Necrotizing Enterocolitis, Infant Formula & Oligosaccharides – Doxycycline & Alzheimer’s – Coffee & Inflammation

Digested formula but not digested fresh human milk causes death of intestinal cells in vitro: implications for necrotizing enterocolitis

“Necrotizing enterocolitis is a medical condition where a portion of the bowel dies. It typically occurs in newborns that are either premature or otherwise unwell. Symptoms may include poor feeding, bloating, decreased activity, blood in the stool, or vomiting of bile.”[*]

In this experiment scientists tested different infant formulas and breastmilk for interactions with digestive enzymes. The resulting fluid was tested against a number of different cell types to see the effect. Digested infant formulas caused significant increases in death of white blood cells, and cells which line blood cells and organs. Scientists believe the increased cell death was related to increasing free fatty acids from infant formula interactions with digestive enzymes.

Premature infants fed formula are more likely to develop necrotizing enterocolitis than those who are breastfed, but the mechanisms of intestinal necrosis in NEC and protection by breast milk are unknown…
Lipase digestion of formula, but not milk, caused significant death of neutrophils (ranging from 47 to 99% with formulas vs. 6% with milk) with similar results in endothelial and epithelial cells. FFAs were significantly elevated in digested formula vs. milk and death from formula was significantly decreased with lipase inhibitor pretreatment, or treatments to bind FFAs. Protease digestion significantly increased FFA binding capacity of formula and milk but only enough to decrease cytotoxicity from milk…
Our results indicate that numerous digested formulas are cytotoxic, whereas digested fresh breast milk is not. We show that cytotoxicity is due to the detergent action of high concentrations of FFAs, a mechanism for cell death that is independent of cell type.”

Breast Milk is recommended for prevention of necrotising enterocolitis. In the past few years some studies have been showing that human breast oligosaccharides (chains of sugar) provide a significant amount of protection against gastrointestinal mediated disease in newborns. Animal experiments suggest some of these oligosaccharides can protect against necrotizing enterocolitis.


Sialylated galacto-oligosaccharides and 2′-fucosyllactose reduce necrotising enterocolitis in neonatal rats.

2′-fucosyllactose, or 2-fl is a human breast milk oligosaccharide that has been somewhat researched in the last few years. This animal study shows 2-fl and anothel oligosaccharide (Sia-GOS) have protective effects against formula associated necrotising enterocolitis.

“The formula fed group had significantly elevated pathology scores of 2·02 (sd 0·63). Although the addition of GOS to the formula had no protective effect and generated scores of 2·00 (sd 0·63), the addition of Sia-GOS or 2’FL significantly lowered pathology scores to 1·32 (sd 0·56) (P<0·0034) and 1·43 (sd 0·51) (P<0·0040), respectively. The results warrant further studies to investigate the underlying mechanisms and to assess safety and efficacy in human neonates.”

There’s a free trial of some of these oligosaccharides ongoing in Europe. Check out glycom if you’re interested.[*]

Doxycycline counteracts neuroinflammation restoring memory in Alzheimer’s disease mouse models

This experiment looked at the effect of doxycycline on an animal model of Alzheimer’s disease. Doxycycline is an older antibiotic that has been in use for 60 years. The study found that the Alzheimer type mice had improved memory with doxycycline treatment. Both pre-treatment and acute treatment with doxycycline were beneficial. Improvement was associated with lowered inflammation but not plaque reduction.

“We herein show that 15-16 months old APP/PS1dE9 (APP/PS1) AD mice receiving DOXY under different treatment regimens recovered their memory without plaque reduction. An acute DOXY treatment was, also, sufficient to improve APP/PS1 mouse memory, suggesting an action against soluble AβOs. This was confirmed in an AβO-induced mouse model, where the AβO-mediated memory impairment was abolished by a DOXY pre-treatment. Since AβOs induce memory impairment through glial activation, assessing the anti-inflammatory action of DOXY we found that in both the AβO-treated and APP/PS1 mice, the memory recovery was associated with a lower neuroinflammation. Our data promote DOXY as a hopeful repositioned drug counteracting crucial neuropathological AD targets.”

Javamide-II found in coffee is better than caffeine in suppressing TNF-alpha production in PMA/PHA-treated lymphocytic Jurkat cells.

TNF-alpha of is an inflammatory signalling protein. It is involved in the response to pathogens and is believed to inhibit the growth of tumours. Dysregulation of TNF-alpha has been implicated in Alzheimer’s, cancer, obesity, insulin resistance, type II diabetes, depression, inflammatory bowel disease, and so on. In many cases, lowering chronically elevated TNF-alpha is beneficial.

Purified caffeine, the potent stimulant in coffee, has been shown to regulate elevated TNF-alpha. This cell study compared the effect of another compound found in coffee against caffeine and found that Javamide-II is more potent than caffeine at suppressing TNFa.

Recent studies suggested positive benefits of coffee consumption on inflammation-related diseases such as liver diseases and diabetes where activated lymphocytes and TNF-alpha are critically implicated. Interestingly, some reports suggested that javamide-II found in coffee may have anti-inflammation activity greater than caffeine, but there is limited information about its effect on TNF-alpha production by activated lymphocytes. Therefore, the inhibitory effect of javamide-II on TNF-alpha was investigated in PMA/PHA-treated lymphocytic Jurkat cells. At 5 µM, javamide-II, not caffeine, inhibited TNF-alpha production in the cells (45±4 %; P < 0.001)…
These data suggested that javamide-II may be a potent compound to suppress TNF-alpha production more efficiently than caffeine by inhibiting ERK phosphorylation in the Jurkat cells.