The human distal gut harbours a vast ensemble of microbes (the microbiota) that provide important metabolic capabilities, including the ability to extract energy from otherwise indigestible dietary polysaccharides. Studies of a few unrelated, healthy adults have revealed substantial diversity in their gut communities, as measured by sequencing 16S rRNA genes, yet how this diversity relates to function and to the rest of the genes in the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies of lean and obese mice suggest that the gut microbiota affects energy balance by influencing the efficiency of calorie harvest from the diet, and how this harvested energy is used and stored. Here we characterize the faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers, to address how host genotype, environmental exposure and host adiposity influence the gut microbiome. Analysis of 154 individuals yielded 9,920 near full-length and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their microbiomes. The results reveal that the human gut microbiome is shared among family members, but that each person's gut microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation between adult monozygotic and dizygotic twin pairs. However, there was a wide array of shared microbial genes among sampled individuals, comprising an extensive, identifiable 'core microbiome' at the gene, rather than at the organismal lineage, level. Obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathways. These results demonstrate that a diversity of organismal assemblages can nonetheless yield a core microbiome at a functional level, and that deviations from this core are associated with different physiological states (obese compared with lean).

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A core gut microbiome in obese and lean twins

Obesity is now so common within the world's population that it is beginning to replace undernutrition and infectious diseases as the most significant contributor to ill health. In particular, obesity is associated with diabetes mellitus, coronary heart disease, certain forms of cancer, and sleep-breathing disorders. Obesity is defined by a body-mass index (weight divided by square of the height) of 30 kg m(-2) or greater, but this does not take into account the morbidity and mortality associated with more modest degrees of overweight, nor the detrimental effect of intra-abdominal fat. The global epidemic of obesity results from a combination of genetic susceptibility, increased availability of high-energy foods and decreased requirement for physical activity in modern society. Obesity should no longer be regarded simply as a cosmetic problem affecting certain individuals, but an epidemic that threatens global well being.

Obesity as a medical problem

Metabolic syndrome is associated with abdominal obesity, blood lipid disorders, inflammation, insulin resistance or full-blown diabetes, and increased risk of developing cardiovascular disease. Proposed criteria for identifying patients with metabolic syndrome have contributed greatly to preventive medicine, but the value of metabolic syndrome as a scientific concept remains controversial. The presence of metabolic syndrome alone cannot predict global cardiovascular disease risk. But abdominal obesity - the most prevalent manifestation of metabolic syndrome - is a marker of 'dysfunctional adipose tissue', and is of central importance in clinical diagnosis. Better risk assessment algorithms are needed to quantify diabetes and cardiovascular disease risk on a global scale.

Abdominal obesity and metabolic syndrome

https://mootha.med.harvard.edu/PubPDFs/Wu1999.pdf

Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(12)60735-1.pdf

Correlates of physical activity: why are some people physically active and others not?

We undertook this study to determine whether there are differences in the responses of different persons to long-term overfeeding and to assess the possibility that genotypes are involved in such differences. After a two-week base-line period, 12 pairs of young adult male monozygotic twins were overfed by 4.2 MJ (1000 kcal) per day, 6 days a week, for a total of 84 days during a 100-day period. The total excess amount each man consumed was 353 MJ (84,000 kcal). During overfeeding, individual changes in body composition and topography of fat deposition varied considerably. The mean weight gain was 8.1 kg, but the range was 4.3 to 13.3 kg. The similarity within each pair in the response to overfeeding was significant (P less than 0.05) with respect to body weight, percentage of fat, fat mass, and estimated subcutaneous fat, with about three times more variance among pairs than within pairs (r approximately 0.5). After adjustment for the gains in fat mass, the within-pair similarity was particularly evident with respect to the changes in regional fat distribution and amount of abdominal visceral fat (P less than 0.01), with about six times as much variance among pairs as within pairs (r approximately 0.7). We conclude that the most likely explanation for the intrapair similarity in the adaptation to long-term overfeeding and for the variations in weight gain and fat distribution among the pairs of twins is that genetic factors are involved. These may govern the tendency to store energy as either fat or lean tissue and the various determinants of the resting expenditure of energy.

https://www.nejm.org/doi/pdf/10.1056/NEJM199005243222101

The Response to Long-Term Overfeeding in Identical Twins

We have limited ourselves to the deleterious effects of the absence of thyroid hormones on the development of the central nervous system and have not discussed the problems caused by hyperthyroidism. A short "critical period" during which thyroid hormones are essential for normal maturation of the CNS is evident at anatomical, biochemical, and neurophysiological levels. In the last decade we have made progress toward understanding the mechanism of action of thyroid hormones, due in part to numerous studies of the ontogenesis and distribution of the nuclear T3 receptor. These studies can indicate where the molecular events that control the growth and maturation of the brain are initiated. However, much further research in this area is needed to comprehend further the relation between thyroid hormones and brain development.

Thyroid hormones and brain development.

Screening for congenital hypothyroidism: Results of screening one million North American infants

Preliminary report on a mass screening program for neonatal hypothyroidism.

The hypothalamic content of thyrotropin-releasing hormone (TRH), the pituitary concentrationof thyroid-stimulating hormone (TSH),and the serum concentrations of TSH, thyroxine(T4), and triiodothyronine (T3) have been determinedat different intervals during the first 50days following birth in the rat. From a minimumconcentration of 1 pg/μg protein at birth, the hypothalamicconcentration of TRH increased to amaximum of 5 to 6 pg between 16 and 28 daysof age. Serum and pituitary TSH concentrationsincreased to maximum levels by the end qf thefirst post-natal week; the elevated hormone levelswere then maintained to the end of the thirdpost-natal week. Circulating thyroid hormone concentrationswere very low at birth. T4 increasedrapidly between days 4 and 16 to reach a peakconcentration of 6 μg/100 ml, while T3 followeda parallel pattern with a peak concentration of108 ng/100 ml obtained only at day 28. Thesedata indicate that, in the rat, components of thehypothalamic-pituitary-thyroid axis develop simultaneou...

Jean H. Dussault

Papers

The Response to Long-Term Overfeeding in Identical Twins

Thyroid hormones and brain development.

Screening for congenital hypothyroidism: Results of screening one million North American infants

Preliminary report on a mass screening program for neonatal hypothyroidism.

Development of the Hypothalamic-Pituitary-Thyroid Axis in the Neonatal Rat