Early Microbe Contact and Obesity Risk

Evidence Of Causality?

Abstract

The industrialized societies worldwide are in the middle of epidemics of diet-related chronic diseases, obesity being the common denominator. Lately, these conditions have been linked with a distinct microbiota composition in affected individuals different from that of healthy individuals. In particular, dysbiosis during critical stages of development induces lasting alterations in the immune and metabolic phenotype. The compositional development of the gut microbiota, again, is highly sensitive to environmental influences such as maternal health and nutrition, the mode of delivery, early feeding and antibiotic use. Shifts in the microbiota by high-energy diet increase energy extraction and storage, provoke a low-grade inflammatory response and impair gut barrier function, and, consequently, result in obesity and metabolic disease. A lower abundance of butyrate-producing bacteria and lower overall richness of bacteria has been associated with increased metabolic disease risk in humans. Recent reports suggest that Akkermansia type bacteria or butyrate producing microbes may have anti-inflammatory potential and enhance intestinal barrier function, which may both alleviate obesity and related metabolic complications. Thus we are not directly what we eat or our mother eats, but what our microbiota eat and how the collective composition of the microbiome is modified by the diet. On this basis, altering the intestinal microecosystem may be taken as a key target to attain prophylactic or therapeutic effects in metabolic and inflammatory conditions. Tools for such modulation include specific probiotic bacteria and potentially also non-digestible carbohydrate components able to modify microbiota composition and activity.

OBESITY – A SIGNATURE OF DYSBIOSIS?

Obesity with its comorbidities can be viewed as a major public health problem of our times and the velocity of propagation is highest in children and young adults. Obesity comprises the most prevalent nutritional disorder among children throughout the world. Furthermore, being overweight or obese is an intergenerational condition ^(1,2), transmissible via a vicious circle: obese children often become obese adults and maternal obesity over-nourishes the fetus, thereby programming adult size and health with a heightened risk of obesity later in life (Fig. 1). Importantly, these steps are linked to changes in the gut microbiota composition, potentially causally. In fact, humans and microbes accomplish bidirectional exchange of endocrine, immune and neural signals with targets in metabolic, immune, humoral and neural pathways ⁽³⁾.

FIGURE 1: The co-evolution of the gut microbiota composition and host metabolic programming.

Dysbiosis indicates an imbalance in the taxonomic composition of the gut microbiota. Firstly, an age-appropriate composition appears to be fundamental to health. The meconium microbiome of infants born to mothers with diabetes mellitus (DM) is enriched with the same bacterial taxa as those reported in the fecal microbiome of adult DM patients. Precocious maturation of the microbiota during early infancy has been linked to overweight development in a Singaporean birth cohort, in accordance with reports from Finland of lower numbers of bifidobacteria in breast-fed children with overweight development later in life. Undernourished Bangladeshi and Malawi children, again, exhibited a younger gut microbiota profile than expected for their chronological age, indicating hindrance of the compositional maturation of the gut microbiota. Secondly, pregnancy induces a shift in gut microbiota composition by increasing the number of pro-inflammatory bacteria, including Proteobacteria. The connection of the microbiota changes to the metabolic adaptation during pregnancy, which ensure the growth and development of the fetus, remains elusive. Nevertheless, excessive weight gain during pregnancy exaggerates the microbiota deviation, and maternal obesity is associated with differences in the gut microbiota throughout infancy ⁽³⁾. It remains to be established by clinical research, whether these microbiota alterations are causes or consequences of the intergenerational vicious circle of obesity.

Sources of Early Microbe Contact: Recognition of Clinical Practices Interfering with the Healthy Host-Microbe Co-Maturation

Microbial colonization of the gut starts during the fetal period by microbes, which can be either cultured or characterized by DNA-based methods from the placenta and amniotic fluid ^(1,4) (Fig. 1). The first colonizing microbes present in amniotic fluid and meconium belong to Escherichia genus and lactic acid bacteria, including members of the genera Leuconostoc, Enterococcus, and Lactococcus. Thereafter, the exposure to specific species in neonates is facilitated by the mode of delivery: vaginally delivered newborns harbor microbes from the genera Bacteroides, Bifidobacterium, Parabacteroides and Escherichia.

The developing gut microbiota is prone to perturbations by external factors particularly in the perinatal period and early infancy ^(1,5,6). Newborns receive a significant inoculum of bacteria from the birth canal and maternal gut during vaginal delivery and, consequently, the neonatal gut microbiota is characterized by maternal lactobacilli during the first week of life (Fig. 1). Individuals born by Caesarean section (CS) delivery, especially when given antibiotics, are devoid of these colonizers and harbor bacteria originating from the maternal skin. In CS delivered infants, the fecal microbiome contains among others Enterobacter, Staphylococcus, including S. aureus, Streptococcus and Veillonella. Such colonization suggests that bacteria originate from the mother's skin, oral mucosa and the environment. The impact of the mode of delivery on gut microbiota composition may still be detected at the age of seven years. Exposure to antibiotics, which is particularly common in the perinatal period, is also known to exert a disruptive effect on the gut microbiota but little is known of the effects of early antibiotic administration on the long-term compositional development of the intestinal ecosystem. After the neonatal period, diet is the most important factor modulating the gut microbiota with breast milk favoring the predominance of bifidobacteria in the infant gut.

Gut Microbiota and the Development of Obesity–Establishing Causality and Uncovering Mechanisms

Differences in gut microbiota composition and particularly a shift in the relative abundances of the phyla Bacteroidetes and Firmicutes between obese and lean individuals have been reported in both clinical and experimental animal studies. More specifically, increased Proteobacteria have been considered markers or “signatures” of intestinal dysbiosis ⁽⁷⁾ while Akkermansia muciniphila, a member of Verrucomicrobia, appears to correlate inversely with inflammation and altered adipose tissue metabolism ⁽⁸⁾. After the recognition of the association between altered gut microbiota composition and obesity, a number of observations suggesting that gut microbiota changes may play a causal role in weight accumulation and not only reflect the dietary habits of the host have been reported. Firstly, longitudinal studies have demonstrated that changes in gut microecology precede the development of overweight and may be detected already during the first weeks or months of life in infants who display excessive weight gain in later life. Secondly, epidemiological studies suggest that factors, which are known to disturb early infant gut colonization, such as CS delivery or antibiotic exposure are also associated with increased risk of later overweight and obesity. Thirdly, the data indicating that a Western diet with high fat and energy content is associated with reduced gut microbiota diversity have been complemented with observations according to which dietary changes resulting in gut microbiota restoration also affect host weight and physiology. Accordingly, weight loss on a low-energy diet is accompanied with an increase in intestinal Bacteroidetes and a decrease in Firmicutes and thus results in a gut microbiota profile resembling that of lean individuals. In addition, gut microbiota modulation by non-digestible carbohydrates has been shown to result in weight loss and alleviate the inflammation associated with metabolic disorders in obese children. On the other hand, the improvement of metabolic health and clinical outcomes during a six-week dietary intervention study was reported to be modulated by the abundance of fecal Akkermansia muciniphila in obese adults ⁽⁹⁾.

Finally, convincing evidence of a causal relationship between gut dysbiosis and the development of obesity has been obtained from experimental studies demonstrating that the obese phenotype may be transmitted to a lean individual by intestinal microbiota transfer ⁽⁶⁾. Colonizing germ-free mice with the gut microbiota from an obese mouse or human is sufficient to cause significant weight and fat accumulation in these animals. Intriguingly, according to a recent case report, fecal transplantation from an obese donor to alleviate recurrent diarrhea caused by Clostridium difficile was associated with the development of obesity in the recipient.

Taken together, these data corroborate the hypothesis of a vicious circle in obesity development (Fig. 1). The dysbiosis resulting from an obesogenic diet increases energy harvest from the diet already abundant in energy, and contributes to the inflammatory immune milieu, which perpetuates the detrimental effects of weight gain. In other words, dysbiosis is a necessary step in programming of the obese phenotype, and the trait is transmissible by the microbiota. Whether reprogramming, i.e. bringing the gut microbiota and intestinal immune milieu back to balance, can be achieved by dietary means remains to be established.

Specific Strains of the Gut Microbiota As Tools for Reprogramming the Host-Microbe Interaction

Probiotics were recently redefined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” supporting the use of this wording in the future ⁽¹⁰⁾. The most frequently used probiotic bacterial genera are lactic acid bacteria, mainly from the Lactobacillus genus. Bifidobacterium species probiotics are also common, but increasingly also other genera, such as the Enterococcus, Streptococcus, Leuconostoc, are used. Moreover, probiotics may belong to even other domains such as Saccharomyces. More recently novel probiotic species have been suggested, and for example the effects of Akkermansia muciniphila are currently assessed in human intervention studies and Butyricicoccus pullicaecorum, a butyrate producing bacterium, is being assessed preclinically for future probiotic potential in balancing intestinal barrier dysfunctions. Studies on obese subjects are few, but the first studies suggest that probiotic supplementation with perinatal dietary counseling may reduce the risk of gestational diabetes and central adiposity as compared to those receiving placebo or dietary counseling alone. Future research should concentrate on studying both the clinical safety and efficacy of current probiotics and on discovering new probiotics with clearly defined targets in the gut microbiota and host physiology.