gut microbiota

Causal relationship between gut microbiota and prostate cancer contributes to the gut-prostate axis: insights from a Mendelian randomization study

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Abstract

Background

Changes in gut microbiota abundance have been linked to prostate cancer development. However, the causality of the gut-prostate axis remains unclear.

Methods

The genome-wide association study (GWAS) data for gut microbiota sourced from MiBioGen (n = 14,306), alongside prostate cancer summary data from PRACTICAL (n = 140,254) and FinnGen Consortium (n = 133,164). Inverse-variance-weighted (IVW) was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl), after diligently scrutinizing potential sources of heterogeneity and horizontal pleiotropy via the rigorous utilization of Cochran’s Q test, the MR-PRESSO method, and MR-Egger. We used meta-analysis methods in random effects to combine the Mendelian randomization (MR) estimates from the two sources.

Results

The pooled analyses of MR results show that genus Eubacterium fissicatena (OR = 1.07, 95% CI 1.01 to 1.13, P = 0.011) and genus Odoribacter (OR = 1.14, 95% CI 1.01 to 1.27, P = 0.025) were positively associated with prostate cancer. However, genus Adlercreutzia (OR = 0.89, 95% CI 0.83 to 0.96, P = 0.002), Roseburia (OR = 0.90, 95% CI 0.83 to 0.99, P = 0.03), Holdemania (OR = 0.92, 95% CI 0.86 to 0.97, P = 0.005), Flavonifractor (OR = 0.85, 95% CI 0.74 to 0.98, P = 0.024) and Allisonella (OR = 0.93, 95% CI 0.89 to 0.98, P = 0.011) seems to be a protective factor for prostate cancer. Sensitivity analysis found no significant heterogeneity, horizontal pleiotropy, or reverse causal links in all causal associations.

Conclusion

This MR study lends support to a causal relationship between genetically predicted gut microbiota and prostate cancer. Research on the gut-prostate axis, along with further multi-omics analyses, holds significant implications for the prevention and treatment of prostate cancer.

Introduction

In men globally, prostate cancer represents 7% of all new cancer diagnoses, with a pronounced prevalence in Western nations [1]. Notably, it emerges as the second leading cause of cancer-associated mortality in this demographic, culminating in over 350,000 deaths annually [2]. Given this, the urgency of early detection in potentially high-risk individuals, accompanied by swift therapeutic interventions, becomes paramount in curbing both the incidence and mortality rates linked to this malignancy.

The gut microbiota, a diverse collection of microorganisms in the digestive tract, is vital in determining and sustaining the host’s health via interactions like nutrient processing and immune system modulation. Obesity and high-fat consumption are linked to Prostate cancer risks, with lifestyle, particularly dietary habits, influencing the gut microbiome [3]. It’s long been believed that certain bacteria can cause persistent, mild inflammation, potentially triggering prostate cancer. Although the current positive correlation between prostatitis and prostate cancer rates may be the result of detection bias [4]. Poutahidis et al. [5] demonstrated that gastrointestinal bacterial infections can enhance prostatic intraepithelial neoplasia (PIN) and microinvasive carcinoma in vivo. Additionally, individuals diagnosed with prostate cancer showed significant increases in proinflammatory Bacteroides and Streptococcus species. Antibiotics promote selection for resistant bacteria by enhancing the proliferation of pathogenic strains. Research indicates that antibiotic use elevates the risk of infections from Clostridium difficile and methicillin-resistant Staphylococcus aureus [6]. Tulstrup et al. [7] found that changes in the microbiota due to antibiotics can alter intestinal permeability, thereby heightening the risk of neoplastic alterations. Earlier research has demonstrated that prostate cancer patients exhibiting elevated oestrogen levels may possess intestinal bacterial genes capable of oestrogen metabolism. Such metabolic activity can expedite carcinogenesis by activating polycyclic aromatic hydrocarbons (PAHs) [8,9,10]. Escherichia coli commonly resides in the human gut. Murine studies have indicated a potential link between E. coli and prostatitis development [11]. Moreover, Campylobacter jejuni has been identified as an inducer of cell cycle arrest and cellular death through its toxin production. Notably, Clostridium can transform gut glucocorticoids into androgens through side chain cleavage, contributing synergistically to the progression of prostate cancer [12]. While numerous studies have investigated the link between specific gut microbes and prostate cancer, the causal relationship between them remains unclear [13, 14].

Mendelian randomization (MR) emerges as a method of instrumental variable (IV) analysis that harnesses single nucleotide polymorphisms (SNPs) derived from genome-wide association studies (GWAS) as tools to deduce causal associations between two traits [15]. MR approximates the inherent attributes of a RCT and exhibits a reduced susceptibility to the impact of covariates. Moreover, its operational simplicity and cost-effectiveness enhance its appeal [16]. Consequently, we conducted a two-sample MR utilizing aggregated data from accessible GWAS repositories. This approach facilitated an exploration of the conceivable etiological correlation between gut microbiota and the risk of Prostate cancer through a comprehensive meta-analysis.

Discussion

In this study, large-scale GWAS data using European ancestry, combined with MR and meta-analyses demonstrated a potential causal link between gut microbiome and prostate cancer.

Despite the anatomical distance between the prostate and the gut, a substantial body of research suggests a potential link between the gut microbiome and both prostate cancer development and drug resistance. Liss et al. [30] conducted a study utilizing 16S rRNA sequencing to analyze the gut microbiota of 133 American men who underwent prostate biopsies. Their findings indicated elevated levels of Streptococcus and Bacteroides species in men diagnosed with prostate cancer. Further genome studies indicate that alterations in folate and arginine pathways, possibly influenced by gut microbes, may play a role in prostate cancer risk. Golombos et al. [13] observed a greater prevalence of Bacteroides massiliensis in individuals with prostate cancer in comparison to the healthy control group. Conversely, Faecalibacterium prausnitzii and Eubacterium rectalie exhibited higher relative abundances among the control group. Elevation of F.prausnitzii and E.rectalie is associated with the formation of anti-inflammatory butyrate, resulting in a symbiotic and protective effect [31, 32].

The results of data pooled from the PRACTICAL and FinnGen consortiums indicate that the genus Eubacterium fissicatena and Odoribacter are associated with an increased risk of prostate cancer. Conversely, the genus Adlercreutzia, Roseburia, Holdemania, Flavonifractor, and Allisonella are potential protective factors against prostate cancer. In fact, the gut microbiome tends to be influenced by host genetics. Xu et al. [33] demonstrated that Odoribacter had nominally significant heritability estimates (0.476), implying its potential role as a genetic carcinogenic factor for prostate cancer. The Eubacterium fissicatena group may be associated with in vivo metabolism. Nutritional investigations have shown a significant increase in the abundance of the E. fissicatena group in populations following a low-calorie diet for 6 days a week [34]. Despite the absence of specific studies on the relationship between the E. fissicatena group and prostate cancer, Zang et al. discovered a causal relationship between E. fissicatena and psoriasis. This finding suggests that gut microbes play a role in mediating the modulation of relevant immune responses [35].

Equol, a secondary metabolite of daidzein produced by the intestinal microbiota, is significantly associated with a reduced risk of prostate cancer in Japanese men, as indicated by plasma equol levels in a study [36]. Additionally, a positive correlation was detected between the genus Adlercreutzia and S-equol concentration [37]. Roseburia, a Gram-positive anaerobic bacterium, induces cancer cell apoptosis through the inhibition of histone deacetylases and related signaling pathways. It also contributes to immune homeostasis and has anti-inflammatory properties by producing short-chain fatty acids [38]. While research on the role of Holdemania, Flavonifractor, and Allisonella in prostate cancer is limited, their correlation with colorectal cancer and metabolism suggests potential roles in immune function, inflammation, and hormone levels. These factors have been implicated in the development and progression of prostate cancer [39, 40]. The effects of bacteria on prostate cancer risk are likely multifactorial, involving a combination of specific microbial activities, host responses, and interactions within the broader microbiome [41]. Eubacteriales from the same order may have different effects on prostate cancer, which is related to the fact that different species in the same bacterial order may have different metabolic pathways and produce different metabolites. Secondly, the functions of bacteria will vary according to the host and environment, and finally we cannot ignore the interactions between bacterial groups [42]. As research in this field progresses, a more nuanced understanding of these complexities will likely emerge.

4.1 Strength and limitation

Our MR analysis has the following advantages. Firstly, the sample size in the GWAS was large and the study strictly adhered to the three assumptions of MR, thus reducing confounders and reverse bias. Secondly, the study population included only individuals of European origin, minimizing population stratification interference. Finally, sensitivity analyses and different model estimations were used to ensure the reliability of the results.

However, certain limitations are unavoidable. Firstly, we assumed of a linear relationship between gut microbiota and prostate cancer risk, disregarding the potential presence of U-shaped associations. Furthermore, the generalizability of our results to different racial groups and various subtypes of prostate cancer is uncertain. Additionally, data limitations such as individual dietary habits and environmental factors may lead to confounding factors. Consequently, further molecular experiments are imperative to corroborate the findings of this study.

5 Conclusion

This MR study unveils genetic evidence supporting a causal link between gut microbiota and prostate cancer. The multi-omics-based platform is anticipated to offer fresh perspectives on prostate cancer diagnosis and treatment by delving into the pathogenic mechanisms and potential bacterial biomarkers.

Midlife Cognition Tied to Gut Microbiota

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But not many specific microbial features were strongly linked with cognitive function

A computer rendering of bacteria on the intestinal epithelium surface

Gut microbiota was linked with midlife cognition, researchers found.

In a large population-based sample, β-diversity, a measure of gut microbial community composition, was significantly associated with cognitive scores in a cross-sectional analysis of middle-age CARDIA participants, reported Katie Meyer, ScD, of University of North Carolina at Chapel Hill, and co-authors.

Several specific genera also were tied to one or more measures of cognitive function, the researchers wrote in JAMA Network Open.

“There has been a lot of research on the gut microbiota in animal models, as well as in small, often clinic-based samples,” Meyer told MedPage Today. “Our study provides data supporting findings from other studies, but in a more representative sample.”

“In addition, the age of CARDIA participants — 48 to 60 — illustrates that these associations can be observed before appreciable cognitive decline,” Meyer pointed out. “The study of cognitive function in middle-aged adults is valuable because it can provide clues to early declines.”

Research about the gut-liver-brain axis has shown connections between the digestive system and dementia or Alzheimer’s disease, though whether relationships are causal is not clear.

Several studies have shown associations between gut microbes and neurological outcomes, including cognition. While mechanisms have not been fully established, there’s growing support for a role in microbiota-generated short-chain fatty acids, Meyer and colleagues noted.

The researchers analyzed data collected from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) cohort in four U.S. metropolitan centers from 2015 to 2016. They sequenced stool DNA and analyzed gut microbial measures, including β-diversity (between-person), α-diversity (within-person), and taxonomy.

They used six clinic-administered tests to assess cognitive status — the Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), timed Stroop test, category fluency, and letter fluency — and derived a global measure from these scores.

Microbiome and cognitive data were available for 597 CARDIA participants who had a mean age of 55. Overall, 44.7% were men, and 45.2% were Black.

Most findings for α-diversity and cognition were not significant. Multivariate analysis of variance tests for β-diversity were statistically significant for nearly all cognition measures, except letter fluency.

In fully adjusted models, after accounting for demographic variables, health behaviors, and clinical covariates:

  • Barnesiella was positively associated with the global measure (β 0.16, 95% CI 0.08-0.24), DSST (β 1.18, 95% CI 0.35-2.00), and category fluency (β 0.59, 95% CI 0.31-0.87)
  • Lachnospiraceae FCS020 group was positively associated with DSST (β 2.67, 95% CI 1.10-4.23)
  • Akkermansia was positively associated with DSST (β 1.28, 95% CI 0.39-2.17)
  • Sutterella was negatively associated with MoCA (β −0.27, 95% CI −0.44 to −0.11)

“Findings from our genera-specific analysis are consistent with proposed pathways through production of the short-chain fatty acid butyrate, many members of which are within class Clostridia,” Meyer and co-authors wrote. “In animal models, administration of butyrate has been shown to be protective against vascular dementia and cognitive impairment, as well as against metabolic risk factors for cognitive decline and dementia.”

Longitudinal studies are needed to see how declining health itself may influence the gut microbial community, the researchers noted. Results seen in midlife may not translate to mild cognitive impairment or later disease states, they added.

“It’s important to recognize that we are still learning about how to characterize the role of this dynamic ecological community and delineate mechanistic pathways,” Meyer said.

“This is reflected in our findings,” she added. “The strongest results from our study were from a multivariate statistical analysis that can be considered a test of the overall community, and we were not able to identify many specific microbial features that were strongly related to cognitive function.”

Early lifestyle habits may influence gut microbiota, cardiometabolic health in teens

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Early lifestyle habits, including sleep duration, dietary intake and physical activity level, may shape gut microbiota in late adolescence, likely influencing cardiometabolic health, according to study findings presented at the European Society for Paediatric Endocrinology annual meeting .

“These preliminary findings are relevant because the gut microbiota, in animal models and adults, has been associated with obesity and cardiovascular health,” Melanie Henderson, MD, PhD, FRCPC, a pediatric endocrinologist at CHU Sainte-Justine and a clinical assistant professor in the department of pediatrics at Université de Montréal, told Endocrine Today. “We can hypothesize that early lifestyle habits may modulate the gut microbiota, which in turn may alter cardiometabolic health. Interventions targeting the microbiota may be a novel and promising treatment and prevention strategy for cardiometabolic disease.”

 

Henderson and colleagues analyzed data from 22 children with at least one parent with obesity participating in the QUALITY cohort, a prospective study of 630 children with a parental history of obesity. Researchers assessed lifestyle habits at age 8 to 10 years, age 10 to 12 years and age 15 to 17 years, including physical activity (via 7-day accelerometry), self-reported screen time, dietary intake (three non-consecutive 24-hour dietary recalls) and self-reported sleep duration. Fitness was measured by VO2 peak. Researchers also conducted 16s-rRNA-based microbial profiling of stool samples obtained from children at age 15 to 17 years (14 normal weight, six with overweight and two with obesity) to determine the composition and diversity of the gut microbiota.

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Early lifestyle habits, including sleep duration, dietary intake and physical activity level, may shape gut microbiota in late adolescence
 

The researchers found that fitness in children aged 15 to 17 years was positively correlated with measures of microbiome diversity (r = 0.33-0.41 across indices). Additionally, researchers observed positive correlations between fitness in children aged 10 to 12 years and greater microbiotal diversity 5 years later (Shannon r = 0.7; P = .001; Simpson r = 0.51; P = .03).

In children aged 15 to 17 years, both total dietary fat intake and saturated fat intake were negatively correlated with the Simpson index (r = –0.5; P = .019 and r = –0.43; P = .046), respectively). There was also a negative trend observed between total and saturated fat consumption in children aged 8 to 10 years and measures of microbiotal diversity at age 15 to 17 years, though the findings did not rise to significance. At ages 8 to 10 years and ages 15 to 17 years, researchers found that percent carbohydrate intake was positively correlated with the Simpson index (r = 0.43; P = .049 and r = 0.49; P = .021, respectively). Researchers also noted a trend toward a positive correlation between self-reported sleep duration and indices of microbiotal diversity in children aged 15 to 17 years, with the strongest correlation observed with the Shannon index (r = 0.39; P = .08).

Early lifestyle habits, including sleep duration, dietary intake and physical activity level, may shape gut microbiota in late adolescence, likely influencing cardiometabolic health, according to study findings presented at the European Society for Paediatric Endocrinology annual meeting .

“These preliminary findings are relevant because the gut microbiota, in animal models and adults, has been associated with obesity and cardiovascular health,” Melanie Henderson, MD, PhD, FRCPC, a pediatric endocrinologist at CHU Sainte-Justine and a clinical assistant professor in the department of pediatrics at Université de Montréal, told Endocrine Today. “We can hypothesize that early lifestyle habits may modulate the gut microbiota, which in turn may alter cardiometabolic health. Interventions targeting the microbiota may be a novel and promising treatment and prevention strategy for cardiometabolic disease.”

Henderson and colleagues analyzed data from 22 children with at least one parent with obesity participating in the QUALITY cohort, a prospective study of 630 children with a parental history of obesity. Researchers assessed lifestyle habits at age 8 to 10 years, age 10 to 12 years and age 15 to 17 years, including physical activity (via 7-day accelerometry), self-reported screen time, dietary intake (three non-consecutive 24-hour dietary recalls) and self-reported sleep duration. Fitness was measured by VO2 peak. Researchers also conducted 16s-rRNA-based microbial profiling of stool samples obtained from children at age 15 to 17 years (14 normal weight, six with overweight and two with obesity) to determine the composition and diversity of the gut microbiota.

#

Early lifestyle habits, including sleep duration, dietary intake and physical activity level, may shape gut microbiota in late adolescence
 

The researchers found that fitness in children aged 15 to 17 years was positively correlated with measures of microbiome diversity (r = 0.33-0.41 across indices). Additionally, researchers observed positive correlations between fitness in children aged 10 to 12 years and greater microbiotal diversity 5 years later (Shannon r = 0.7; P = .001; Simpson r = 0.51; P = .03).

In children aged 15 to 17 years, both total dietary fat intake and saturated fat intake were negatively correlated with the Simpson index (r = –0.5; P = .019 and r = –0.43; P = .046), respectively). There was also a negative trend observed between total and saturated fat consumption in children aged 8 to 10 years and measures of microbiotal diversity at age 15 to 17 years, though the findings did not rise to significance. At ages 8 to 10 years and ages 15 to 17 years, researchers found that percent carbohydrate intake was positively correlated with the Simpson index (r = 0.43; P = .049 and r = 0.49; P = .021, respectively). Researchers also noted a trend toward a positive correlation between self-reported sleep duration and indices of microbiotal diversity in children aged 15 to 17 years, with the strongest correlation observed with the Shannon index (r = 0.39; P = .08).

PAGE BREAK

Physical activity and screen time were not associated with microbiota diversity, according to the researchers.

The findings suggest that microbiome diversity in late adolescence may be modulated by lifestyle habits, Henderson said.

“I want to stress, however, that these are preliminary findings in a small group of children, and further research is definitely warranted,” Henderson said. – by Regina Schaffer

Gut microbiota: an Indicator to Gastrointestinal Tract Diseases

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Abstract

Purpose

Gut microbiota is predicted to play a key role in manifestation of gastrointestinal tract cancers. The human gastrointestinal tract is a complex and abundant network of microbial community. Gut microbiota depicts the microbe population living in our intestine. Humans harbour more than 1014 microbes in the gut, and the diversity and densities of the microbiota increase from stomach to colon.

Methods

The beneficial relationship between endogenous microbiota and the eukaryotic hosts helps in maintaining various metabolic activities of the body as well as temperature and pH balance. Studies using culturing methods have suggested that the oesophagus is either sterile or contains only a few transient microbes that originates from the oropharynx by swallowing or from the stomach by gastroesophageal reflux. However, metagenomics suggest that large numbers of uncultured organisms are harboured in the human gut.

Results

Observations suggest that research directed towards manipulation of the gut microbiota can be employed in prevention as well as treatment of these conditions. Well-designed, randomized, placebo-controlled human studies using probiotics and/or prebiotics are necessary to formulate the directions for prevention and therapy.

Conclusions

Change in gut microbes in gastrointestinal (GI) tract may have major implication in gastric cancer, the fifth most occurring malignancy in the world. Affected population manifests multiple conditions and diseases, which majorly includes inflammatory bowel disease and colorectal malignancy.

Fecal Transplants Transmit Viruses, Too

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Fecal matter transplants may transfer nonpathogenic viruses along with beneficial bacteria, scientists show.

Fecal matter transplantation can help to boost populations of “good” gut bacteria in patients undergoing treatment for persistent infections by pathogenic bacteria such as Clostridium difficile, and is being trialed as a therapy for other gastrointestinal problems like irritable bowel syndrome and ulcerative colitis. But bacteria are not the only microbes being transplanted, according to a study led by researchers at the University of Pennsylvania’s Perelman School of Medicine. The findings, published today (March 29) in mBio, show that nonpathogenic viruses also make the trip.

“Donors are screened very extensively for gastrointestinal diseases and other infectious diseases,” study coauthor Frederic Bushman of Penn said in a statement. “However you worry about the unknown unknowns, infectious agents that might be bad, but [are] not screened for.”

To investigate what else might be transplanted by the technique, the researchers analyzed fecal matter administered to three children with chronic ulcerative colitis from a single healthy donor. Each child received up to 30 of these transplants over two to four months.

“We could see bacterial viruses moving between humans and we were able to learn some things about transmission,” said Bushman in the statement. However, he added, “we did not see any viruses that grow on animal cells that may be of concern for infecting and harming patients. We saw mostly temperate bacteriophages.”

These phages are of relatively little concern as a health risk, although they could conceivably carry toxins or contribute to antibiotic resistance in a recipient. In their paper, the authors concluded that further characterization of the microbes being transferred during fecal transplantation could help to “guide development of safest practices.”

A low-fibre diet could affect gut microbiota diversity over generations

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Every time you eat whole grains, fresh fruit and vegetables – foods very rich in dietary fibre, which is a type of carbohydrate present in plants – you are not only taking care of your health, but also nourishing some of the trillion microbes inhabiting your gut that, in turn, take care of you. And as a new study suggests, your diet not only conditions your health and microbial community but also those of your children, grandchildren and even great grandchildren.

According to the results of research led by microbiologists of Stanford University and published inNature, you do not just pass your genes on to your offspring, but also a whole gut ecosystem shaped in response to your dietary habits. If fibre intake plummets, so does the richness and diversity of bacteria living in the gut.

In a study conducted with mice, Justin and Erica Sonnenburg and colleagues at Stanford Universitywanted to simulate the effects of a low-fibre diet on the gut microbes of mice. To do so, they transplanted microbiota from a human donor (a 36-year-old American man) to a group of 10 germ-free mice.

They then separated the rodents into two groups: one was fed a diet rich in fibre and the other just the opposite. The animals were monitored for seven weeks and although in the beginning the microorganisms present in the mice’s guts in both groups were similar, after some weeks therodents on the low-fibre diet showed a depletion in the diversity of their gut microbiota. In fact, they had 60% fewer bacteria species compared with the animals following the control diet.

Researchers switched the food regime of the microbiota-depleted mice and put them on the control diet to check whether they could recover some microbial diversity. This was partly achieved when a high-fibre diet was reintroduced, although 33% of all species remained at low or undetectable levels.

What about those mice’s offspring? Would they also suffer the consequences of this depletion? In order to answer this question, the scientists bred four generations of both groups of mice. They observed that the pups from the mice following a low-fibre diet showed a reduced microbial richness in every generation. Indeed, the fourth generation showed 72% less microbiota diversity.If those pups were switched to a high-fibre diet, their microbial community experienced a small recovery, but remained 67% lower than in rodents that had always been fed with a high-fibre diet.

Recent studies have linked the benefits of higher dietary fibre intake to less cardiovascular disease and lower body weight. Nevertheless, humans cannot metabolise the complex dietary carbohydrates found in fruit and vegetables nor obtain energy from them; rather, gut microbiota does it for us.

In light of the results of this research, it seems that once an entire population has experienced the depletion of key bacterial species, simply ‘eating right’ may no longer be enough to restore these lost species to the guts of individuals within that population.

We must not forget, however, that the study has been carried out with mice, so caution must be exercised before extrapolating results to humans. In fact, as the authors point out in their article, the next step will be to test whether the same results are relevant to humans.

A low-fibre diet could affect gut microbiota diversity over generations

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low fibre diet

Every time you eat whole grains, fresh fruit and vegetables – foods very rich in dietary fibre, which is a type of carbohydrate present in plants – you are not only taking care of your health, but also nourishing some of the trillion microbes inhabiting your gut that, in turn, take care of you. And as a new study suggests, your diet not only conditions your health and microbial community but also those of your children, grandchildren and even great grandchildren.

According to the results of research led by microbiologists of Stanford University and published inNature, you do not just pass your genes on to your offspring, but also a whole gut ecosystem shaped in response to your dietary habits. If fibre intake plummets, so does the richness and diversity of bacteria living in the gut.

In a study conducted with mice, Justin and Erica Sonnenburg and colleagues at Stanford Universitywanted to simulate the effects of a low-fibre diet on the gut microbes of mice. To do so, they transplanted microbiota from a human donor (a 36-year-old American man) to a group of 10 germ-free mice.

They then separated the rodents into two groups: one was fed a diet rich in fibre and the other just the opposite. The animals were monitored for seven weeks and although in the beginning the microorganisms present in the mice’s guts in both groups were similar, after some weeks therodents on the low-fibre diet showed a depletion in the diversity of their gut microbiota. In fact, they had 60% fewer bacteria species compared with the animals following the control diet.

Researchers switched the food regime of the microbiota-depleted mice and put them on the control diet to check whether they could recover some microbial diversity. This was partly achieved when a high-fibre diet was reintroduced, although 33% of all species remained at low or undetectable levels.

What about those mice’s offspring? Would they also suffer the consequences of this depletion? In order to answer this question, the scientists bred four generations of both groups of mice. They observed that the pups from the mice following a low-fibre diet showed a reduced microbial richness in every generation. Indeed, the fourth generation showed 72% less microbiota diversity.If those pups were switched to a high-fibre diet, their microbial community experienced a small recovery, but remained 67% lower than in rodents that had always been fed with a high-fibre diet.

Recent studies have linked the benefits of higher dietary fibre intake to less cardiovascular disease and lower body weight. Nevertheless, humans cannot metabolise the complex dietary carbohydrates found in fruit and vegetables nor obtain energy from them; rather, gut microbiota does it for us.

In light of the results of this research, it seems that once an entire population has experienced the depletion of key bacterial species, simply ‘eating right’ may no longer be enough to restore these lost species to the guts of individuals within that population.

We must not forget, however, that the study has been carried out with mice, so caution must be exercised before extrapolating results to humans. In fact, as the authors point out in their article, the next step will be to test whether the same results are relevant to humans.

Advancing gut microbiome research using cultivation

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Highlights

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New simple cultivation methods will expand gut microbiota reference collections.

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Expanded reference collections enable detailed study of gut microbial physiology.

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Cultivation-based multiplex phenotyping can assign phenotypes to specific taxa.

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Cultivation and metagenomics enables testing of microbiome–disease relationships.

Culture-independent approaches have driven the field of microbiome research and illuminated intricate relationships between the gut microbiota and human health. However, definitively associating phenotypes to specific strains or elucidating physiological interactions is challenging for metagenomic approaches. Recently a number of new approaches to gut microbiota cultivation have emerged through the integration of high-throughput phylogenetic mapping and new simplified cultivation methods. These methodologies are described along with their potential use within microbiome research. Deployment of novel cultivation approaches should enable improved studies of xenobiotic tolerance and modification phenotypes and allow a drastic expansion of the gut microbiota reference genome catalogues. Furthermore, the new cultivation methods should facilitate systematic studies of the causal relationship between constituents of the microbiota and human health accelerating new probiotic development.

How Delivery And Breastfeeding Impact Your Baby’s Gut Bacteria And Future Health

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Our digestive system is home to nearly 100 trillion bacteria, commonly referred to as our gut microbiome. A new study of 98 Swedish infants over the first year of life finds a connection between the development of each child’s gut microbiome and the way he or she is both delivered and fed. While vaginal delivery meant greater bacterial similarity between mother and child, the decision to breastfeed also impacted the constitution of a baby’s gut microbiome… and so his or her health.

Our gut bacteria make an invaluable contribution to our metabolism by helping us break down complex carbohydrates and starches. These bacteria also play a crucial role in the development of our immune systems and even produce vitamins and hormones that direct the storage of fats. These reasons suggest to scientists that our gut microbiota act as an organ in-and-of themselves. As such, our gut microbiome establishes a foundation for our metabolism and immunity and quite possibly even our behavior.

Taken all together, these bacteria weigh up to four and a quarter pounds and the total number of genes in these various species of bacteria outnumber our human genes. Only since the advent of genetic sequencing technologies has the microbiome more fully revealed itself and its impact on our health.

Crucially, bacteria are said to colonize our gut, with the first residents making the general environment most hospitable to themselves, more hostile to those who come later. How the gut is colonized in our earliest days of life is therefore key to our future health and our future lives.

For the current study, researchers from the University of Gothenburg and the Beijing Genomics Institute-Shenzhen applied metagenomic analysis on fecal samples from 98 Swedish infants and their mothers over their first year of life in order to assess the impact of mode of delivery and feeding on the establishment of the gut microbiota. What they found supported past research in this area.

As suspected, the earliest bacterial colonizers are derived from the mother. Importantly, the microbiome of vaginally delivered infants showed more resemblance to their mothers than C-section babies. However, C-section babies still received some of their mother’s microbes, which passed on through the skin and mouth.

Next, the researchers observed how the population of bacteria shifted depending on what each child ate. The decision to breastfeed or bottle-feed was key, as nutrition is a main driver of infant gut microbiome development. The end of breastfeeding is a key moment in the maturation process of the gut. Certain types of bacteria thrive on the nutrients breast milk provides and once they are no longer available, other bacteria emerge that are more commonly seen in adults.

“Our results strongly suggest that cessation of breastfeeding rather than introduction of solid foods is the major driver in the development of an adult microbiota,” wrote the authors in their conclusion. Bon appetit!

Source: Backhed F, Roswall J, Peng Y, et al. Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. Cell Host and Microbe. 2015.

Do Antibiotics Raise Diabetes Risk via Gut Microbiota?

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People who take multiple courses of antibiotics may face an increased risk of developing both type 1 and type 2 diabetes, potentially through alterations in gut microbiota, conclude US researchers.

The team, led by Ben Boursi, MD, a postdoctoral researcher in the department of gastroenterology at the University of Pennsylvania, Philadelphia, found that the risk of diabetes was increased by up to 37%, depending on the type of antibiotic and the number of courses prescribed.

“Overprescription of antibiotics is already a problem around the world as bacteria become increasingly resistant to their effects,” commented Dr Boursi in a statement.

“Our findings are important, not only for understanding how diabetes may develop, but as a warning to reduce unnecessary antibiotic treatments that might do more harm than good.”

The study was published online ahead of print March 24 in the European Journal of Endocrinology.

The More Courses of Antibiotics, the Greater the Risk

Dr Boursi explained that studies both in animal models and humans have shown an association between changes in gut microbiota in response to antibiotic exposure and obesity, insulin resistance, and diabetes.

Speaking to Medscape Medical News, he noted: “In mice, we know that germ-free mice are lean and, by fecal transplantation, we can transmit obesity to them. We also know that low dose of penicillin may induce obesity in mice models.”
He added that there have been several studies in humans indicating that exposure to antibiotics in early childhood is associated with an increased risk of obesity in later life, while other investigations have reported differences in gut microbiota between people with and without diabetes.

To investigate further, Dr Boursi and colleagues conducted a nested case-control study using data from the Health Improvement Network (THIN), a UK population-based database, from which they identified 1,804,170 patients with acceptable medical records.

As diabetes is associated with an increased risk of infection, the team wanted to exclude all cases with prediabetes or undiagnosed diabetes. To do that, they removed all patients diagnosed with diabetes within 183 days of starting follow-up and included only patients with exposure to antibiotics more than 1 year prior to the index date.
From the original cohort, they were able to select 208,002 diabetes patients and 815,576 controls matched for age, sex, general practice site, and duration of follow-up before the index date.

Conditional logistic regression analysis revealed that exposure to a single antibiotic prescription was not associated with an increased risk of diabetes, adjusted for body mass index (BMI), smoking, last blood glucose level, and the number of infections before the index date, alongside a history of coronary artery disease and hyperlipidemia.

However, treatment with two to five courses of antibiotics was linked to an increased risk of diabetes with penicillin, cephalosporins, macrolides, and quinolones, at adjusted odds ratios (ORs) ranging from 1.08 for penicillin to 1.15 for quinolones.

The highest risk for diabetes was seen among people who received more than five courses of quinolones, at an adjusted OR of 1.37. An increased risk of diabetes was also seen in patients who took more than five courses of tetracyclines, at an adjusted OR of 1.21.

Interestingly, the researchers were unable to find an association between diabetes risk and treatment with imidazole, antiviral drugs, and antifungals, regardless of the number of courses.

To account for further possible confounding factors, the researchers repeated the analysis only in individuals without skin or urinary-tract infections, which are more common among diabetes patients. This had no impact on the results.

Next Steps

When the analysis was restricted to type 1 diabetes, the risk was increased only following exposure to more than five courses of penicillin or two to five courses of cephalosporin, at odds ratios of 1.41 and 1.63, respectively.

Commenting on the findings, study coauthor Yu-Xiao Yang, MD, assistant professor of medicine and epidemiology, University of Pennsylvania, pointed out their investigation was observational in nature.

“We are not able to establish cause and effect necessarily, but it is actually pretty consistent with the experimental data, which is more definitive in terms of the animal data than in humans.”

Dr Yang said that the next step for the team will be to expand their focus, as the antibiotics data “provide indirect evidence suggesting the importance of gut microbiota on metabolic outcomes, including diabetes.”

Describing their findings as “important evidence,” he concluded: “Based on this indirect evidence and existing data in animals, we are planning to more directly investigate the effect of altered microbe environments in humans.”