoside, tartrate, and ethylenediaminetetraacetic acid. While we did not identify the source of these xenobiotics in our participants, all could be found in cosmetics and hygiene products.”

Algorithm predicts preterm birth

Using machine learning models, the team also developed an algorithm based on metabolite levels that can predict preterm birth with good accuracy, potentially paving the way for early diagnostics.

Though the predictions were more accurate than models based on microbiome data and maternal characteristics (such as age, BMI, race, preterm birth history, and prior births), the new model still needs improvement and further validation before it could be used in the clinic.

Despite the current limitations, Korem says, “our results demonstrate that vaginal metabolites have the potential to predict, months in advance, which women are likely to deliver early.”

Source:
Journal reference:

Kindschuh, W.F., et al. (2023) Preterm birth is associated with xenobiotics and predicted by the vaginal metabolome. Nature Microbiology. doi.org/10.1038/s41564-022-01293-8.

Gut-dwelling bacteria can promote the desire to exercise, study shows

Some species of gut-dwelling bacteria activate nerves in the gut to promote the desire to exercise, according to a study in mice that was led by researchers at the Perelman School of Medicine at the University of Pennsylvania. The study was published today in Nature, and reveals the gut-to-brain pathway that explains why some bacteria boost exercise performance.

In the study, the researchers found that differences in running performance within a large group of lab mice were largely attributable to the presence of certain gut bacterial species in the higher-performing animals. The researchers traced this effect to small molecules called metabolites that the bacteria produce-;metabolites that stimulate sensory nerves in the gut to enhance activity in a motivation-controlling brain region during exercise.

If we can confirm the presence of a similar pathway in humans, it could offer an effective way to boost people’s levels of exercise to improve public health generally.”

Christoph Thaiss, PhD, Study Senior Author, Assistant Professor of Microbiology, Penn Medicine

Thaiss and colleagues set up the study to search broadly for factors that determine exercise performance. They recorded the genome sequences, gut bacterial species, bloodstream metabolites, and other data for genetically diverse mice. They then measured the amount of daily voluntary wheel running the animals did, as well as their endurance.

The researchers analyzed these data using machine learning, seeking attributes of the mice that could best explain the animals’ sizeable inter-individual differences in running performance. They were surprised to find that genetics seemed to account for only a small portion of these performance differences-;whereas differences in gut bacterial populations appeared to be substantially more important. In fact, they observed that giving mice broad-spectrum antibiotics to get rid of their gut bacteria reduced the mice’s running performance by about half.

Ultimately, in a years-long process of scientific detective work involving more than a dozen separate laboratories at Penn and elsewhere, the researchers found that two bacterial species closely tied to better performance, Eubacterium rectale and Coprococcus eutactus, produce metabolites known as fatty acid amides (FAAs). The latter stimulate receptors called CB1 endocannabinoid receptors on gut-embedded sensory nerves, which connect to the brain via the spine. The stimulation of these CB1 receptor-studded nerves causes an increase in levels of the neurotransmitter dopamine during exercise, in a brain region called the ventral striatum.

The striatum is a critical node in the brain’s reward and motivation network. The researchers concluded that the extra dopamine in this region during exercise boosts performance by reinforcing the desire to exercise.

“This gut-to-brain motivation pathway might have evolved to connect nutrient availability and the state of the gut bacterial population to the readiness to engage in prolonged physical activity,” said study co-author, J. Nicholas Betley, PhD, an associate professor of Biology at the University of Pennsylvania’s School of Arts and Sciences. “This line of research could develop into a whole new branch of exercise physiology.”

The findings open up many new avenues of scientific investigation. For example, there was evidence from the experiments that the better-performing mice experienced a more intense “runner’s high”-;measured in this case by a reduction in pain sensitivity-;hinting that this well-known phenomenon is also at least partly controlled by gut bacteria. The team now plans further studies to confirm the existence of this gut-to-brain pathway in humans.

Apart from possibly offering cheap, safe, diet-based ways of getting ordinary people running and optimizing elite athletes’ performance, he added, the exploration of this pathway might also yield easier methods for modifying motivation and mood in settings such as addiction and depression.

The study was led by Penn Medicine scientist Lenka Dohnalová. Other Penn Medicine authors include: Patrick Lundgren, Jamie Carty, Nitsan Goldstein, Lev Litichevskiy, Hélène Descamps, Karthikeyani Chellappa, Ana Glassman, Susanne Kessler, Jihee Kim, Timothy Cox, Oxana Dmitrieva-Posocco, Andrea Wong, Erik Allman, Soumita Ghosh, Nitika Sharma, Kasturi Sengupta, Mark Sellmyer, Garret FitzGerald, Andrew Patterson, Joseph Baur, Amber Alhadeff, and Maayan Levy.

The study was supported in part by the National Institutes of Health (S10-OD021750, DP2AG067492, R01-DK-129691, , P01-DK119130 and R01-DK115578), the Pew Charitable Trust, the Edward Mallinckrodt, Jr. Foundation, the Agilent Early Career Professor Award, the Global Probiotics Council, the IDSA Foundation, the Thyssen Foundation, the Human Frontier Science Program, and Penn Medicine, including the Dean’s Innovation Fund.

Source:
Journal reference:

Dohnalová, L., et al. (2022) A microbiome-dependent gut–brain pathway regulates motivation for exercise. Nature. doi.org/10.1038/s41586-022-05525-z.