Science Progress (2005), 88(3)

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The molecular basis of lactose intolerance

ANTHONY K. CAMPBELLa, JONATHAN P. WAUDb AND STEPHANIE B. MATTHEWSb

ABSTRACT

A staggering 4000 million people cannot digest lactose, the sugar in milk,

properly. All mammals, apart from white Northern Europeans and few tribes

in Africa and Asia, lose most of their lactase, the enzyme that cleaves lactose

into galactose and glucose, after weaning. Lactose intolerance causes gut and

a range of systemic symptoms, though the threshold to lactose varies

considerably between ethnic groups and individuals within a group. The

molecular basis of inherited hypolactasia has yet to be identified, though two

polymorphisms in the introns of a helicase upstream from the lactase gene

correlate closely with hypolactasia, and thus lactose intolerance. The

symptoms of lactose intolerance are caused by gases and toxins produced

by anaerobic bacteria in the large intestine. Bacterial toxins may play a key

role in several other diseases, such as diabetes, rheumatoid arthritis, multiple

sclerosis and some cancers. The problem of lactose intolerance has been

exacerbated because of the addition of products containing lactose to various

foods and drinks without being on the label. Lactose intolerance fits exactly

the illness that Charles Darwin suffered from for over 40 years, and yet was

never diagnosed. Darwin missed something else – the key to our own

evolution – the Rubicon some 300 million years ago that produced lactose

and lactase in sufficient amounts to be susceptible to natural selection.

Keywords: lactose, lactase, lactose intolerance, milk, hypolactasia,

evolution, Darwin, bacterial toxins

Extracellular sensors and extracellular alarmones, which permit cross-talk between organisms, determine the levels of alkali tolerance and trigger alkali-induced acid sensitivity in Escherichia coli

ROBIN J. ROWBURY AND MARGARET GOODSON

ABSTRACT

For several stress responses in Escherichia coli, switching on involves

conversion by the stress of an extracellular stress sensor (an extracellular

sensing component, ESC) to an extracellular induction component (EIC),

the latter functioning as an alarmone and inducing the response. The aim of

this study was to establish whether alkali tolerance induction at pH 9.0,

alkali sensitisation induced at pH 5.5 and the acid sensitisation induced at

pH 9.0 involve sensing of pH changes by ESCs. The techniques involved

made use of studies with cell-free culture filtrates. With respect to the

inducible responses under test, these filtrates were prepared either from

induced or uninduced cultures and filtrates from uninduced cultures were also

activated in vitro, by the pH stress, in the absence of bacteria. Tests were

then made to examine whether EICs (known to be needed for all these

systems) are formed by activation, at the appropriate pH values, of filtrates

from pH 7.0-grown cultures (i.e. uninduced culture filtrates); appearance of

an EIC on activation would indicate the presence in the uninduced culture

filtrate of an ESC. The studies showed that all three systems use ESCs to

detect pH changes. Tests involving attempted enzymic and physical inactivation

of the ESCs, and attempted removal of the ESCs by dialysis, showed

that the ESC involved in alkali sensitisation is a small very heat-resistant

protein. Strikingly, protease only partially inactivated the ESCs needed for

alkali tolerance induction and for acid sensitisation; each system may be

complex, involving both protein and non-protein (RNA?) ESCs, although

other explanations are possible. It was also established that appropriate

killed cultures can induce all three responses when incubated with pH 7.0-

grown living cultures. The occurrence of ESCyEIC pairs for these three

responses has led to the evolution of early warning systems for each, the

diffusibility of the EICs, and their interaction with non-producers, allowing

them to act pheromonally, inducing sensitive organisms to stress tolerance,

prior to exposure to stressor.

Keywords: acid sensitivity induction; alkali sensitisation; alkali tolerance

induction; ASI; cross-talk; Escherichia coli; extracellular alarmones;

extracellular sensing components; extracellular induction components;

intercellular communication; modification of sensors; novel sensing

mechanisms