Continuing Part 1 by curating a partial outline of a 2021 review:

“This review focuses on the biological and beneficial effects of dietary betaine (trimethylglycine), a naturally occurring and crucial methyl donor.

Betaine has a neuroprotective role, preserves myocardial function, and prevents pancreatic steatosis. Betaine also attenuates oxidant stress, endoplasmic reticulum stress, inflammation, and cancer development.

• Betaine Protects against Development of Alcohol-Induced Hepatic Steatosis
• Betaine Protects against Detrimental Effects of HCV and Ethanol on Innate Immunity
• Betaine Maintains Intestinal Epithelial Barrier Integrity
• Betaine Maintains Adipose Function

Human intervention studies showed no adverse effects with 4 g/day supplemental administration of betaine in healthy subjects. However, overweight subjects with metabolic syndrome showed a significant increase in total and LDL-cholesterol concentrations. These effects were not observed with 3 g/day of betaine administration.

We suggest betaine as a promising therapeutic for clinical use to treat these aforementioned diseases as well as other liver-/non-liver-related diseases and conditions.”

https://www.mdpi.com/2079-7737/10/6/456/htm “Beneficial Effects of Betaine: A Comprehensive Review”

This review cited a 2020 study Transgenerational Inheritance of Betaine-Induced Epigenetic Alterations in Estrogen-Responsive IGF-2/IGFBP2 Genes in Rat Hippocampus (not freely available):

“Hippocampal expression of aromatase, estrogen receptor α, and estrogen-related receptor β is downregulated in F1, together with estrogen-responsive insulin-like growth factor 2/insulin-like growth factor binding protein 2 (IGF-2/IGFBP2) genes. However, all these genes are upregulated in F2, which follows the same pattern of F0.

Imprinting control region of IGF-2 gene is hypomethylated in F1 but hypermethylated in F2 and F0. In contrast, the promoter DNA methylation status of all affected genes is hypermethylated in F1 but hypomethylated in F2 and F0.”

• Intergenerational flip-flops of F₀ phenotypes to opposite F₁ phenotypes back to F₀ phenotypes in the F₂ generation can’t conclusively demonstrate transgenerational epigenetic inheritance of alterations due to betaine consumption during pregnancy.
• Those researchers had to continue on to a F₃ female generation for transgenerational results, because F₂ generation cells were present in F₁ fetuses, and were potentially affected during pregnant F₀ treatments.

I came across this paper through a citation chain initiated by Dr. Paul Clayton’s blog post Foie Gras:

“Thanks to our modern diet and lifestyle, nonalcoholic fatty liver disease (NAFLD) is now reckoned to affect an astonishing quarter of the world’s population.”