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Weight changes

Weight changes alters molecular microbiome and gene expression

Even with modest weight gain - about 6 pounds - the human body changed in dramatic fashion at the molecular level, when study participants lost the weight, most of the rest of the body's systems recalibrated back to their original states

The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine. They found that as people gain or lose excess weight they exhibit notable changes in their microbiome, cardiovascular system, immune system and levels of gene expression.

"The goal here was to characterize what happens during weight gain and loss at a level that no one has ever done before," said co-senior author, Dr Michael Snyder, professor of genetics at Stanford. "We also really wanted to learn how prediabetic folks might differ in terms of their personal omics profiles and their molecular responses to weight fluctuation."

The paper, ‘Integrative Personal Omics Profiles during Periods of Weight Gain and Loss’, published in Cell Systems, Snyder and his colleagues found that even with modest weight gain - about 6 pounds - the human body changed in dramatic fashion at the molecular level. Bacterial populations morphed, immune responses and inflammation flared, and molecular pathways associated with heart disease activated. When study participants lost the weight, most of the rest of the body's systems recalibrated back to their original states, the study found.

Snyder and colleagues have a particular interest in understanding weight change on the microscale among people who are insulin resistant, meaning their glucose-processing ability is compromised, because it's a common precursor to Type 2 diabetes. To that end, the study compared differences in baseline omics of insulin-resistant participants with those of healthy individuals. The researchers then looked at two major questions: How does weight gain affect omics profiles and what happens once that weight is lost?

"Big data will be critical to the future of medicine, and things like these integrative omics profiles will offer an understanding of how the human body responds, in a very personal way, to different challenges. I think it will be a critical part of managing human health in the future."

The study included 23 participants – 13 were insulin-resistant and 10 were insulin-sensitive or able to process insulin normally; all had BMI of between 25-35. The researchers pooled information from each person's transcriptome, a collection of molecules that reveal patterns of DNA expression; proteome, the complete set of proteins an individual actively produces; microbiome; and genome.

At the outset of the study, Snyder and his team found notable baseline differences between the insulin-resistant and insulin-sensitive groups. Among disparities in protein production and microbial populations, Snyder spotted one big discrepancy: molecular markers for inflammation were only found in the bloodstreams of insulin-resistant participants. Inflammation is a known issue in people with diabetes, and early omics profiling like this, Snyder said, could help flag inflammation-associated molecules in people who are not diabetic but at risk for the disease.

"In these analyses, we're looking at individual molecules that are changing, and then we're expanding them to the pathway level," said Snyder. "So, when we find a molecule that seems out of whack, we then ask if it falls into any larger pathways in the body."

After looking for differences at baseline, the researchers changed up the parameters. The participants received a high-calorie diet, and after 30 days they had on average gained 6 pounds. With moderate weight gain inflammation markers went up in both the insulin-resistant and healthy groups. In insulin-sensitive participants, a microbial population called Akkermansia muciniphila, which is known to protect against insulin resistance also increased. But perhaps the most striking change was a shift in gene expression associated with increased risk for a type of heart failure called dilated cardiomyopathy, in which the heart cannot pump blood efficiently to the rest of the body, Snyder explained.

"That was quite surprising. I didn't expect 30 days of overeating to change the whole heart pathway," he said. "But this all fits with how we think of the human body - it's a whole system, not just a few isolated components, so there are systemwide changes when people gain weight."

However, once the participants had dropped the excess weight, their microbes, molecules and gene-expression levels bounced back to their normal levels, for the most part.

However, a small subset of weight-gain-associated shifts in protein and molecule production did persist, even after participants had shed the extra pounds, the study found. There's not enough evidence to draw concrete clinical conclusions, but it is an indication that some of these effects could be longer-lasting.

He added that even though there were trends in shifts, each participant exhibited particular changes to his or her own specific profile, which highlights the importance of deep, integrative sequencing and data collection when diagnosing and treating patients with precision-health tools.

"Big data will be critical to the future of medicine, and things like these integrative omics profiles will offer an understanding of how the human body responds, in a very personal way, to different challenges," said Snyder. "I think it will be a critical part of managing human health in the future."

Co-authors of the study were Drs Wenyu Zhou, Hannes Röst, Kévin Contrepois, Brian Piening, Tracey McLaughlin, professor of medicine at Stanford and George Weinstock, professor and director of microbial genomics at the Jackson Laboratory, an independent, non-profit biomedical research institution.

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