283 ‒ Gut health & the microbiome: improving and maintaining the microbiome, probiotics, & more

KEYPOINTS

• 01

  The microbiome is seeded at birth, peaks early in life and loses diversity with age.

  Colleen Cutcliffe is a biochemist who worked in pharma and DNA sequencing before co-founding the microbiome company Pendulum. She defines the microbiome as all the bacteria, viruses, fungi and yeasts living in and on us. The womb is nearly sterile. Initial seeding comes largely from passage through the birth canal, then breast milk, food and environment expand diversity. Diversity peaks around the years 'when you could eat whatever you wanted,' then declines with age. She considers the '10-to-1' ratio of microbes to human cells questionable. Their importance lies in what they produce, not their numbers.

• 02

  There aren't really 'good' and 'bad' bugs. Context decides.

  Bacteria are independent organisms that can divide every 10–15 minutes, so they evolve fast. That speed drives antibiotic resistance, but it also lets your gut community adapt to what you feed it. After a week of eating abroad your microbiome can look very different. Many healthy people carry Clostridioides difficile at low levels without harm. Peter compares this to calling cholesterol 'good' or 'bad.' The Human Microbiome Project, a one-time snapshot of more than 10,000 people, showed people differ hugely at the strain level, with more overlap in function.

• 03

  Butyrate from fermented fiber is one of the most important things gut microbes make.

  In the oxygen-free distal colon, bacteria ferment fiber we can't digest into short-chain fatty acids, ultimately butyrate. Colon cells are the only cells that use butyrate as their main fuel, and low butyrate is associated with poor colon health, including colon cancer. Butyrate also triggers receptors on gut L cells that release GLP-1. Colleen says recommendations are roughly 20–30 g of fiber a day, far above what most Americans eat. Peter notes his daily green drink supplies vitamins and polyphenols but not meaningful fiber.

• 04

  C. diff shows the power of restoring a gut ecosystem.

  Antibiotics act like 'a nuclear bomb' on the microbiome. If a resistant C. diff strain survives, it multiplies unchecked and can become fatal. More antibiotics cure it only about 70% of the time, by Colleen's figure. Fecal microbiota transplant (FMT) re-establishes competition and succeeds about 99% of the time. Colonoscopic delivery works better than capsules, likely because freeze-drying loses diversity. She says the FDA once tried to halt FMT but reversed course after an outcry from patients and doctors. The risks: unknown pathogens, and donors' metabolic traits may transfer, including case reports of new obesity after transplant.

• 05

  FMT is a 'messy drug.' The goal is to isolate the strains that matter.

  Transplants from lean to obese mice, or human microbiomes into mice, reliably shift body weight, and FMT has been tried in type 2 diabetes. But a single donor's stool changes with travel, diet and antibiotics, so dosing can't be standardized. Pendulum's premise was to identify specific beneficial strains and manufacture them reproducibly. Akkermansia is a strict anaerobe that a single oxygen exposure can kill. Contract manufacturers kept sending back dead batches, so the company built its own roughly $10 million plant.

• 06

  Many probiotics barely deliver live organisms.

  Most products contain Lactobacillus and Bifidobacterium, which tolerate some oxygen and are easy to grow. Manufacturing involves growing cultures in large vats, centrifuging, then freeze-drying, which kills a large share: for hardy common strains Colleen estimates about 50–80% survive, and early on her company sometimes lost 90%. Cheap capsules may dissolve in stomach acid, while enteric-coated or time-release capsules reach the gut. She argues CFU counts can overstate live, active cells, so Pendulum reports 'active fraction units' (AFU) counted by flow cytometry. Its products should stay refrigerated.

• 07

  Akkermansia drives GLP-1 release in three ways.

  Akkermansia muciniphila, linked to bariatric surgery work by Lee Kaplan at MGH, has a surface protein (Amuc_1100) that signals L cells via TLR2. It secretes a protein called P9 that stimulates L cells, and it makes propionate, which Clostridium butyricum and related strains convert to butyrate, activating receptors that trigger GLP-1. It also maintains the gut's protective mucus layer. Unlike injected semaglutide, this would produce meal-timed, physiological GLP-1 pulses, so Peter and Colleen agree it wouldn't produce drug-level weight loss.

• 08

  The company's 76-person pilot trial found modest glucose benefits, with clear caveats.

  Colleen describes a double-blind, placebo-controlled pilot in people with type 2 diabetes, with three arms. Over 90 days, a five-strain formula including Akkermansia lowered A1C by about 0.6 points versus placebo and reduced glucose spikes on an oral glucose tolerance test by 34%. A subset without Akkermansia didn't reach statistical significance. Diet wasn't logged. After a 30-day washout, about 15–20% kept Akkermansia levels. Colleen is the company's CEO. The product costs about $165 a month, a lower-dose version $49. Further data are mostly customer reports, an unblinded cravings pilot, and about a dozen investigator-led trials using donated product.